Umesh Masharani, MB, BS, MRCP(UK)
ESSENTIALS OF DIAGNOSIS
Type 1 diabetes
Polyuria, polydipsia, and weight loss associated with random plasma glucose ≥ 200 mg/dL (11.1 mmol/L).
Plasma glucose of ≥ 126 mg/dL (7.0 mmol/L) after an overnight fast, documented on more than one occasion.
Ketonemia, ketonuria, or both.
Islet autoantibodies are frequently present.
Type 2 diabetes
Most patients are over 40 years of age and obese.
Polyuria and polydipsia. Ketonuria and weight loss generally are uncommon at time of diagnosis. Candidal vaginitis in women may be an initial manifestation. Many patients have few or no symptoms.
Plasma glucose of ≥ 126 mg/dL after an overnight fast on more than one occasion. Two hours after 75 g oral glucose, diagnostic values are ≥ 200 mg/dL (11.1 mmol).
HbA1c ≥ 6.5%
Hypertension, dyslipidemia, and atherosclerosis are often associated.
The latest data estimate 25.8 million people (8.3%) in the United States had diabetes mellitus, of which approximately 1 million have type 1 diabetes and most of the rest have type 2 diabetes. A third group that was designated as “other specific types” by the American Diabetes Association (ADA) (Table 27–1) number only in the thousands. Among these are the rare monogenic defects of either B cell function or of insulin action, primary diseases of the exocrine pancreas, endocrinopathies, and medication-induced diabetes. Updated information about the prevalence of diabetes in the United States is available from the Centers for Disease Control and Prevention (http://www.cdc.gov/diabetes/pubs/estimates.htm#prev).
Table 27–1. Other specific types of diabetes mellitus.
Classification & Pathogenesis
Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either a deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate for the resistance.
This form of diabetes is due to pancreatic islet B cell destruction predominantly by an autoimmune process in over 95% of cases (type 1A) and idiopathic in < 5% (type 1B). The rate of pancreatic B cell destruction is quite variable, being rapid in some individuals and slow in others. Type 1 diabetes is usually associated with ketosis in its untreated state. It occurs at any age but most commonly arises in children and young adults with a peak incidence before school age and again at around puberty. It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic B cells fail to respond to all insulinogenic stimuli. Exogenous insulin is therefore required to reverse the catabolic state, prevent ketosis, reduce the hyperglucagonemia, and reduce blood glucose.
Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental factors. Genes that are related to the HLA locus contribute about 40% of the genetic risk. About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4, compared with 45–50% of white controls. HLA-DQ genes are even more specific markers of type 1 susceptibility, since a particular variety (HLA-DQB1*0302) is found in the DR4 patients with type 1, while a “protective” gene (HLA-DQB1*0602) is often present in the DR4 controls. The other important gene that contributes to about 10% of the genetic risk is found at the 5′ polymorphic region of the insulin gene. This polymorphic region affects the expression of the insulin gene in the thymus and results in depletion of insulin-specific T lymphocytes. In linkage studies, 16 other genetic regions of the human genome have been identified as being important to pathogenesis. Many of the genes linked to these additional loci play important roles in the function and regulation of the immune response. Mutations in genes associated with T cell tolerance can also cause autoimmune diabetes. The autoimmune regulatory gene (AIRE) product regulates the expression of several proteins in the thymus causing the deletion of self-reactive T cells. Type 1 diabetes mellitus as well as other autoimmune disorders (autoimmune polyglandular syndrome 1) develop in 20% of individuals with homozygote mutations in AIRE.FOXP3, an X chromosome gene, encodes a transcription factor required for the formation of regulatory T cells. Mutations in FOXP3lead to very early type 1 diabetes mellitus and other autoimmune endocrinopathies (immunodysregulation polyendocrinopathy enteropathy X-linked [IPEX] syndrome). Most patients with type 1 diabetes mellitus have circulating antibodies to islet cells (ICA), glutamic acid decarboxylase 65 (GAD65), insulin (IAA), tyrosine phosphatase IA2 (ICA-512), and zinc transporter 8 (ZnT8) at the time the diagnosis is made (Table 27–2). These antibodies facilitate screening for an autoimmune cause of diabetes, particularly screening siblings of affected children, as well as adults with atypical features of type 2 diabetes mellitus. Screening with GAD65, ICA-512, IAA, and ZnT8 autoantibodies may identify about 98% of people who have an autoimmune basis for their beta cell loss. Antibody levels decline with increasing duration of disease. Also, low levels of anti-insulin antibodies develop in almost all patients once they are treated with insulin.
Table 27–2. Diagnostic sensitivity and specificity of autoimmune markers in patients with newly diagnosed type 1 diabetes mellitus.
Family members of diabetic probands are at increased lifetime risk for developing type 1 diabetes mellitus. A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child’s father has it. The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic proband. If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%. The highest risk is for identical twins, where the concordance rate is 25–50%.
Some patients with a milder expression of type 1 diabetes mellitus initially retain enough B cell function to avoid ketosis, but as their B cell mass diminishes later in life, dependence on insulin therapy develops. Islet cell antibody surveys among northern Europeans indicate that up to 15% of “type 2” diabetic patients may actually have this mild form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA). Evidence for environmental factors playing a role in the development of type 1 diabetes include the observation that the disease is more common in Scandinavian countries and becomes progressively less frequent in countries nearer and nearer to the equator. Also, the risk for type 1 diabetes increases when individuals who normally have a low risk emigrate to the Northern Hemisphere. For example, Pakistani children born and raised in Bradford, England have a higher risk for developing type 1 diabetes compared with children who lived in Pakistan all their lives.
Which environmental factor is responsible for the increased risk is not known. There have been a number of different hypotheses including infections with certain viruses (mumps, rubella, Coxsackie B4) and consumption of cow’s milk. Also, in developed countries, childhood infections have become less frequent and so perhaps the immune system becomes dysregulated with development of autoimmunity and conditions such as asthma and diabetes. This theory is referred to as the hygiene hypothesis. Part of the difficulty in determining the causative environmental factor is that autoimmune injury is initiated many years before the clinical presentation of diabetes.
This represents a heterogeneous group of conditions that used to occur predominantly in adults, but it is now more frequently encountered in children and adolescents. More than 90% of all diabetic persons in the United States are included under this classification. Circulating endogenous insulin is sufficient to prevent ketoacidosis but is inadequate to prevent hyperglycemia in the face of increased needs owing to tissue insensitivity (insulin resistance).
Genetic and environmental factors combine to cause both the insulin resistance and the beta cell loss. Most epidemiologic data indicate strong genetic influences, since in monozygotic twins over 40 years of age, concordance develops in over 70% of cases within a year whenever type 2 diabetes develops in one twin. Genome-wide association studies have made considerable progress in identifying the at-risk genes. So far, more than 30 genetic loci have been associated with an increased risk of type 2 diabetes. A significant number of the identified loci appear to code for proteins that have a role in beta cell function or development. One of the genetic loci with the largest risk effect is TCF7L2. This gene codes for a transcription factor involved in the WNT signaling pathway that is required for normal pancreatic development. Alleles at other genetic loci (CDKAL1, SLC30A8, HHEX-IDE, CDKN2A/B, KCNJ11, and IGF2BP2) are thought to affect insulin secretion. Two loci (FTO and MC4R) affect fat mass and obesity risk. The PPARG locus has been implicated in insulin resistance. The loci identified to date still explain only some of the heritable risk for diabetes; clearly, other loci remain to be discovered.
Early in the disease process, hyperplasia of pancreatic B cells occurs and probably accounts for the fasting hyperinsulinism and exaggerated insulin and proinsulin responses to glucose and other stimuli. With time, chronic deposition of amyloid in the islets may combine with inherited genetic defects progressively to impair B cell function.
Obesity is the most important environmental factor causing insulin resistance. The degree and prevalence of obesity varies among different racial groups with type 2 diabetes. While obesity is apparent in no more than 30% of Chinese and Japanese patients with type 2, it is found in 60–70% of North Americans, Europeans, or Africans with type 2 and approaches 100% of patients with type 2 among Pima Indians or Pacific Islanders from Nauru or Samoa.
Visceral obesity, due to accumulation of fat in the omental and mesenteric regions, correlates with insulin resistance; subcutaneous abdominal fat seems to have less of an association with insulin insensitivity. There are many patients with type 2 diabetes who, while not overtly obese, have increased visceral fat; they are termed the “metabolically obese.” Exercise may affect the deposition of visceral fat as suggested by CT scans of Japanese wrestlers, whose extreme obesity is predominantly subcutaneous. Their daily vigorous exercise program prevents accumulation of visceral fat, and they have normal serum lipids and euglycemia despite daily intakes of 5000–7000 kcal and development of massive subcutaneous obesity.
A number of mechanisms may operate to cause the insulin resistance associated with obesity. Free fatty acid levels are increased in obesity, and their oxidation by skeletal muscle leads to a decrease in insulin-mediated glucose disposal, that is, insulin resistance. Adipocytes secrete molecules (adipokines) that can affect insulin signaling. Examples include adiponectin, which enhances insulin action, and resistin, which impairs insulin action; abnormal levels of these types of molecules in obesity may contribute to the development of resistance. Macrophages and other immune cells in adipose tissue are activated in response to an increase in adipocyte lipid stores. They release a variety of molecules, including tissue necrosis factor alpha and interleukin-6, that impair insulin signaling.
Hyperglycemia per se can impair insulin action by causing accumulation of hexosamines in muscle and fat tissue and by inhibiting glucose transport (acquired glucose toxicity). Correction of hyperglycemia reverses this acquired insulin resistance.
The enzyme glucokinase is a rate-limiting step in glycolysis and determines the rate of adenosine triphosphate (ATP) production from glucose and the insulin secretory response in the beta cell. MODY 2, due to glucokinase mutations, is usually quite mild, associated with only slight fasting hyperglycemia and few if any microvascular diabetic complications. It generally responds well to hygienic measures or low doses of oral hypoglycemic agents. MODY 3, due to mutations in hepatic nuclear factor 1 alpha is the most common form, accounting for two-thirds of all MODY cases. The clinical course is of progressive beta cell failure and need for insulin therapy. Mutations in both alleles of glucokinase present with more severe neonatal diabetes. Mutation in one allele of the pancreatic duodenal homeobox 1 (PDX1) causes diabetes usually at a later age (˜ 35 years) than other forms of MODY; mutations in both alleles of PDX1 causes pancreatic agenesis.
Figure 27–1. Acanthosis nigricans of the axilla, with typical dark coloration and velvety appearance and texture. (Used with permission from Umesh Masharani, MB, BS, MRCP(UK).)
Figure 27–2. Acanthosis nigricans of the nape of the neck, with typical dark and velvety appearance. (Used with permission from Umesh Masharani, MB, BS, MRCP(UK).)
Table 27–3. Secondary causes of hyperglycemia.
High-titer anti-insulin receptor antibodies that inhibit insulin binding causes a clinical syndrome characterized by severe insulin resistance, glucose intolerance or diabetes mellitus, and acanthosis nigricans. These patients usually have other autoimmune disorders. There are reports of spontaneous remission or remission with cytotoxic therapy.
Many medications are associated with carbohydrate intolerance or frank diabetes (Table 27–3). The medications act by decreasing insulin secretion or by increasing insulin resistance or both. Cyclosporine and tacrolimus impair insulin secretion; sirolimus principally increases insulin resistance. These agents contribute to the development of new-onset diabetes after transplantation. Corticosteroids increase insulin resistance but may also have an effect on beta cell function; in a case control study and a large population cohort study, oral corticosteroids doubled the risk for development of diabetes. Thiazide diuretics and beta-blockers modestly increase the risk for diabetes. Treating the hypokalemia due to thiazides may reverse the hyperglycemia. Atypical antipsychotics, particularly olanzapine and clozapine, have been associated with increased risk of glucose intolerance. These medications cause weight gain and insulin resistance but may also impair beta cell function; an increase in rates of diabetic ketoacidosis has been reported.
Chronic pancreatitis or subtotal pancreatectomy reduces the number of functioning B cells and can result in a metabolic derangement very similar to that of genetic type 1 diabetes except that a concomitant reduction in pancreatic A cells may reduce glucagon secretion so that relatively lower doses of insulin replacement are needed.
Insulin Resistance Syndrome (Syndrome X; Metabolic Syndrome)
Twenty-five percent of the general nonobese, nondiabetic population has insulin resistance of a magnitude similar to that seen in type 2 diabetes. These insulin-resistant nondiabetic individuals are at much higher risk for developing type 2 diabetes than insulin-sensitive persons. In addition to diabetes, these individuals have increased risk for elevated plasma triglycerides, lower high-density lipoproteins (HDLs), and higher blood pressure—a cluster of abnormalities termed syndrome X or metabolic syndrome. These associations have now been expanded to include small, dense, low-density lipoprotein (LDL), hyperuricemia, abdominal obesity, prothrombotic state with increased levels of plasminogen activator inhibitor type 1 (PAI-1), and proinflammatory state. These clusters of abnormalities significantly increase the risk of atherosclerotic disease.
It has been postulated that hyperinsulinemia and insulin resistance play a direct role in these metabolic abnormalities, but supportive evidence is inconclusive. Although hyperinsulinism and hypertension often coexist in whites, that is not the case in blacks or Pima Indians. Moreover, patients with hyperinsulinism due to insulinoma are not hypertensive, and there is no fall in blood pressure after surgical removal of the insulinoma restores normal insulin levels. The main value of grouping these disorders as a syndrome, however, is to remind clinicians that the therapeutic goals are not only to correct hyperglycemia but also to manage the elevated blood pressure and dyslipidemia that result in increased cerebrovascular and cardiac morbidity and mortality in these patients.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014 Jan;37(Suppl 1):S81–4. [PMID: 24357215]
Weight loss despite normal or increased appetite is a common feature of type 1 when it develops subacutely. The weight loss is initially due to depletion of water, glycogen, and triglycerides; thereafter, reduced muscle mass occurs as amino acids are diverted to form glucose and ketone bodies.
Lowered plasma volume produces symptoms of postural hypotension. Total body potassium loss and the general catabolism of muscle protein contribute to the weakness.
Paresthesias may be present at the time of diagnosis, particularly when the onset is subacute. They reflect a temporary dysfunction of peripheral sensory nerves, which clears as insulin replacement restores glycemic levels closer to normal, suggesting neurotoxicity from sustained hyperglycemia.
When absolute insulin deficiency is of acute onset, the above symptoms develop abruptly. Ketoacidosis exacerbates the dehydration and hyperosmolality by producing anorexia and nausea and vomiting, interfering with oral fluid replacement.
The patient’s level of consciousness can vary depending on the degree of hyperosmolality. When insulin deficiency develops relatively slowly and sufficient water intake is maintained, patients remain relatively alert and physical findings may be minimal. When vomiting occurs in response to worsening ketoacidosis, dehydration progresses and compensatory mechanisms become inadequate to keep serum osmolality below 320–330 mosm/L. Under these circumstances, stupor or even coma may occur. The fruity breath odor of acetone further suggests the diagnosis of diabetic ketoacidosis.
Hypotension in the recumbent position is a serious prognostic sign. Loss of subcutaneous fat and muscle wasting are features of more slowly developing insulin deficiency. In occasional patients with slow, insidious onset of insulin deficiency, subcutaneous fat may be considerably depleted.
Many patients with type 2 diabetes are overweight or obese. Even those who are not significantly obese often have characteristic localization of fat deposits on the upper segment of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. This centripetal fat distribution is characterized by a high waist circumference; a waist circumference > 40 inches (102 cm) in men and 35 inches (88 cm) in women is associated with an increased risk of diabetes. Some patients may have acanthosis nigricans, which is associated with significant insulin resistance; the skin in the axilla, groin, and back of neck is hyperpigmented and hyperkeratotic (Figures 27–1 and 27–2). Mild hypertension is often present in obese diabetics. Eruptive xanthomas on the flexor surface of the limbs and on the buttocks and lipemia retinalis due to hyperchylomicronemia can occur in patients with uncontrolled type 2 diabetes who also have a familial form of hypertriglyceridemia.
Hyperglycemic hyperosmolar coma can also be present; in these cases, patients are profoundly dehydrated, hypotensive, lethargic or comatose but without Kussmaul respirations.
A normal renal threshold for glucose as well as reliable bladder emptying is essential for interpretation.
Nondiabetic glycosuria (renal glycosuria) is a benign asymptomatic condition wherein glucose appears in the urine despite a normal amount of glucose in the blood, either basally or during a glucose tolerance test. Its cause may vary from mutations in the SGLT2 gene coding for sodium-glucose transporter 2 (familial renal glycosuria) to one associated with dysfunction of the proximal renal tubule (Fanconi syndrome, chronic kidney disease), or it may merely be a consequence of the increased load of glucose presented to the tubules by the elevated glomerular filtration rate during pregnancy. As many as 50% of pregnant women normally have demonstrable sugar in the urine, especially during the third and fourth months. This sugar is practically always glucose except during the late weeks of pregnancy, when lactose may be present.
Table 27–4. Criteria for the diagnosis of diabetes.
Blood samples for plasma glucose are obtained at 0 and 120 minutes after ingestion of glucose. An oral glucose tolerance test is normal if the fasting venous plasma glucose value is < 100 mg/dL (5.6 mmol/L) and the 2-hour value falls below 140 mg/dL (7.8 mmol/L). A fasting value of 126 mg/dL (7 mmol/L) or higher or a 2-hour value of > 200 mg/dL (11.1 mmol/L) is diagnostic of diabetes mellitus. Patients with 2-hour value of 140–199 mg/dL (7.8–11.1 mmol/L) have impaired glucose tolerance. False-positive results may occur in patients who are malnourished, bedridden, or afflicted with an infection or severe emotional stress.
Since glycohemoglobins circulate within red blood cells whose life span lasts up to 120 days, they generally reflect the state of glycemia over the preceding 8–12 weeks, thereby providing an improved method of assessing diabetic control. The HbA1c value, however, is weighted to more recent glucose levels (previous month) and this explains why significant changes in HbA1c are observed with short-term (1 month) changes in mean plasma glucose levels. Measurements should be made in patients with either type of diabetes mellitus at 3- to 4-month intervals. In patients monitoring their own blood glucose levels, HbA1c values provide a valuable check on the accuracy of monitoring. In patients who do not monitor their own blood glucose levels, HbA1c values are essential for adjusting therapy. There is a linear relationship between the HbA1c and the average glucose levels in the previous 3 months. In a study using a combination of intermittent seven-point capillary blood glucose profiles (preprandial, postprandial, and bedtime) and intermittent continuous glucose monitoring data, the change in glucose values was 28.7 mg/dL for every 1% change in HbA1c. Substantial individual variability exists, however, between HbA1c and mean glucose concentration. For HbA1c values between 6.9% and 7.1%, the glucose levels ranged from 125 mg/dL to 205 mg/dL (6.9–11.4 mmol/L; 95% CIs). For HbA1c of 6%, the mean glucose levels ranged from 100 mg/dL to 152 mg/dL (5.5–8.5 mmol/L); and for 8% they ranged from 147 mg/dL to 217 mg/dL (8.1–12.1 mmol/L). For this reason, caution should be exercised in estimating average glucose levels from measured HbA1c.
The accuracy of HbA1c values can be affected by hemoglobin variants or traits; the effect depends on the specific hemoglobin variant or derivative and the specific assay used. Immunoassays that use an antibody to the glycated amino terminus of beta globin do not recognize the terminus of the gamma globin of hemoglobin F. In patients with high levels of hemoglobin F, immunoassays give falsely low values of HbA1c. Cation-exchange chromatography separates hemoglobin species by charge differences. Hemoglobin variants that co-elute with HbA1c can lead to an overestimation of the HbA1c value. Chemically modified derivatives of hemoglobin such as carbamoylation (in end-stage chronic kidney disease) or acetylation (high-dose aspirin therapy) can similarly co-elute with HbA1c by some assay methods. The National Glycohemoglobin Standardization Program website (www.ngsp.org) has information on the impact of frequently encountered hemoglobin variants and traits on the results obtained with the commonly used HbA1c assays.
Any condition that shortens erythrocyte survival or decreases mean erythrocyte age (eg, recovery from acute blood loss, hemolytic anemia) will falsely lower HbA1c irrespective of the assay method used. Intravenous iron and erythropoietin therapy for treatment of anemia in chronic kidney disease also falsely lower HbA1c levels. Alternative methods such as fructosamine (see below) should be considered for these patients. Vitamins C and E are reported to falsely lower test results possibly by inhibiting glycation of hemoglobin.
The ADA has endorsed using the HbA1c as a diagnostic test for type 1 and type 2 diabetes (Table 27–4). A cutoff value of 6.5% was chosen because the risk for retinopathy increases substantially above this value. The advantages of using the HbA1c to diagnose diabetes is that there is no need to fast; it has lower intraindividual variability than the fasting glucose test and the oral glucose tolerance test; and it provides an estimate of glucose control for the preceding 2–3 months. People with HbA1c levels of 5.7–6.4% should be considered at high risk for developing diabetes (prediabetes). The diagnosis should be confirmed with a repeat HbA1c test, unless the patient is symptomatic with plasma glucose levels > 200 mg/dL (11.1 mmol/L). This test is not appropriate to use in populations with high prevalence of hemoglobinopathies or in conditions with increased red cell turnover.
The clinician should be aware of the limitations of the self-monitoring glucose systems. First, some older meters require input of a code for each batch of strips; failure to enter the code can result in misleading results. Many of the newer meters no longer require this step. Second, increases or decreases in hematocrit can decrease or increase the measured glucose values. The mechanism underlying this effect is not known but presumably it is due to the impact of red cells on the diffusion of plasma into the reagent layer. Third, the meters and the test strips are calibrated over the glucose concentrations ranging from 60 mg/dL (3.3 mmol/L) to 160 mg/dL (8.9 mmol/L) and the accuracy is not as good for higher and lower glucose levels. When the glucose is < 60 mg/dL (3.3 mmol/L), the difference between the meter and the laboratory value may be as much as 20%. Fourth, glucose oxidase–based amperometric systems underestimate glucose levels in the presence of high oxygen tension. This may be important in the critically ill who are receiving supplemental oxygen; under these circumstances, a glucose dehydrogenase–based system may be preferable. Fifth, glucose-dehydrogenase pyrroloquinoline quinone (GDH-PQQ) systems may report falsely high glucose levels in patients who are receiving parenteral products containing nonglucose sugars such as maltose, galactose, or xylose or their metabolites. Patients have been given falsely high glucose values resulting in life-threatening hypoglycemia. Sixth, some meters have been approved for measuring glucose in blood samples obtained at alternative sites such as the forearm and thigh. There is, however, a 5- to 20-minute lag in the glucose response on the arm with respect to the glucose response on the finger. Forearm blood glucose measurements could therefore result in a delay in detection of rapidly developing hypoglycemia.
There is great interest in using the data obtained from these continuous glucose monitoring systems to automatically deliver insulin by continuous subcutaneous insulin infusion pump. Algorithms have been devised to link continuous glucose monitoring to insulin delivery and preliminary clinical studies appear promising.
Sacks DB et al; National Academy of Clinical Biochemistry; Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care. 2011 Jun;34(6):e61–99. [PMID: 21617108]
Clinical Trials in Diabetes
Findings of the Diabetes Complications and Control Trial (DCCT) and of the United Kingdom Prospective Diabetes Study (UKPDS), have confirmed the beneficial effects of improved glycemic control in both type 1 and type 2 diabetes.
The Diabetes Control and Complications Trial, a long-term therapeutic study involving 1441 patients with type 1 diabetes mellitus, reported that “near” normalization of blood glucose resulted in a delay in the onset and a major slowing of the progression of established microvascular and neuropathic complications of diabetes during a follow-up period of up to 10 years. Multiple insulin injections (66%) or insulin pumps (34%) were used in the intensively treated group, who were trained to modify their therapy in response to frequent glucose monitoring. The conventionally treated groups used no more than two insulin injections, and clinical well-being was the goal with no attempt to modify management based on HbA1c determinations or the glucose results.
In half of the patients, a mean hemoglobin A1c of 7.2% (normal: < 6%) and a mean blood glucose of 155 mg/dL (8.6 mmol/L) were achieved using intensive therapy, while in the conventionally treated group HbA1c averaged 8.9% with an average blood glucose of 225 mg/dL (12.5 mmol/L). Over the study period, which averaged 7 years, there was an approximately 60% reduction in risk between the two groups in regard to diabetic retinopathy, nephropathy, and neuropathy. The intensively treated group also had a nonsignificant reduction in the risk of macrovascular disease of 41% (95% CI, –10 to 68). Intensively treated patients had a threefold greater risk of serious hypoglycemia as well as a greater tendency toward weight gain. However, there were no deaths definitely attributable to hypoglycemia in any persons in the DCCT study, and no evidence of posthypoglycemic cognitive damage was detected.
Subjects participating in the DCCT study were subsequently enrolled in a follow-up observational study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Even though the between-group differences in mean HbA1c narrowed over 4 years, the group assigned to intensive therapy had a lower risk of retinopathy at 4 years, microalbuminuria at 7 to 8 years, and impaired glomerular filtration rate (< 60 mL/min/1.73 m2) at 22 years of continued study follow-up. Moreover, by the end of the 11-year follow-up period, the intensive therapy group had significantly reduced their risk of any cardiovascular disease events by 42% (95% CI, 9% to 23%; P = 0.02). Thus, it seems that the benefits of good glucose control persist even if control deteriorates at a later date.
The general consensus of the ADA is that intensive insulin therapy associated with comprehensive self-management training should become standard therapy in patients with type 1 diabetes mellitus after the age of puberty. Exceptions include those with advanced chronic kidney disease and the elderly, since in these groups the detrimental risks of hypoglycemia outweigh the benefits of tight glycemic control.
The Diabetes Prevention Program was aimed at discovering whether treatment with either diet and exercise or metformin could prevent the onset of type 2 diabetes in people with impaired glucose tolerance; 3234 overweight men and women aged 25–85 years with impaired glucose tolerance participated in the study. Intervention with a low-fat diet and 150 minutes of moderate exercise (equivalent to a brisk walk) per week reduced the risk of progression to type 2 diabetes by 71% compared with a matched control group. Participants taking 850 mg of metformin twice a day reduced their risk of developing type 2 diabetes by 31%, but this intervention was relatively ineffective in those who were either less obese or in the older age group.
With the demonstration that intervention can be successful in preventing progression to diabetes in these subjects, a recommendation has been made to change the terminology from the less comprehensible “impaired glucose tolerance” to “prediabetes.” The latter is a term that the public can better understand and thus respond to by implementing healthier diet and exercise habits.
The United Kingdom Prospective Diabetes Study, a multicenter study, was designed to establish, in type 2 diabetic patients, whether the risk of macrovascular or microvascular complications could be reduced by intensive blood glucose control with oral hypoglycemic agents or insulin and whether any particular therapy was of advantage. A total of 3867 patients aged 25–65 years with newly diagnosed diabetes were recruited between 1977 and 1991, and studied over 10 years. The median age at baseline was 54 years; 44% were overweight (> 120% over ideal weight); and baseline HbA1c was 9.1%. Therapies were randomized to include a control group on diet alone and separate groups intensively treated with either insulin or sulfonylurea (chlorpropamide, glyburide, or glipizide). Metformin was included as a randomization option in a subgroup of 342 overweight or obese patients, and much later in the study an additional subgroup of both normal-weight and overweight patients who were responding unsatisfactorily to sulfonylurea therapy were randomized to either continue on their sulfonylurea therapy alone or to have metformin combined with it. Subsequently, an additional modification was made to evaluate whether tight control of blood pressure with stepwise antihypertensive therapy would prevent macrovascular and microvascular complications in 758 hypertensive patients among this UKPDS population compared with 390 of them whose blood pressure was treated less intensively. The tight control group was randomly assigned to treatment with either an angiotensin-converting enzyme (ACE) inhibitor (captopril) or a beta-blocker (atenolol). Both medications were stepped up to maximum dosages of 100 mg/d and then, if blood pressure remained higher than the target level of < 150/85 mm Hg, more medications were added in the following stepwise sequence: a diuretic, slow-release nifedipine, methyldopa, and prazosin—until the target level of tight control was achieved. In the control group, hypertension was conventionally treated to achieve target levels < 180/105 mm Hg, but these patients were not prescribed either ACE inhibitors or beta-blockers.
Intensive treatment with either sulfonylureas, metformin, combinations of those two, or insulin achieved mean HbA1c levels of 7%. This level of glycemic control decreased the risk of microvascular complications (retinopathy and nephropathy) in comparison with conventional therapy (mostly diet alone), which achieved mean levels of HbA1c of 7.9%. Weight gain occurred in intensively treated patients except when metformin was used as monotherapy. No adverse cardiovascular outcomes were noted regardless of the therapeutic agent. In the overweight or obese subgroup, metformin therapy was more beneficial than diet alone in reducing the number of cases that progressed to diabetes as well as decreasing the number of patients who suffered myocardial infarctions and strokes. Hypoglycemic reactions occurred in the intensive treatment groups, but only one death from hypoglycemia was documented during 27,000 patient-years of intensive therapy.
Tight control of blood pressure (median value 144/82 mm Hg vs 154/87 mm Hg) substantially reduced the risk of microvascular disease and stroke but not myocardial infarction. In fact, reducing blood pressure by this amount had substantially greater impact on microvascular outcomes than that achieved by lowering HbA1c from 7.9% to 7%. An epidemiologic analysis of the UKPDS data did show that every 10 mm Hg decrease in updated mean systolic blood pressure was associated with 11% reduction in risk for myocardial infarction. More than half of the patients needed two or more medications for adequate therapy of their hypertension, and there was no demonstrable advantage of ACE inhibitor therapy over therapy with beta-blockers with regard to diabetes end points. Use of a calcium channel blocker added to both treatment groups appeared to be safe over the long term in this diabetic population despite some controversy in the literature about its safety in diabetics.
Like the DCCT trialists, the UKPDS researchers performed post-trial monitoring to determine whether there were long-term benefits of having been in the intensively treated glucose and blood pressure arms of the study. The between-group differences in HbA1c were lost within the first year of follow-up, but the reduced risk (24%, P = 0.001) of development or progression of microvascular complications in the intensively treated group persisted for 10 years. The intensively treated group also had significantly reduced risk of myocardial infarction (15%, P = 0.01) and death from any cause (13%, P = 0.007) during the follow-up period. The subgroup of overweight or obese subjects who were initially randomized to metformin therapy showed sustained reduction in risk of myocardial infarction and death from any cause in the follow-up period. The between-group blood pressure differences disappeared within 2 years of the end of the trial. Unlike the sustained benefits seen with glucose control, there were no sustained benefits from having been in the more tightly controlled blood pressure group. Both blood pressure groups were at similar risk for microvascular events and diabetes-related end points during the follow-up period.
Thus, the follow-up of the UKPDS type 2 diabetes cohort showed that, as in type 1 diabetes, the benefits of good glucose control persist even if control deteriorates at a later date. Blood pressure benefits, however, last only as long as the blood pressure is well controlled.
The Steno-2 study was designed in 1990 to validate the efficacy of targeting multiple concomitant risk factors (diet, smoking cessation, exercise, and pharmacologic interventions) for both microvascular and macrovascular disorders in type 2 diabetes. A prospective, randomized, open, blinded end point design was used where 160 patients with type 2 diabetes and microalbuminuria were assigned to conventional therapy with their general practitioner or to intensive care at the Steno Diabetes Center. The intensively treated group had stepwise introduction of lifestyle and pharmacologic interventions aimed at keeping glycated hemoglobin < 6.5%, blood pressure < 130/80 mm Hg; total cholesterol < 175 mg/dL (4.5 mmol/L), and triglycerides < 150 mg/dL (1.7 mmol/L). All the intensively treated group received ACE inhibitors and if intolerant, an angiotensin II-receptor blocker. The lifestyle component of intensive intervention included reduction in dietary fat intake to < 30% of total calories; smoking cessation program; light to moderate exercise; daily vitamin-mineral supplement of vitamin C, E, and chromium picolinate. Initially, aspirin was only given as secondary prevention to patients with a history of ischemic cardiovascular disease; later, all patients received aspirin. After a mean follow-up of 7.8 years, cardiovascular events (eg, myocardial infarction, angioplasties, coronary bypass grafts, strokes, amputations, vascular surgical interventions) developed in 44% of patients in the conventional arm and only in 24% in the intensive multifactorial arm—about a 50% reduction. Rates of nephropathy, retinopathy, and autonomic neuropathy were also lower in the multifactorial intervention arm by 62% and 63%, respectively.
The persons who participated in this trial were subsequently enrolled in an observational follow-up study for an average of 5.5 years. Even though the significant differences in glycemic control and levels of risk factors of cardiovascular disease between the groups had disappeared by the end of the follow-up period, the interventional group continued to have a lower risk of retinal photocoagulation, renal failure, cardiovascular end points, and cardiovascular mortality.
The data from the UKPDS and this study provide support for guidelines recommending vigorous treatment of concomitant microvascular and cardiovascular risk factors in patients with type 2 diabetes.
The ACCORD study was a randomized controlled study designed to determine whether normal HbA1c levels would reduce the risk of cardiovascular events in middle-aged or older individuals with type 2 diabetes. About 35% of the 10,251 recruited subjects had established cardiovascular disease at study entry. The intensive arm of the study was discontinued after 3.5 years of follow-up because of more unexplained deaths in the intensive arm when compared with the control arm (22%, P = 0.020). Analysis of the data at time of discontinuation showed that the intensively treated group (mean HbA1c6.4%) had a 10% reduction in cardiovascular event rate compared with the standard treated group (mean HbA1c 7.5%), but this difference was not statistically significant.
The ADVANCE trial randomly assigned 11,140 patients with type 2 diabetes to standard or intensive glucose control. The primary outcomes were major macrovascular cardiovascular events (nonfatal myocardial infarction or stroke or death from cardiovascular causes) or microvascular events. Overall, one-third (32%) of the subjects had established cardiovascular disease at study entry. After a median follow-up of 5 years, there was a nonsignificant reduction (6%) in major macrovascular event rate in the intensively treated group (mean HbA1c 6.5%) compared with the standard therapy group (HbA1c7.3%).
The Veteran Administration Diabetes Trial (VADT) randomly assigned 1791 patients (97% men) from age 50 to 69 years with type 2 diabetes to standard or intensive glucose control. The primary outcome was a composite of myocardial infarction, death from cardiovascular causes, heart failure, vascular surgery, inoperable coronary artery disease, and amputation for gangrene. All the patients had optimized blood pressure and lipid levels. After a median follow-up of 5.6 years, there was no significant difference in the primary cardiovascular outcome in the intensively treated group (HbA1c 6.9%) compared with the standard therapy (HbA1c 8.4%). Within this larger study, there was an embedded study evaluating the impact of the intensive therapy on patients who were subcategorized as having low, moderate, and high coronary calcium scores on CT scans. Patients with low coronary calcium score showed a reduced number of cardiovascular events with intensive therapy.
Thus, the ACCORD, ADVANCE, and VADT results do not provide support for the hypothesis that near-normal glucose control in patients with type 2 diabetes will reduce cardiovascular events. It is, however, important not to over-interpret the results of these three studies. The results do not exclude the possibility that cardiovascular benefits might accrue with longer duration of near-normal glucose control. In the UKPDS, risk reductions for myocardial infarction and death from any cause were only observed during 10 years of post-trial follow-up. Specific subgroups of type 2 diabetic patients may also have different outcomes. The ACCORD, ADVANCE, and VADT studies recruited patients who had diabetes for 8–10 years and one-third of them already had established cardiovascular disease. Patients in the UKPDS, in contrast, had newly diagnosed diabetes and only 7.5% had a history of macrovascular disease. It is possible that the benefits of tight glycemic control on macrovascular events are attenuated in patients with longer duration of diabetes or with established vascular disease. Specific therapies used to lower glucose may also affect cardiovascular event rate or mortality. Severe hypoglycemia occurred more frequently in the intensively treated groups of the ACCORD, ADVANCE, and VADT studies; the ACCORD investigators were not able to exclude undiagnosed hypoglycemia as a potential cause for the increased death rate in the intensive treatment group.
A formal meta-analysis performed of the raw trial data from the ACCORD, ADVANCE, VADT, and UKPDS studies found that allocation to more intensive glucose control reduced the risk of myocardial infarction by 15% (hazard ratio 0.85, 95% CI 0.76–0.94). This benefit occurred in patients who did not have preexisting macrovascular disease.
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977–86. [PMID: 8366922]
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998 Sep 12;352(9131):837–53. [PMID: 9742976]
A well-balanced, nutritious diet remains a fundamental element of therapy. The ADA recommends about 45–65% of total daily calories in the form of carbohydrates; 25–35% in the form of fat (of which < 7% are from saturated fat), and 10–35% in the form of protein. In patients with type 2 diabetes, limiting the carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. In addition, in those patients with obesity and type 2 diabetes, weight reduction by caloric restriction is an important goal of the diet. Patients with type 1 diabetes or type 2 diabetes who take insulin should be taught “carbohydrate counting,” so they can administer their insulin bolus for each meal based on its carbohydrate content. In obese individuals with diabetes, an additional goal is weight reduction by caloric restriction (see Chapter 29).
The current recommendations for both types of diabetes continue to limit cholesterol to 300 mg daily, and individuals with LDL cholesterol more than 100 mg/dL (2.6 mmol/L) should limit dietary cholesterol to 200 mg daily. High protein intake may cause progression of kidney disease in patients with diabetic nephropathy; for these individuals, a reduction in protein intake to 0.8 kg/d (or about 10% of total calories daily) is recommended.
Exchange lists for meal planning can be obtained from the American Diabetes Association and its affiliate associations or from the American Dietetic Association (http://www.eatright.org), 216 W. Jackson Blvd., Chicago, IL 60606 (312-899-0040).
Eating low glycemic index foods results in lower glucose levels after meals. Low glycemic index foods have values of 55 or less and include many fruits, vegetables, grainy breads, pasta, and legumes. High glycemic index foods have values of 70 or greater and include baked potato, white bread, and white rice. Glycemic index is lowered by presence of fats and protein when food is consumed in a mixed meal. Even though it may not be possible to accurately predict the glycemic index of a particular food in the context of a meal, it is reasonable to choose foods with low glycemic index.
Fructose represents a “natural” sugar substance that is a highly effective sweetener, induces only slight increases in plasma glucose levels, and does not require insulin for its metabolism. However, because of potential adverse effects of large amounts of fructose on raising serum cholesterol, triglycerides, and LDL cholesterol, it does not have any advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.
Sugar alcohols, also known as polyols or polyalcohol, are commonly used as sweeteners and bulking agents. They occur naturally in a variety of fruits and vegetables but are also commercially made from sucrose, glucose, and starch. Examples are sorbitol, xylitol, mannitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates (HSH). They are not as easily absorbed as sugar, so they do not raise blood glucose levels as much. Therefore, sugar alcohols are often used in food products that are labeled as “sugar free,” such as chewing gum, lozenges, hard candy, and sugar-free ice cream. However, if consumed in large quantities, they will raise blood glucose and can cause bloating and diarrhea.
The medications for treating type 2 diabetes (Table 27–5) fall into several categories: (1) Medications that primarily stimulate insulin secretion by binding to the sulfonylurea receptor: Sulfonylureas remain the most widely prescribed medications for treating hyperglycemia. The meglitinide analog repaglinide and the D-phenylalanine derivative nateglinide also bind the sulfonylurea receptor and stimulate insulin secretion. (2) Medications that primarily lower glucose levels by their actions on the liver, muscle, and adipose tissue: Metformin works in the liver. The thiazolidinediones appear to have their main effect on skeletal muscle and adipose tissue. (3) Medications that principally slow intestinal absorption of glucose: The alpha-glucosidase inhibitors acarbose and miglitol are such currently available therapies. (4) Medications that mimic incretin effect or prolong incretin action: Glucagon-like peptide 1 (GLP1) receptor agonists and DPP 4 inhibitors fall into this category. (5) Medications that inhibit reabsorption of filtered glucose in the kidney: The sodium-glucose co-transporter inhibitors dapagliflozin and canagliflozin are two such agents. (6) Others: Pramlintide lowers glucose by suppressing glucagon and slowing gastric emptying. The mechanisms by which bromocriptine and colesevelam lower glucose levels have not been defined. The medications are discussed in detail below. A framework for planning treatment using medications from these six categories is offered later in this chapter.
Table 27–5. Drugs for treatment of type 2 diabetes mellitus.
Sulfonylureas are used in patients with type 2 but not type 1 diabetes, since these medications require functioning pancreatic B cells to produce their effect on blood glucose. Sulfonylureas are metabolized by the liver and apart from acetohexamide, whose metabolite is more active than the parent compound, the metabolites of all the other sulfonylureas are weakly active or inactive. The metabolites are excreted by the kidney and, in the case of the second-generation sulfonylureas, partly excreted in the bile. Sulfonylureas are generally contraindicated in patients with severe liver or kidney impairment. Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in < 0.1% of users.
(1) First-generation sulfonylureas (tolbutamide, tolazamide, acetohexamide, chlorpropamide)—Tolbutamide is rapidly oxidized in the liver to inactive metabolites, and its approximate duration of effect is relatively short (6–10 hours). Tolbutamide is probably best administered in divided doses (eg, 500 mg before each meal and at bedtime); however, some patients require only one or two tablets daily with a maximum dose of 3000 mg/d. Because of its short duration of action, which is independent of kidney function, tolbutamide is relatively safe to use in renal impairment. Prolonged hypoglycemia has been reported rarely with tolbutamide, mostly in patients receiving certain antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal medications to treat candidiasis. These medications apparently compete with tolbutamide for oxidative enzyme systems in the liver, resulting in maintenance of high levels of unmetabolized, active sulfonylurea in the circulation.
Tolazamide, acetohexamide, and chlorpropamide are rarely used. Chlorpropamide has a prolonged biologic effect, and severe hypoglycemia can occur especially in the elderly as their renal clearance declines with aging. Its other side effects include alcohol-induced flushing and hyponatremia due to its effect on vasopressin secretion and action.
(2) Second-generation sulfonylureas (glyburide, glipizide, gliclazide, glimepiride)—Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times more potent than tolbutamide. These medications should be used with caution in patients with cardiovascular disease or in elderly patients, in whom prolonged hypoglycemia would be especially dangerous.
The usual starting dose of glyburide is 2.5 mg/d, and the average maintenance dose is 5–10 mg/d given as a single morning dose; maintenance doses higher than 20 mg/d are not recommended. Some reports suggest that 10 mg is a maximum daily therapeutic dose, with 15–20 mg having no additional benefit in poor responders and doses over 20 mg actually worsening hyperglycemia. A “Press Tab” formulation of “micronized” glyburide—easy to divide in half with slight pressure if necessary—is available. Glyburide is metabolized in the liver into products with hypoglycemic activity, which probably explains why assays specific for the unmetabolized compound suggest a plasma half-life of only 1–2 hours, yet the biologic effects of glyburide are clearly persistent 24 hours after a single morning dose in diabetic patients. Glyburide is unique among sulfonylureas in that it not only binds to the pancreatic B cell membrane sulfonylurea receptor but also becomes sequestered within the B cell. This may also contribute to its prolonged biologic effect despite its relatively short circulating half-life.
Glyburide has few adverse effects other than its potential for causing hypoglycemia, which at times can be prolonged. Flushing has rarely been reported after ethanol ingestion. It does not cause water retention, as chlorpropamide does, but rather slightly enhances free water clearance. Glyburide should not be used in patients with liver failure and chronic kidney disease because of the risk of hypoglycemia. Elderly patients are at particular risk for hypoglycemia even with relatively small daily doses.
The recommended starting dose of glipizide is 5 mg/d, with up to 15 mg/d given as a single daily dose before breakfast. When higher daily doses are required, they should be divided and given before meals. The maximum dose recommended by the manufacturer is 40 mg/d, although doses above 10–15 mg probably provide little additional benefit in poor responders and may even be less effective than smaller doses. For maximum effect in reducing postprandial hyperglycemia, glipizide should be ingested 30 minutes before meals, since rapid absorption is delayed when the medication is taken with food.
At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy should therefore not be used in patients with liver failure. Because of its lower potency and shorter duration of action, it is preferable to glyburide in elderly patients. Glipizide has also been marketed as Glucotrol-XL. It provides extended release during transit through the gastrointestinal tract with greater effectiveness in lowering prebreakfast hyperglycemia than the shorter-duration immediate-release standard glipizide tablets. However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over glyburide.
Gliclazide (not available in the United States) is another intermediate duration sulfonylurea with a duration of action of about 12 hours. The recommended starting dose is 40–80 mg/d with a maximum dose of 320 mg. Doses of 160 mg and above are given as divided doses before breakfast and dinner. The medication is metabolized by the liver; the metabolites and conjugates have no hypoglycemic effect. An extended release preparation is available.
Glimepiride has a long duration of effect with a half-life of 5 hours allowing once or twice daily dosing. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound. A single daily dose of 1 mg/d has been shown to be effective, and the maximal recommended dose is 8 mg. It is completely metabolized by the liver to relatively inactive metabolic products.
Mitiglinide is a benzylsuccinic acid derivative that binds to the sulfonylurea receptor and is similar to repaglinide in its clinical effects. It has been approved for use in Japan.
Metformin’s therapeutic effects primarily derive from the increasing hepatic adenosine monophosphate-activated protein kinase activity, which reduces hepatic gluconeogenesis and lipogenesis. Metformin is a substrate for organic cation transporter 1, which is abundantly expressed in hepatocytes and in the gut.
Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins, and is not metabolized in humans, being excreted unchanged by the kidneys.
Metformin is the first-line therapy for patients with type 2 diabetes. The current recommendation is to start this medication at diagnosis. A side benefit of metformin therapy is its tendency to improve both fasting and postprandial hyperglycemia and hypertriglyceridemia in obese diabetics without the weight gain associated with insulin or sulfonylurea therapy. Metformin is ineffective in patients with type 1 diabetes. Patients with chronic kidney disease should not be given this medication because failure to excrete it would produce high blood and tissue levels of metformin that could stimulate lactic acid overproduction. In the United States, metformin use is not recommended at or above a serum creatinine level of 1.4 mg/dL in women and 1.5 mg/dL in men. In the United Kingdom, the recommendations are to review metformin use when the serum creatinine exceeds 130 mcmol/L (1.5 mg/dL) or the estimated glomerular filtration rate falls below 45 mL/min per 1.73 m2. The medication should be stopped if the serum creatinine exceeds 150 mcmol/L (1.7mg/dL) or the estimated glomerular filtration rate is below 30 mL/min per 1.73 m2. Patients with liver failure or persons with excessive alcohol intake should not receive this medication—lactic acid production from the gut and other tissues, which rises during metformin therapy, could result in lactic acidosis when defective hepatocytes cannot remove the lactate or when alcohol-induced reduction of nucleotides interferes with lactate clearance.
The maximal dosage of metformin is 2.55 g, although little benefit is seen above a total dose of 2000 mg. It is important to begin with a low dose and increase the dosage very gradually in divided doses—taken with meals—to reduce minor gastrointestinal upsets. A common schedule would be one 500 mg tablet three times a day with meals or one 850 mg or 1000 mg tablet twice daily at breakfast and dinner. Up to 2000 mg of the extended-release preparation can be given once a day. Lower doses should be used in patients with estimated glomerular filtration rates between 30 and 45 mL/min per 1.73 m2.
The most frequent side effects of metformin are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal discomfort, diarrhea), which occur in up to 20% of patients. These effects are dose-related, tend to occur at onset of therapy, and often are transient. However, in 3–5% of patients, therapy may have to be discontinued because of persistent diarrheal discomfort. In a retrospective analysis, it has been reported that patients switched from immediate-release metformin to comparable dose of extended-release metformin experienced fewer gastrointestinal side effects.
Hypoglycemia does not occur with therapeutic doses of metformin, which permits its description as a “euglycemic” or “antihyperglycemic” medication rather than an oral hypoglycemic agent. Dermatologic or hematologic toxicity is rare. Metformin interferes with the calcium dependent absorption of vitamin B12-intrinsic complex in the terminal ileum; vitamin B12 deficiency can occur after many years of metformin use. Periodic screening with vitamin B12 levels should be considered, especially in patients with peripheral neuropathy or if a macrocytic anemia develops. Increased intake of dietary calcium may prevent the metformin-induced B12 malaborption.
Lactic acidosis has been reported as a side effect but is uncommon with metformin in contrast to phenformin. While therapeutic doses of metformin reduce lactate uptake by the liver, serum lactate levels rise only minimally if at all, since other organs such as the kidney can remove the slight excess. However, if tissue hypoxia occurs, the metformin-treated patient is at higher risk for lactic acidosis due to compromised lactate removal. Similarly, when kidney function deteriorates, affecting not only lactate removal by the kidney but also metformin excretion, plasma levels of metformin rise far above the therapeutic range and block hepatic uptake enough to provoke lactic acidosis without associated increases in lactic acid production. Almost all reported cases have involved subjects with associated risk factors that should have contraindicated its use (kidney, liver, or cardiorespiratory insufficiency, alcoholism, advanced age). Acute kidney failure can occur rarely in certain patients receiving radiocontrast agents. Metformin therapy should therefore be temporarily halted on the day of radiocontrast administration and restarted a day or two later after confirmation that renal function has not deteriorated.
Two medications of this class, rosiglitazone and pioglitazone, are available for clinical use. Both are effective as monotherapy and in combination with sulfonylureas or metformin or insulin, lowering HbA1c by 1% to 2%. When used in combination with insulin, they can result in a 30–50% reduction in insulin dosage, and some patients can come off insulin completely. Rosiglitazone is primarily metabolized by the CYP 2C8 isoenzyme and pioglitazone is metabolized by CYP 2C8 and CYP 3A4.
The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia. Patients inadequately managed on sulfonylureas can do well on a combination of sulfonylurea and rosiglitazone or pioglitazone.
These medications have some additional effects apart from glucose lowering. Rosiglitazone therapy is associated with increases in total cholesterol, LDL cholesterol (15%), and HDL cholesterol (10%). There is a reduction in free fatty acids of about 8–15%. The changes in triglycerides were generally not different from placebo. Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL cholesterol (15%) but did not cause a consistent change in total cholesterol and LDL cholesterol levels. A prospective randomized comparison of the metabolic effects of pioglitazone and rosiglitazone showed similar effects on HbA1c and weight gain. Pioglitazone-treated persons, however, had lower total cholesterol, LDL cholesterol, and triglycerides when compared with rosiglitazone-treated persons. Small prospective studies have demonstrated that treatment with these medications leads to improvements in the biochemical and histologic features of nonalcoholic fatty liver disease. The thiazolidinediones also may limit vascular smooth muscle proliferation after injury, and there are reports that pioglitazone can reduce neointimal proliferation after coronary stent placement. Finally, in one double-blind, placebo-controlled study, rosiglitazone was shown to be associated with a decrease in the ratio of urinary albumin to creatinine excretion.
Safety concerns and some troublesome side effects have emerged about this class of medications that significantly limit their use. A meta-analysis of 42 randomized clinical trials with rosiglitazone suggested that this medication increases the risk of angina pectoris or myocardial infarction. A meta-analysis of clinical trials with pioglitazone did not show similar findings. Although conclusive data were lacking, the European Medicines Agency suspended the use of rosiglitazone in Europe. In the United States, the FDA established a restricted distribution program. A subsequent large prospective clinical trial (the RECORD study) failed to confirm the meta-analysis finding and the restrictions were lifted in the United States. It is unlikely, however, that there is going to be a resurgence in its use and pioglitazone is likely to remain the preferred agent.
Edema occurs in about 3–4% of patients receiving monotherapy with rosiglitazone or pioglitazone. The edema occurs more frequently (10–15%) in patients receiving concomitant insulin therapy and may result in heart failure. The medications are contraindicated in diabetic individuals with New York Heart Association class III and IV cardiac status. Thiazolidinediones have also been reported as being associated with new onset or worsening macular edema. Apparently, this is a rare side effect, and most of these patients also had peripheral edema. The macular edema resolved or improved once the medication was discontinued.
In experimental animals, rosiglitazone stimulates bone marrow adipogenesis at the expense of osteoblastogenesis resulting in a decrease in bone density. An increase in fracture risk in women (but not men) has been reported with both rosiglitazone and pioglitazone. The fracture risk is in the range of 1.9 per 100 patient-years with the thiazolidinedione compared to 1.1 per 100 patient years on comparison treatment. In at least one study of rosiglitazone, the fracture risk was increased in premenopausal as well as postmenopausal women.
Other side effects include anemia, which occurs in 4% of patients treated with these medications; it may be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs, especially when the medication is combined with a sulfonylurea or insulin. Some of the weight gain is fluid retention, but there is also an increase in total fat mass. In preclinical studies with pioglitazone, bladder tumors were observed in male rats receiving clinically relevant doses of the medication. In a planned 5-year interim analysis of data from a long-term observational cohort study of patients taking pioglitazone, an increased bladder cancer risk was observed with increasing dose and duration of pioglitazone use, reaching statistical significance after 24 months of exposure. In a study sponsored by the manufacturer to evaluate the impact of pioglitazone on macrovascular events (PROactive study), a safety analysis noted 14 cases of bladder cancer in the treated group and 5 cases in the placebo group (P = 0.04). Although there are currently no recommendations regarding screening for bladder cancer, this should be considered in patients receiving long-term pioglitazone therapy.
Troglitazone, the first medication in this class to go into widespread clinical use, was withdrawn from clinical use because of medication-associated fatal liver failure. Although rosiglitazone and pioglitazone have not been reported to cause liver injury, the FDA recommends that they should not be used in patients with clinical evidence of active liver disease or pretreatment elevation of the alanine aminotransferase (ALT) level that is 2.5 times greater than the upper limit of normal. Liver biochemical tests should be performed prior to initiation of treatment and periodically thereafter.
The principal adverse effect, seen in 20–30% of patients, is flatulence. This is caused by undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends to discourage excessive carbohydrate consumption and promotes improved compliance of type 2 patients with their diet prescriptions. When acarbose is given alone, there is no risk of hypoglycemia. However, if combined with insulin or sulfonylureas, it might increase the risk of hypoglycemia from these agents. A slight rise in hepatic aminotransferases has been noted in clinical trials with acarbose (5% versus 2% in placebo controls, and particularly with doses > 300 mg/d). The levels generally return to normal on stopping the medication.
In the UKPDS, approximately 2000 patients on diet, sulfonylurea, metformin, or insulin therapy were randomized to acarbose or placebo therapy. By 3 years, 60% of the patients had discontinued the medication, mostly because of gastrointestinal symptoms. If one looked only at the 40% who remained on the medication, they had a 0.5% lower HbA1c compared with placebo.
In addition to its insulin stimulatory effect, GLP-1 also has a number of other pancreatic and extrapancreatic effects. It suppresses glucagon secretion and so may ameliorate the hyperglucagonemia that is present in people with diabetes and improve postprandial hyperglycemia. GLP-1 preserves islet integrity and reduces apoptotic cell death of human islet cells in culture. In mice, streptozotocin-induced apoptosis is significantly reduced by coadministration of exendin-4 or exenatide, a GLP-1 receptor agonist. GLP-1 acts on the stomach delaying gastric emptying; the importance of this effect on glucose lowering is illustrated by the observation that antagonizing the deceleration of gastric emptying markedly reduces the glucose lowering effect of GLP-1. GLP-1 receptors are present in the central nervous system, and intracerebroventricular administration of GLP-1 in wild type mice, but not in GLP-1 receptor knockout mice, inhibits feeding. Type 2 diabetic patients undergoing GLP-1 infusion are less hungry; it is unclear whether this is mainly due to a deceleration of gastric emptying or whether there is a central nervous system effect as well.
Exenatide (Exendin 4) is a GLP-1 receptor agonist isolated from the saliva of the Gila Monster (a venomous lizard) that is more resistant to DPP-4 action and cleared by the kidney. Its half-life is 2.4 hours, and its glucose lowering effect is about 6 hours. When this medication is given to patients with type 2 diabetes by subcutaneous injection twice daily, it lowers blood glucose and HbA1c levels. Exenatide appears to have the same effects as GLP-1 on glucagon suppression and gastric emptying. In clinical trials, adding exenatide therapy to patients with type 2 diabetes already taking metformin or a sulfonylurea, or both, further lowered the HbA1c value by 0.4% to 0.6% over a 30-week period. These patients also experienced a weight loss of 3–6 pounds. In an open label extension study up to 80 weeks, the HbA1c reduction was sustained, and there was further weight loss (to a total loss of about 10 pounds). The main side effect was nausea, affecting over 40% of the patients. The nausea was dose-dependent and declined with time. The risk of hypoglycemia was higher in persons taking sulfonylureas. The FDA reported 30 post-marketing reports of acute pancreatitis in patients taking exenatide. The pancreatitis was severe (hemorrhagic or necrotizing) in 6 instances, and two of these patients died. Many of these patients had other risk factors for pancreatitis, but the possibility remains that the medication was causally responsible for some cases. Patients taking exenatide should be advised to seek immediate medical care if they experience unexplained persistent severe abdominal pain. The FDA also reported 16 cases of renal impairment and 62 cases of acute kidney injury in patients taking exenatide. Some of these patients had preexisting kidney disease, and others had one or more risk factors for kidney disease. A number of patients reported nausea, vomiting, and diarrhea; it is possible that these side effects cause volume depletion and contributed to the development of the renal injury. The delay in gastric emptying may affect the absorption of some other medications; therefore, antibiotics and oral contraceptives should be taken 1 hour before exenatide doses. Low-titer antibodies against exenatide develop in over one-third (38%) of patients, but the clinical effects are not attenuated. High-titer antibodies develop in a subset of patients (~6%), and in about half of these cases, an attenuation of glycemic response has been seen. Exenatide stimulates C-cell tumors in rodents and the drug is therefore contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome type 2.
Exenatide is dispensed as two fixed-dose pens (5 mcg and 10 mcg). It is injected 60 minutes before breakfast and before dinner. Patients should be prescribed the 5 mcg pen for the first month and, if tolerated, the dose can then be increased to 10 mcg twice a day. The medication is not recommended in patients with glomerular filtration rate <30 mL/min.
Exenatide LAR is a once weekly preparation that is dispensed as a powder (2 mg). It is suspended in the provided diluent just prior to injection. In comparative clinical trials, the long-acting drug lowers the HbA1c level a little more than the twice daily drug. It is as well tolerated, with nausea being the predominant side effect.
Liraglutide is a soluble fatty acid acylated GLP-1 analog (with replacement of lysine with arginine at position 34 and the attachment of a C16 acyl chain to a lysine at position 26). The fatty-acyl GLP-1 retains affinity for GLP-1 receptors but the addition of the C 16 acyl chain allows for noncovalent binding to albumin, both hindering DPP-4 access to the molecule and contributing to a prolonged half-life and duration of action. The half-life is approximately 12 hours, allowing the medication to be injected once a day.
In clinical trials lasting 26 and 52 weeks, adding liraglutide to the therapeutic regimen (metformin, sulfonylurea, thiazolidinedione) of patients with type 2 diabetes further lowered the HbA1c value. Depending on the dose and design of the study, the HbA1c decline was in the range of 0.6% to 1.5%. The patients had sustained weight loss of 1–6 pounds.
Like exenatide, the most frequent side effects were nausea (28%) and vomiting (10%). There was also an increased incidence of diarrhea. About 2–5% of participants withdrew from the studies because of the gastrointestinal symptoms. In clinical trials, there were seven cases of pancreatitis in the liraglutide treated group with one case in the comparison group (2.2 vs. 0.6 cases per 1000 patient-years). Liraglutide stimulates C-cell neoplasia and causes medullary thyroid carcinoma in rats. Human C-cells express very few GLP1-receptors, and the relevance to human therapy is unclear; however, because of the animal data, the medication should not be used in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) syndrome type 2. The FDA is conducting ongoing investigation into the risks of pancreatitis and pancreatic duct metaplasia.
The dosing is initiated at 0.6 mg daily, increased after 1 week to 1.2 mg daily. If needed, an additional increase in dose to 1.8 mg is recommended for optimal glycemic control. Titration is also based on tolerability. There is limited experience using the medication in renal failure but no dose adjustment is recommended.
Sitagliptin, when used in clinical trials alone and in combination with metformin and pioglitazone, improved HbA1c from 0.5% to 1.4%. The usual dose of sitagliptin is 100 mg once daily, but the dose is reduced to 50 mg daily if the calculated creatinine clearance is 30–50 mL/min and to 25 mg for clearances < 30 mL/min. Unlike exenatide, sitagliptin does not cause nausea or vomiting. It also does not result in weight loss. The main adverse effect appears to be a predisposition to nasopharyngitis or upper respiratory tract infection. A small increase in neutrophil count of ~200 cells/mcL has also occurred. Since its FDA approval and clinical use, there have been reports of serious allergic reactions to sitagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. There have also been reports of pancreatitis (88 cases including 2 cases of hemorrhagic or necrotizing pancreatitis). The frequency of these events is unclear. A number of neuropeptides, growth factors, cytokines, and chemokines are potential DPP-4 substrates; DPP-4 inhibitors prolong the actions of neuropeptide Y and substance P. It is unknown whether the effects of DPP-4 inhibitors on the actions of neuropeptide Y and substance P over a long-term period will have negative consequences.
Saxagliptin, when added to the therapeutic regimen (metformin, sulfonylurea, thiazolidinedione) of patients with type 2 diabetes, further lowered the HbA1c value by about 0.7–0.9%. The dose is 2.5 mg or 5 mg once a day. The 2.5-mg dose should be used in patients with calculated creatinine clearance < 50 mL/min. It lowers HbA1c by about 0.6% when added to metformin or glyburide or thiazolidine in various 24-week clinical trials. The medication does not cause weight gain or loss. The main adverse reactions were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. There is also small reversible dose-dependent reduction in absolute lymphocyte count, which remains within normal limits. Hypersensitivity reactions, such as urticaria and facial edema, occurred in 1.5% of patients taking the medication compared with 0.4% receiving placebo. The metabolism of saxagliptin is by CYP3A4/5; thus, strong inhibitors or inducers of CYP3A4/5 will affect the pharmacokinetics of saxagliptin and its active metabolite.
Linagliptin lowers HbA1c by about 0.4–0.6% when added to metformin, sulfonylurea, or pioglitazone. The dose is 5 mg daily and, since it is primarily excreted unmetabolized via the bile, no dose adjustment is needed in patients with renal failure. The adverse reactions include nasopharyngitis and hypersensitivity reactions (urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity). In one study, there were eight cases of pancreatitis in 4687 patients exposed to drug (4311 patient years) with 0 cases in 1183 patients receiving placebo (433 patient years).
Vildagliptin lowers HbA1c by about 0.5–1% when added to the therapeutic regimen of patients with type 2 diabetes. The dose is 50 mg once or twice daily. Adverse reactions include upper respiratory tract infections, nasopharyngitis, dizziness, and headache. Rare cases of hepatic dysfunction, including hepatitis, have been reported. Liver function testing is recommended quarterly during the first year of use and periodically thereafter. Animal studies using much higher doses of DPP-4 inhibitors and GLP1-receptor agonists than are used in humans caused expansion of pancreatic ductal glands and generation of premalignant pancreatic intraepithelial (PanIN) lesions that have the potential to progress to pancreatic adenocarcinoma. There is, however, currently no evidence that these drugs cause pancreatic cancer in humans.
Canagliflozin reduces the threshold for glycosuria from a plasma glucose threshold of ~180 mg/dL to 70–90 mg/dL. It has been shown to reduce HbA1c by 0.6–1% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of 2–5 kg. The usual dose is 100 mg daily but up to 300 mg daily can be used in patients with normal kidney function.
Dapagliflozin is an SGLT2 inhibitor that has been shown to reduce HbA1c levels by 0.5–0.8% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of about 2–4 kg. The usual dose is 10 mg daily but 5 mg daily is the recommended initial dose in patients with hepatic failure.
As might be expected, the efficacy of the SGLT2 inhibitors is reduced in chronic kidney disease. Canagliflozin is contraindicated in patients with estimated glomerular filtration rate < 45 mL/min/1.73 m2. The main side effects are increased incidence of genital infections and urinary tract infections affecting ~8–9% of patients. The glycosuria can cause intravascular volume contraction and hypotension. Canagliflozin caused a modest increase in LDL cholesterol levels (4–8%). Also, in clinical trials, patients taking dapagliflozin had higher rates of breast cancer (nine cases vs none in comparator arms) and bladder cancer (10 cases vs 1 in placebo arm). These cancer rates exceeded the expected rates in age-matched reference diabetes population.
Bromocriptine, a dopamine 2 receptor agonist, has been shown to modestly lower HbA1c by 0.1–0.5% when compared to baseline and 0.4–0.5% compared to placebo. The tablet dose is 0.8 mg and the daily dose is 2 (1.6 g) to 6 (4.8 mg) tablets as tolerated. Common side effects are nausea, vomiting, dizziness, and headache.
Colesevelam, the bile acid sequesterant, when added to metformin or sulfonylurea or insulin lowered HbA1c 0.3– 0.4 % when compared to baseline and 0.5–0.6% compared to placebo. HbA1c lowering, however, was not observed in a single monotherapy clinical trial comparing colesevelam to placebo. Colesevelam use is associated with ~20% increase in triglyceride levels. Other adverse effects include constipation and dyspepsia.
With their modest glucose lowering and significant side effects, using bromocriptine or colesevelam to treat diabetes is not recommended.
Insulin is indicated for type 1 diabetes as well as for type 2 diabetic patients with insulinopenia whose hyperglycemia does not respond to diet therapy either alone or combined with other hypoglycemic medications.
Table 27–6. Summary of bioavailability characteristics of the insulins.
Human insulin is produced by recombinant DNA techniques (biosynthetic human insulin) as Humulin (Eli Lilly) and as Novolin (Novo Nordisk). It is dispensed as either regular (R) or NPH (N) formulations. Five analogs of human insulin—three rapidly acting (insulin lispro, insulin aspart, insulin glulisine) and two long-acting (insulin glargine and insulin detemir)—have been approved by the FDA for clinical use (Table 27–7). Animal insulins are no longer available in the United States. All currently available insulins contain < 10 ppm of proinsulin and are labeled as “purified.” These purified insulins preserve their potency, so that refrigeration is recommended but not crucial. During travel, reserve supplies of insulin can be readily transported for weeks without losing potency if protected fromextremes of heat or cold. All the insulins in the United States are available in a concentration of 100 units/mL (U100) and dispensed in 10 mL vials or 0.3 mL cartridges or prefilled disposable pens. For use in rare cases of severe insulin resistance, regular insulin in a concentration of 500 units/mL (U500) is available in 10 mL vial.
Table 27–7. Insulin preparations available in the United States.1
(1) Regular insulin— Regular insulin is a short-acting soluble crystalline zinc insulin whose effect appears within 30 minutes after subcutaneous injection and lasts 5–7 hours when usual quantities are administered. Intravenous infusions of regular insulin are particularly useful in the treatment of diabetic ketoacidosis and during the perioperative management of insulin-requiring diabetics. Regular insulin is indicated when the subcutaneous insulin requirement is changing rapidly, such as after surgery or during acute infections—although the rapidly acting insulin analogs may be preferable in these situations.
For markedly insulin-resistant persons who would otherwise require large volumes of insulin solution, a U500 preparation of human regular insulin is available. Since a U500 syringe is not available, when U500 insulin is required in cases of severe insulin resistance, a U100 insulin syringe or tuberculin syringe must be used to measure doses. The clinician should carefully note dosages in both units and volume to avoid overdosage.
(2) Rapidly acting insulin analogs—Insulin lispro (Humalog), is an insulin analog produced by recombinant technology, wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29 and lysine has been moved from B29 to B28. Insulin aspart (Novolog), is a single substitution of proline by aspartic acid at position B28. Insulin glulisine (Apidra) differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid. These changes result in these three analogs that have less tendency to form hexamers, in contrast to human insulin. When injected subcutaneously, the analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as soon as 1 hour—in contrast to regular human insulin, whose hexamers require considerably more time to dissociate and become absorbed. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with the circulating half-life, or with their immunogenicity, which are all identical with those of human regular insulin.
Clinical trials have demonstrated that the optimal times of preprandial subcutaneous injection of comparable doses of the rapidly acting insulin analogs and of regular human insulin are 20 minutes and 60 minutes, respectively, before the meal. While this more rapid onset of action has been welcomed as a great convenience by diabetic patients who object to waiting as long as 60 minutes after injecting regular human insulin before they can begin their meal, patients must be taught to ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia during the meal. Another desirable feature of rapidly acting insulin analogs is that their duration of action remains at about 4 hours irrespective of dosage. This contrasts with regular insulin, whose duration of action is prolonged when larger doses are used.
The rapidly acting analogs are also commonly used in pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, persons using insulin lispro had lower HbA1c values and improved postprandial glucose control with the same frequency of hypoglycemia. In the event of pump failure, however, users of the rapidly acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.
While insulin aspart has been approved for intravenous use (eg, in hyperglycemic emergencies), there is no advantage in using insulin aspart over regular insulin by this route.
(1) NPH (neutral protamine Hagedorn or isophane) insulin—NPH is an intermediate-acting insulin whose onset of action is delayed by combining 2 parts soluble crystalline zinc insulin with 1 part protamine zinc insulin. This produces equivalent amounts of insulin and protamine, so that neither is present in an uncomplexed form (“isophane”).
Its onset of action is delayed to 2–4 hours, and its peak response is generally reached in about 6–7 hours. Because its duration of action is often < 24 hours (with a range of 10–20 hours), most patients require at least two injections daily to maintain a sustained insulin effect. Occasional vials of NPH insulin have tended to show unusual clumping of their contents or “frosting” of the container, with considerable loss of bioactivity. This instability is rare and occurs less frequently if NPH human insulin is refrigerated when not in use and if bottles are discarded after 1 month of use.
(2) Insulin glargine—Insulin glargine is an insulin analog in which the asparagine at position 21 of the A chain of the human insulin molecule is replaced by glycine and two arginines are added to the carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule closer to neutral, making it more soluble in an acidic environment. In contrast, human insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin, which, when injected into the neutral pH environment of the subcutaneous tissue, forms microprecipitates that slowly release the insulin into the circulation. It lasts for about 24 hours without any pronounced peaks and is given once a day to provide basal coverage. This insulin cannot be mixed with the other human insulins because of its acidic pH. When this insulin was given as a single injection at bedtime to type 1 patients in clinical trials, fasting hyperglycemia was better controlled with less nocturnal hypoglycemia when compared to NPH insulin.
Although limited clinical data suggest that insulin glargine is safe in pregnancy, it is not approved for this use.
(3) Insulin detemir—Insulin detemir is an insulin analog. The tyrosine at position 30 of the beta chain has been removed and a 14-C fatty acid chain (tetradecanoic acid) is attached to the lysine at position 29 by acylation. The fatty acid chain makes the molecule more lipophilic than native insulin and the addition of zinc stabilizes the molecule and leads to formation of hexamers. Its prolonged action is due to dihexamerization and binding of hexamers and dimers to albumin at the injection site as well as binding of the monomer via its fatty acid side chain to albumin in the circulation. The affinity of insulin detemir is fourfold to fivefold lower than that of human soluble insulin and therefore the U100 formulation of insulin detemir has an insulin concentration of 2400 nmol/mL compared with 600 nmol/mL for NPH. The duration of action for insulin detemir is about 17 hours at therapeutically relevant doses. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. This insulin has been reported to have lower within-subject pharmacodynamic variability compared with NPH insulin and insulin glargine. In vitro studies do not suggest any clinically relevant albumin binding interactions between insulin detemir and fatty acids or protein-bound medications. Since there is a vast excess (~400,000) of albumin binding sites available in plasma per insulin detemir molecule, it is unlikely that hypoalbuminemic disease states affect the ratio of bound to free insulin detemir.
The longer-acting insulin analogs cannot be mixed with either regular insulin or the rapidly acting insulin analogs.
Any part of the body covered by loose skin can be used, such as the abdomen, thighs, upper arms, flanks, and upper buttocks. Preparation with alcohol is no longer required prior to injection as long as the skin is clean. Rotation of sites continues to be recommended to avoid delayed absorption when fibrosis or lipohypertrophy occurs from repeated use of a single site. However, considerable variability of absorption rates from different sites, particularly with exercise, may contribute to the instability of glycemic control in certain type 1 patients if injection sites are rotated too frequently in different areas of the body. Consequently, it is best to limit injection sites to a single region of the body and rotate sites within that region. The abdomen is recommended for subcutaneous injections, since regular insulin has been shown to absorb more rapidly from there than from other subcutaneous sites. The effect of anatomic regions appears to be much less pronounced with the analog insulins.
CSII therapy is appropriate for patients with type 1 diabetes who are motivated, mechanically inclined, educated about diabetes (diet, insulin action, treatment of hypoglycemia and hyperglycemia), and willing to monitor their blood glucose four to six times a day. Known complications of CSII include ketoacidosis, which can occur when insulin delivery is interrupted, and skin infections. Another disadvantage is its cost and the time demanded of the clinician and staff in initiating therapy.
V-go (Valeritas) is a mechanical patch pump designed specifically for people with type 2 diabetes who employ a basal/bolus insulin regimen. The device is preset to deliver one of three fixed and flat basal rates (20, 30, or 40 units) for 24 hours (at which point it must be replaced) and there is a button that delivers two units per press to help cover meals.
Pancreas transplantation at the time of kidney transplantation is becoming more widely accepted. Patients undergoing simultaneous pancreas and kidney transplantation have an 83% chance of pancreatic graft survival at 1 year and 69% at 5 years. Solitary pancreatic transplantation in the absence of a need for kidney transplantation is considered only in those rare patients who do not respond to all other insulin therapeutic approaches and who have frequent severe hypoglycemia or who have life-threatening complications related to their lack of metabolic control. Pancreas transplant alone graft survival is 78% at 1 year and 54% at 5 years.
People with type 1 diabetes can become insulin independent after receiving an islet cell transplant. The islets are isolated from donor pancreas using controlled digestion with collagenase followed by density gradient centrifugation. The isolated islets are then infused into the portal vein using a percutaneous transhepatic approach and they lodge in the liver releasing insulin in response to physiologic stimuli. Long-term immunosuppression is necessary to prevent allograft rejection and to suppress the autoimmune process that led to the disease in the first place. Insulin independence for more than 5 years has been demonstrated in patients who got anti-CD3 antibody or anti-thymocyte globulin induction immunosuppression and calcineurin inhibitors, mTor inhibitors, and mycophenolate mofetil as maintenance immunosuppression. Islet cell transplant trials with different kinds and combinations of immunosuppressive agents are currently underway. One major limitation is the need for more than one islet infusion to achieve insulin independence. This is because of significant loss of islets during isolation and the period prior to engraftment. Widespread application of islet transplantation will depend on improving insulin independence rates with one infusion and also demonstrating that the long-term outcomes are as good as those of pancreas transplant alone.
Bennett WL et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011 May 3;154(9):602–13. Erratum in: Ann Intern Med. 2011 Jul 5;155(1):67–8. [PMID: 21403054]
Steps in the Management of the Diabetic Patient
An attempt should be made to characterize the diabetes as type 1 or type 2, based on the clinical features present and on whether or not ketonuria accompanies the glycosuria. Features that suggest end-organ insulin insensitivity to insulin, such as visceral obesity, acanthosis nigricans, or both, must be identified. The family history should document not only the incidence of diabetes in other members of the family but also the age at onset, association with obesity, the need for insulin, and whether there were complications. For the occasional patient, measurement of ICA, GAD65, IAA, and ICA 512 antibodies can help distinguish between type 1 and type 2 diabetes. Many patients with newly diagnosed type 1 diabetes still have significant endogenous insulin production, and C peptide levels do not reliably distinguish between type 1 and type 2 diabetes. Other factors that increase cardiac risk, such as smoking history, presence of hypertension or hyperlipidemia, or oral contraceptive pill use, should be recorded.
Laboratory diagnosis of diabetes should document fasting plasma glucose levels above 126 mg/dL (7 mmol/L) or postprandial values consistently above 200 mg/dL (11.1 mmol/L) or HbA1c of at least 6.5% and whether ketonuria accompanies the glycosuria. An HbA1c measurement is also useful for assessing the effectiveness of future therapy. Baseline values include fasting plasma triglycerides, total cholesterol and HDL-cholesterol, electrocardiography, kidney function studies, peripheral pulses, and neurologic, podiatric, and ophthalmologic examinations to help guide future assessments.
Since diabetes is a lifelong disorder, education of the patient and the family is probably the most important obligation of the clinician who provides initial care. The best persons to manage a disease that is affected so markedly by daily fluctuations in environmental stress, exercise, diet, and infections are the patients themselves and their families. The “teaching curriculum” should include explanations by the clinician or nurse of the nature of diabetes and its potential acute and chronic hazards and how they can be recognized early and prevented or treated. Self-monitoring of blood glucose should be emphasized, especially in insulin-requiring diabetic patients, and instructions must be given on proper testing and recording of data.
Patients taking insulin should have an understanding of the actions of basal and bolus insulins. They should be taught to determine whether the basal dose is appropriate and how to adjust the rapidly acting insulin dose for the carbohydrate content of a meal. Patients and their families and friends should be taught to recognize signs and symptoms of hypoglycemia and how to treat low glucose reactions. Strenuous exercise can precipitate hypoglycemia, and patients must therefore be taught to reduce their insulin dosage in anticipation of strenuous activity or to take supplemental carbohydrate. Injection of insulin into a site farthest away from the muscles most involved in the exercise may help ameliorate exercise-induced hypoglycemia, since insulin injected in the proximity of exercising muscle may be more rapidly mobilized. Exercise training also increases the effectiveness of insulin and insulin doses should be adjusted accordingly. Infections can cause insulin resistance, and patients should be instructed on how to manage the hyperglycemia with supplemental rapidly acting insulin.
The targets for blood glucose control should be elevated appropriately in elderly patients since they have the greatest risk if subjected to hypoglycemia and the least long-term benefit from more rigid glycemic control. Advice on personal hygiene, including detailed instructions on foot and dental care, should be provided. All infections (especially pyogenic ones) provoke the release of high levels of insulin antagonists, such as catecholamines or glucagon, and thus bring about a marked increase in insulin requirements. Patients who are taking oral agents may decompensate and temporarily require insulin. Patients should be told about community agencies, such as Diabetes Association chapters, that can serve as a continuing source of instruction.
Finally, vigorous efforts should be made to persuade patients with newly diagnosed diabetes who smoke to give up the habit, since large vessel peripheral vascular disease and debilitating retinopathy are less common in nonsmoking diabetic patients.
Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient. However, certain general principles of management can be outlined for hyperglycemic states of different types.
A combination of rapidly acting insulin analogs and long-acting insulin analogs allows for more physiologic insulin replacement. The rapidly acting insulin analogs have been advocated as a safer and much more convenient alternative to regular human insulin for preprandial use. In a study comparing regular insulin with insulin lispro, daily insulin doses and HbA1c levels were similar, but insulin lispro improved postprandial control, reduced hypoglycemic episodes, and improved patient convenience compared with regular insulin. However, because of their relatively short duration (no more than 3–4 hours), the rapidly acting insulin analogs need to be combined with longer-acting insulins to provide basal coverage and avoid hyperglycemia prior to the next meal. In addition to carbohydrate content of the meal, the effect of simultaneous fat ingestion must also be considered a factor in determining the rapidly acting insulin analog dosage required to control the glycemic increment during and just after the meal. With low-carbohydrate content and high-fat intake, there is an increased risk of hypoglycemia from insulin lispro within 2 hours after the meal. Table 27–8 illustrates a regimen with a rapidly acting insulin analog and insulin detemir or insulin glargine that might be appropriate for a 70-kg person with type 1 diabetes eating meals providing standard carbohydrate intake and moderate to low fat content.
Table 27–8. Examples of intensive insulin regimens using rapidly acting insulin analogs (insulin lispro, aspart, or glulisine) and insulin detemir, or insulin glargine in a 70-kg man with type 1 diabetes.1–3
Insulin glargine is usually given once in the evening to provide 24-hour coverage. This insulin cannot be mixed with any of the other insulins and must be given as a separate injection. There are occasional patients in whom insulin glargine does not seem to last for 24 hours, and in such cases it needs to be given twice a day. As shown, insulin detemir may also need to be given twice a day to get adequate 24-hour basal coverage. Alternatively, small doses of NPH (~3–4 units) can be given with each meal to provide daytime basal coverage with a larger dose at night. Unlike the long-acting insulin analogs, NPH can be mixed in the same syringe as the insulin lispro, insulin aspart, and insulin glulisine.
Continuous subcutaneous insulin infusion (CSII) by portable battery-operated “open loop” devices currently provides the most flexible approach, allowing the setting of different basal rates throughout the 24 hours and permitting patients to delay or skip meals and vary meal size and composition. The dosage is usually based on providing 50% of the estimated insulin dose as basal and the remainder as intermittent boluses prior to meals. For example, a 70-kg man requiring 35 units of insulin per day may require a basal rate of 0.7 units per hour throughout the 24 hours with the exception of 3 AM to 8 AM, when 0.8 units per hour might be appropriate (given the “dawn phenomenon”—reduced tissue sensitivity to insulin between 5 AM and 8 AM). The meal bolus would depend on the carbohydrate content of the meal and the premeal blood glucose value. One unit per 15 g of carbohydrate plus 1 unit for 50 mg/dL (2.8 mmol/L) of blood glucose above a target value (eg, 120 mg/dL [6.7 mmol/L]) is a common starting point. Further adjustments to basal and bolus dosages would depend on the results of blood glucose monitoring. The majority of patients use the rapidly acting insulin analogs in the pumps. One of the more difficult therapeutic problems in managing patients with type 1 diabetes is determining the proper adjustment of insulin dose when the prebreakfast blood glucose level is high. Occasionally, the prebreakfast hyperglycemia is due to the Somogyi effect, in which nocturnal hypoglycemia leads to a surge of counterregulatory hormones to produce high blood glucose levels by 7 AM. However, a more common cause for prebreakfast hyperglycemia is the waning of circulating insulin levels by the morning. Also, the dawn phenomenon is present in as many as 75% of type 1 patients and can aggravate the hyperglycemia.
The diagnosis of the cause of prebreakfast hyperglycemia can be facilitated by self-monitoring of blood glucose at 3 AM in addition to the usual bedtime and 7 AM measurements (Table 27–9). This is required for only a few nights, and when a particular pattern emerges from monitoring blood glucose levels overnight, appropriate therapeutic measures can be taken. The Somogyi effect can be treated by eliminating the dose of intermediate insulin at dinnertime and giving it at a lower dosage at bedtime or by supplying more food at bedtime. When a waning insulin level is the cause, then either increasing the evening dose or shifting it from dinnertime to bedtime (or both) can be effective. A bedtime dose either of insulin glargine or insulin detemir provides more sustained overnight insulin levels than human NPH and may be effective in managing refractory prebreakfast hyperglycemia. If this fails, insulin pump therapy may be required.
Table 27–9. Prebreakfast hyperglycemia: Classification by blood glucose and insulin levels.
For selected patients, medical or surgical options for weight loss should be considered. Orlistat, phentermine/topiramate, and lorcaserin are weight loss medications approved for use in combination with diet and exercise (see Chapter 29).
Orlistat (Xenical) is a reversible inhibitor of gastric and pancreatic lipases and prevents the hydrolysis and absorption of dietary triglycerides. It is available over-the-counter and in prescription strength. In 1-year studies in obese patients with type 2 diabetes, those taking orlistat had lost more weight, had lower HbA1c values, and had improved lipid profiles. The main adverse reactions were gastrointestinal, with oily spotting, oily stool, flatus, and fecal urgency and frequency. Malabsorption of fat-soluble vitamins also occurs, and patients should take a multivitamin tablet containing fat-soluble. vitamins at least 2 hours before or 2 hours after the administration of orlistat. Cases of severe liver injury have been reported with this medication, although a cause and effect relationship has not been established.
Phentermine is a sympathomimetic amine stimulating release of norepinephrine from the hypothalamus. Topiramate is primarily used as an anticonvulsant, but it also appears to reduce appetite. In a 56-week phase 3 study, an extended-release preparation of phentermine/topiramate (Qsymia) together with diet and lifestyle intervention resulted in 10 kg weight loss (9.8%) compared to 1.4 kg (1.2%) with placebo. As might be expected, the diabetes subgroup on active therapy had greater reductions in HbA1c levels; and fewer patients with prediabetes on active therapy progressed to diabetes. The adverse events are consistent with those of the constituent drugs. The most common adverse reactions were paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Topiramate can worsen depression and increase risk of suicidal thoughts. It is also teratogenic and the FDA has required the manufacturer to conduct a risk evaluation and mitigation strategy (REMS). The medication is only available through specialty mail-order pharmacies.
Lorcaserin (Belviq) is a 5-hydroxytryptamine receptor subtype 2C (5-HT2C) agonist. This receptor subclass regulates mood and appetite. In a 52-week study, patients taking lorcaserin had a 8.1 kg weight loss (8.2%) compared to 3.2 kg placebo group (3.3%). The main adverse reactions were headache and nausea. Fenfluramine, an agonist for the 5-HT2B receptor, was associated with serotonin-related cardiac valvulopathy. Activation of the 5-HT2C receptor, however, does not appear to be associated with valvulopathy.
Bariatric surgery (Roux-en-Y, gastric banding, gastric sleeve, biliopancreatic diversion/duodenal switch) typically results in substantial weight loss and improvement in glucose levels. A meta-analysis examining the impact of bariatric surgery on patients with diabetes and BMI of 40 kg/m2 or greater noted that 82% of patients had resolution of clinical and laboratory manifestations of diabetes in the first 2 years after surgery and 62% remained free of diabetes more than 2 years after surgery. The improvement was most marked in the procedure that caused the greatest weight loss (biliopancreatic diversion/duodenal switch). There was, however, a high attrition of patients available for follow-up, and there was little information about different ethnic types. Weight regain does occur after bariatric surgery, and it can be expected that 20–25% of the lost weight will be regained over 10 years. The impact of this weight gain on diabetes recurrence depends principally on the degree of beta cell dysfunction. Also anatomic changes imposed by malabsorptive surgery can result in protein malnutrition, vitamin and mineral deficiencies. Clinically significant deficiencies in calcium; folic acid; iron; and vitamins D, B12, A, and K are common. Thus, patients undergoing malabsorptive procedures require lifelong supplementation and monitoring by a team familiar with possible deficiencies. Both early and late dumping symptoms can also occur.
Nonobese patients with type 2 diabetes frequently have increased visceral adiposity—the so-called metabolically obese normal weight patient. There is less emphasis on weight loss, but exercise remains an important aspect of treatment.
Figure 27–3. Algorithm for the treatment of type 2 diabetes based on the recommendations of the consensus panel of the American Diabetes Association/European Association for the Study of Diabetes.
When diabetes is not well controlled with initial therapy (usually metformin), then a second agent should be added. In patients who experience hyperglycemia after a carbohydrate-rich meal (such as dinner), a short-acting secretagogue (repaglinide or nateglinide) before meals may suffice to get the glucose levels into the target range. Patients with severe insulin resistance may be candidates for pioglitazone. Patients who are very concerned about weight gain may benefit from a trial of GLP-1 receptor agonist or DPP-4 inhibitor or SGLT2 inhibitor. If two agents are inadequate, then a third agent is added, although data regarding efficacy of such combined therapy are limited.
When the combination of oral agents (and injectable GLP-1 receptor agonists) fail to achieve euglycemia in patients with type 2 diabetes, then insulin treatment should be instituted. Various insulin regimens may be effective. One proposed regimen is to continue the oral combination therapy and then simply add a bedtime dose of NPH or long-acting insulin analog (insulin glargine or insulin detemir) to reduce excessive nocturnal hepatic glucose output and improve fasting glucose levels. If the patient does not achieve target glucose levels during the day, then daytime insulin treatment can be initiated. A convenient insulin regimen under these circumstances is a split dose of 70/30 NPH/regular mixture (or Humalog Mix 75/25 or NovoLogMix 70/30) before breakfast and before dinner. If this regimen fails to achieve satisfactory glycemic goals or is associated with unacceptable frequency of hypoglycemic episodes, then a more intensive regimen of multiple insulin injections can be instituted as in patients with type 1 diabetes. Metformin principally reduces hepatic glucose output, and it is reasonable to continue with this medication when insulin therapy is instituted. Pioglitazone, which improves peripheral insulin sensitivity, can be used together with insulin but this combination is associated with more weight gain and peripheral edema. The sulfonylureas also continue to be of benefit. There is limited information on the benefits of continuing the GLP1-receptor agonists or the DPP-4 inhibitors or the SGLT2 inhibitors once insulin therapy is initiated. Weight-reducing interventions should continue even after initiation of insulin therapy and may allow for simplification of the therapeutic regimen in the future.
A reasonable aim of therapy is to approach normal glycemic excursions without provoking severe or frequent hypoglycemia. Criteria for “acceptable” control includes the following: (1) blood glucose levels of 90–130 mg/dL (5–7.2 mmol/L) before meals and after an overnight fast, (2) levels no higher than 180 mg/dL (10 mmol/L) 1 hour after meals and 150 mg/dL (8.3 mmol/L) 2 hours after meals, and (3) HbA1c levels < 7% for nonpregnant adults. Less stringent HbA1c goals may be appropriate in children, those with a history of severe hypoglycemia, limited life expectancy, and advanced microvascular and macrovascular disease. In the elderly frail patient, an HbA1c target of approximately 8% (preprandial blood glucose levels in the range of the 150–159 mg/dL) may be reasonable although formal evidence is lacking. The UKPDS study demonstrated that blood pressure control was as significant or more significant than glycemic control in patients with type 2 diabetes regarding the prevention of microvascular as well as macrovascular complications.
Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012 Jun;35(6):1364–79. [PMID: 22517736]
Switzer SM et al. Intensive insulin therapy in patients with type 1 diabetes mellitus. Endocrinol Metab Clin North Am. 2012 Mar;41(1):89–104. [PMID: 22575408]
Hypoglycemia can occur in patient taking sulfonylureas, repaglinide, and nateglinide, particularly if the patient is elderly, has kidney or liver disease, or is taking certain other medications that alter metabolism of the sulfonylureas (eg, phenylbutazone, sulfonamides, or warfarin). It occurs more frequently with the use of long-acting sulfonylureas than when shorter-acting agents are used. Otherwise, hypoglycemia in insulin-treated patients with diabetes occurs as a consequence of three factors: behavioral issues, impaired counterregulatory systems, and complications of diabetes.
Behavioral issues include injecting too much insulin for the amount of carbohydrates ingested. Drinking alcohol in excess, especially on an empty stomach, can also cause hypoglycemia. In patients with type 1 diabetes, hypoglycemia can occur during or even several hours after exercise, and so glucose levels need to be monitored and food and insulin adjusted. Some patients do not like their glucose levels to be high, and they treat every high glucose level aggressively. These individuals who “stack” their insulin—that is, give another dose of insulin before the first injection has had its full action—can develop hypoglycemia.
Counterregulatory issues resulting in hypoglycemia include impaired glucagon response, sympatho-adrenal responses, and cortisol deficiency. Patients with diabetes of > 5 years duration lose their glucagon response to hypoglycemia. As a result, they are at a significant disadvantage in protecting themselves against falling glucose levels. Once the glucagon response is lost, their sympatho-adrenal responses take on added importance. Unfortunately, aging, autonomic neuropathy, or hypoglycemic unawareness due to repeated low glucose levels further blunts the sympatho-adrenal responses. Occasionally, Addison disease develops in persons with type 1 diabetes mellitus; when this happens, insulin requirements fall significantly, and unless insulin dose is reduced, recurrent hypoglycemia will develop.
Complications of diabetes that increase the risk for hypoglycemia include autonomic neuropathy, gastroparesis, and end-stage chronic kidney disease. The sympathetic nervous system is an important system alerting the individual that the glucose level is falling by causing symptoms of tachycardia, palpitations, sweating, and tremulousness. Failure of the sympatho-adrenal responses increases the risk of hypoglycemia. In addition, in patients with gastroparesis, if insulin is given before a meal, the peak of insulin action may occur before the food is absorbed causing the glucose levels to fall. Finally, in end-stage chronic kidney disease, hypoglycemia can occur presumably because of decreased insulin clearance as well as loss of renal contribution to gluconeogenesis in the postabsorptive state.
To prevent and treat insulin-induced hypoglycemia, the diabetic patient should carry glucose tablets or juice at all times. For most episodes, ingestion of 15 grams of carbohydrate is sufficient to reverse the hypoglycemia. The patient should be instructed to check the blood glucose in 15 minutes and treat again if the glucose level is still low. A parenteral glucagon emergency kit (1 mg) should be provided to every patient with diabetes who is receiving insulin therapy. Family or friends should be instructed how to inject it subcutaneously or intramuscularly into the buttock, arm, or thigh in the event that the patient is unconscious or refuses food. The medication can occasionally cause vomiting, and the unconscious patient should be turned on his or her side to protect the airway. The glucagon mobilizes glycogen from the liver, raising the blood glucose by about 36 mg/dL (2 mmol/L) in about 15 minutes. After the patient recovers consciousness, additional oral carbohydrate should be given. People with diabetes receiving hypoglycemic medication therapy should also wear an identification MedicAlert bracelet or necklace or carry a card in his or her wallet (1-800-ID-ALERT, www.medicalert.org).
Medical personnel treating severe hypoglycemia can give 50 mL of 50% glucose solution by rapid intravenous infusion. If intravenous access is not available, 1 mg of glucagon can be injected intramuscularly.
Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013 Jul 25;369(4):362–72. [PMID: 23883381]
Chronic Complications of Diabetes
Late clinical manifestations of diabetes mellitus include a number of pathologic changes that involve small and large blood vessels, cranial and peripheral nerves, the skin, and the lens of the eye. These lesions lead to hypertension, end-stage chronic kidney disease, blindness, autonomic and peripheral neuropathy, amputations of the lower extremities, myocardial infarction, and cerebrovascular accidents. These late manifestations correlate with the duration of the diabetic state subsequent to the onset of puberty. In type 1 diabetes, end-stage chronic kidney disease develops in up to 40% of patients, compared with < 20% of patients with type 2 diabetes. Proliferative retinopathy ultimately develops in both types of diabetes but has a slightly higher prevalence in type 1 patients (25% after 15 years’ duration). In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death, whereas patients with type 2 diabetes are more likely to have macrovascular diseases leading to myocardial infarction and stroke as the main causes of death. Cigarette use adds significantly to the risk of both microvascular and macrovascular complications in diabetic patients.
Proliferative retinopathy involves the growth of new capillaries and fibrous tissue within the retina and into the vitreous chamber. It is a consequence of small vessel occlusion, which causes retinal hypoxia; this in turn stimulates new vessel growth. New vessel formation may occur at the optic disk or elsewhere on the retina. Prior to proliferation of new capillaries, a preproliferative phase often occurs in which arteriolar ischemia is manifested as cotton-wool spots (small infarcted areas of retina). Vision is usually normal until vitreous hemorrhage or retinal detachment occurs.
Proliferative retinopathy can occur in both types of diabetes but is more common in type 1, developing about 7–10 years after onset of symptoms, with a prevalence of 25% after 15 years’ duration. Proliferative retinopathy is a leading cause of blindness in the United States, particularly since it increases the risk of retinal detachment. Vision-threatening retinopathy virtually never appears in type 1 patients in the first 3–5 years of diabetes or before puberty. Up to 20% of patients with type 2 diabetes have retinopathy at the time of diagnosis, because many were probably diabetic for an extensive period of time before diagnosis. Annual consultation with an ophthalmologist should be arranged for patients who have had type 1 diabetes for more than 3–5 years and for all patients with type 2 diabetes. Patients with any macular edema, severe nonproliferative retinopathy, or any proliferative retinopathy require the care of an ophthalmologist. Extensive “scatter” xenon or argon photocoagulation and focal treatment of new vessels reduce severe visual loss in those cases in which proliferative retinopathy is associated with recent vitreous hemorrhages or in which extensive new vessels are located on or near the optic disk. Macular edema, which is more common than proliferative retinopathy in patients with type 2 diabetes (up to 20% prevalence), has a guarded prognosis, but it has also responded to scatter therapy with improvement in visual acuity if detected early. Injection of bevacizumab (Avastin), an anti-vascular endothelial growth factor (anti-VEGF), into the eye has been shown to stop the growth of the new blood vessels in diabetic eye disease. Avoiding tobacco use and correction of associated hypertension are important therapeutic measures in the management of diabetic retinopathy. There is no contraindication to using aspirin in patients with proliferative retinopathy.
As many as 4000 cases of end-stage chronic kidney disease occur each year among diabetic people in the United States. This is about one-third of all patients being treated for end-stage chronic kidney disease and represents a considerable national health expense.
The cumulative incidence of nephropathy differs between the two major types of diabetes. Patients with type 1 diabetes have a 30–40% chance of having nephropathy after 20 years—in contrast to the much lower frequency in type 2 diabetes patients, in whom only about 15–20% develop clinical kidney disease. However, since there are many more individuals affected with type 2 diabetes, end-stage chronic kidney disease is much more prevalent in type 2 than in type 1 diabetes in the United States and especially throughout the rest of the world. Improved glycemic control and more effective therapeutic measures to correct hypertension—and with the beneficial effects of ACE inhibitors—can reduce the development of end-stage chronic kidney disease among patients with diabetes.
Diabetic nephropathy is initially manifested by proteinuria; subsequently, as kidney function declines, urea and creatinine accumulate in the blood. Sensitive radioimmunoassay methods detect small amounts of urinary albumin—in contrast to the less sensitive dipstick strips, whose minimal detection limit is 0.3–0.5%. Conventional 24-hour urine collections, in addition to being inconvenient for patients, also show wide variability of albumin excretion, since several factors such as sustained erect posture, dietary protein, and exercise tend to increase albumin excretion rates. For these reasons, an albumin-creatinine ratio in an early morning spot urine collected upon awakening is preferable. In the early morning spot urine, a ratio of albumin (mcg/L) to creatinine (mg/L) of < 30 mcg/mg creatinine is normal, and a ratio of 30–300 mcg/mg creatinine suggests abnormal microalbuminuria. At least two early morning spot urine collections over a 3- to 6-month period should be abnormal before a diagnosis of microalbuminuria is justified. Short-term hyperglycemia, exercise, urinary tract infections, heart failure, and acute febrile illness can cause transient albuminuria and so testing for microalbuminuria should be postponed until resolution of these problems.
Subsequent end-stage chronic kidney disease can be predicted by persistent urinary albumin excretion rates exceeding 30 mcg/mg creatinine. Glycemic control as well as a low-protein diet (0.8 g/kg/d) may reduce both the hyperfiltration and the elevated microalbuminuria in patients in the early stages of diabetes and those with incipient diabetic nephropathy. Antihypertensive therapy also decreases microalbuminuria. Evidence from some studies—but not the UKPDS—supports a specific role for ACE inhibitors in reducing intraglomerular pressure in addition to their lowering of systemic hypertension. An ACE inhibitor (captopril, 50 mg twice daily) in normotensive diabetic patients impedes progression to proteinuria and prevents the increase in albumin excretion rate. Since microalbuminuria has been shown to correlate with elevated nocturnal systolic blood pressure, it is possible that “normotensive” diabetic patients with microalbuminuria have slightly elevated systolic blood pressure during sleep, which is lowered during antihypertensive therapy. This action may contribute to the reported efficacy of ACE inhibitors in reducing microalbuminuria in “normotensive” patients.
If treatment is inadequate, then the disease progresses with proteinuria of varying severity occasionally leading to nephrotic syndrome with hypoalbuminemia, edema, and an increase in circulating LDL cholesterol, as well as progressive azotemia. In contrast to all other kidney disorders, the proteinuria associated with diabetic nephropathy does not diminish with progressive end-stage chronic kidney disease (patients continue to excrete 10–11 g daily as creatinine clearance diminishes). As end-stage chronic kidney disease progresses, there is an elevation in the renal threshold at which glycosuria appears.
Patients with diabetic nephropathy should be evaluated and monitored by a nephrologist. There has been gradual improvement in quality of life of diabetic patients receiving dialysis but mortality remains higher than in nondiabetic patients. During 5 years of follow-up in a registry study from Europe, the mortality rate in people with diabetes receiving dialysis was 226.9 deaths/1000 patient years whereas the rate was 151.4 deaths/1000 patients years in people receiving dialysis who did not have diabetes. Diabetic nephropathy accounts for about 20% of kidney transplantations performed annually in the United States.
Diabetic neuropathies are the most common complications of diabetes affecting up to 50% of older patients with type 2 diabetes.
Sensory involvement usually occurs first and is generally bilateral, symmetric, and associated with dulled perception of vibration, pain, and temperature. The pain can range from mild discomfort to severe incapacitating symptoms (see below). The sensory deficit may eventually be of sufficient degree to prevent patients from feeling pain. Patients who have a sensory neuropathy should therefore be examined with a 5.07 Semmes Weinstein filament and those who cannot feel the filament must be considered at risk for unperceived neuropathic injury.
The denervation of the small muscles of the foot result in clawing of the toes and displacement of the submetatarsal fat pads anteriorly. These changes, together with the joint and connective tissue changes, alter the biomechanics of the foot and increase plantar pressures. This combination of decreased pain threshold, abnormally high foot pressures, and repetitive stress (such as from walking) can lead to calluses and ulcerations in the high-pressure areas such as over the metatarsal heads (Figure 27–4). Peripheral neuropathy, autonomic neuropathy, and trauma also predisposes to the development of Charcot arthropathy. An acute case of Charcot foot arthropathy presents with pain and swelling, and if left untreated, leads to a “rocker bottom” deformity and ulceration. The early radiologic changes show joint subluxation and periarticular fractures. As the process progresses, there is frank osteoclastic destruction leading to deranged and unstable joints particularly in the midfoot. Not surprisingly, the key issue for the healing of neuropathic ulcers in a foot with good vascular supply is mechanical unloading. In addition, any infection should be treated with debridement and appropriate antibiotics; healing duration of 8–10 weeks is typical. Occasionally, when healing appears refractory, platelet-derived growth factor (becaplermin [Regranex]) should be considered for local application. A post-marketing epidemiologic study showed increased cancer deaths in patients who had used three or more tubes of becaplermin on their leg or feet ulcers, resulting in a “black box” warning on the medication label. Once ulcers are healed, therapeutic footwear is key to preventing recurrences. Custom molded shoes are reserved for patients with significant foot deformities. Other patients with neuropathy may require accommodative insoles that distribute the load over as wide an area as possible. Patients with foot deformities and loss of their protective threshold should get regular care from a podiatrist. Patients should be educated on appropriate footwear and those with loss of their protective threshold should be instructed to inspect their feet daily for reddened areas, blisters, abrasions, or lacerations.
Figure 27–4. Neuropathic ulcer under the head of the third metatarsal on the foot of a diabetic patient. (From Javier La Fontaine, DPM; reproduced with permission from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)
In some patients, hypersensitivity to light touch and occasionally severe “burning” pain, particularly at night, can become physically and emotionally disabling. Amitriptyline, 25–75 mg at bedtime, has been recommended for pain associated with diabetic neuropathy. Dramatic relief has often resulted within 48–72 hours. This rapid response is in contrast to the 2 or 3 weeks required for an antidepressive effect. Patients often attribute the benefit to having a full night’s sleep. Mild to moderate morning drowsiness is a side effect that generally improves with time or can be lessened by giving the medication several hours before bedtime. This medication should not be continued if improvement has not occurred after 5 days of therapy. If amitriptyline’s anticholinergic effects are too troublesome, then nortriptyline or desipramine in doses of 25–150 mg/d can be used. Tricyclic antidepressants, in combination with the phenothiazine, fluphenazine, have been shown in two studies to be efficacious in painful neuropathy, with benefits unrelated to relief of depression. Gabapentin (900–1800 mg orally daily in three divided doses) has also been shown to be effective in the treatment of painful neuropathy and should be tried if the tricyclic medications prove ineffective. Pregabalin, a congener of gabapentin, has been shown in an 8-week study to be more effective than placebo in treating painful diabetic peripheral neuropathy. However, this medication was not compared with an active control. Also, because of its abuse potential, it has been categorized as a schedule V controlled substance. Duloxetine (60–120 mg), a serotonin and norepinephrine reuptake inhibitor, has been approved for the treatment of painful diabetic neuropathy. In clinical trials, this medication reduced the pain sensitivity score by 40–50%. Capsaicin, a topical irritant, has been found to be effective in reducing local nerve pain; it is dispensed as a cream (Zostrix 0.025%, Zostrix-HP 0.075%) to be rubbed into the skin over the painful region two to four times daily. Gloves should be used for application since hand contamination could result in discomfort if the cream comes in contact with eyes or sensitive areas such as the genitalia. Application of a 5% lidocaine patch over an area of maximal pain has been reported to be of benefit. It is approved for treatment of postherpetic neuralgia and is in clinical trials for the treatment of painful diabetic neuropathy.
Diabetic neuropathic cachexia is a syndrome characterized by a symmetric peripheral neuropathy associated with profound weight loss (up to 60% of total body weight) and painful dysesthesias affecting the proximal lower limbs, the hands, or the lower trunk. Treatment is usually with insulin and analgesics. The prognosis is generally good, and patients typically recover their baseline weight with resolution of the painful sensory symptoms within 1 year.
Involvement of the gastrointestinal system may be manifested by nausea, vomiting, postprandial fullness, reflux or dysphagia, constipation or diarrhea (or both), and fecal incontinence. Gastroparesis should be considered in type 1 diabetic patients in whom unexpected fluctuations and variability in their blood glucose levels develops after meals. Radioisotope studies show marked delay in gastric emptying. Metoclopramide has been of some help in treating diabetic gastroparesis. It is given in a dose of 10 mg orally three or four times a day, 30 minutes before meals and at bedtime. Drowsiness, restlessness, fatigue, and lassitude are common adverse effects. Tardive dyskinesia and extrapyramidal effects can occur, especially when used for longer than 3 months, and the FDA has cautioned against the long-term use of metoclopramide.
Erythromycin appears to bind to motilin receptors in the stomach and has been found to improve gastric emptying over the short term in doses of 250 mg three times daily, but its effectiveness seems to diminish over time. In selected patients, injections of botulinum toxin into the pylorus can reduce pylorus sphincter resistance and enhance gastric emptying. Gastric electrical stimulation has been reported to improve symptoms and quality of life indices in patients with gastroparesis refractory to pharmacologic therapy.
Diarrhea associated with autonomic neuropathy has occasionally responded to broad-spectrum antibiotic therapy (such as rifaximin, metronidazole, amoxicillin/clavulanate, ciprofloxacin, doxycycline), although it often undergoes spontaneous remission. Refractory diabetic diarrhea is often associated with impaired sphincter control and fecal incontinence. Therapy with loperamide, 4–8 mg daily, or diphenoxylate with atropine, two tablets up to four times a day, may provide relief. In more severe cases, tincture of paregoric or codeine (60 mg tablets) may be required to reduce the frequency of diarrhea and improve the consistency of the stools. Clonidine has been reported to lessen diabetic diarrhea; however, its usefulness is limited by its tendency to lower blood pressure in these patients who already have autonomic neuropathy, resulting in orthostatic hypotension. Constipation usually responds to stimulant laxatives such as senna.
Incomplete emptying of the bladder can sometimes occur. Bethanechol in doses of 10–50 mg orally three times a day has occasionally improved emptying of the atonic urinary bladder. Catheter decompression of the distended bladder has been reported to improve its function, and considerable benefit has been reported after surgical severing of the internal vesicle sphincter.
Use of Jobst fitted stockings, tilting the head of the bed, and arising slowly from the supine position can be helpful in treating symptoms of orthostatic hypotension. When such measures are inadequate, then treatment with fludrocortisone 0.1–0.2 mg orally daily can be considered. This medication, however, can result in supine hypertension and hypokalemia. Midodrine (10 mg orally three times a day), an alpha-agonist, can also be used.
Erectile dysfunction can result from neurologic, psychological or vascular causes, or a combination of these causes. There are medical, mechanical, and surgical treatments available for treatment of erectile dysfunction. Penile erection depends on relaxation of the smooth muscle in the arteries of the corpus cavernosum, and this is mediated by nitric oxide-induced cyclic 3′,5′-guanosine monophosphate (cGMP) formation. cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors impair the breakdown of cGMP and improve the ability to attain and maintain an erection. Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) have been shown in placebo-controlled clinical trials to improve erections in response to sexual stimulation. The recommended dose of sildenafil for most patients is one 50-mg tablet taken approximately 1 hour before sexual activity. The peak effect is at 1.5–2 hours, with some effect persisting for 4 hours. Patients with diabetes mellitus using sildenafil reported 50–60% improvement in erectile function. The maximum recommended dose is 100 mg. The recommended dose of both vardenafil and tadalafil is 10 mg. The doses may be increased to 20 mg or decreased to 5 mg based on efficacy and side effects. Tadalafil has been shown to improve erectile function for up to 36 hours after dosing. Low doses are available for daily use. In clinical trials, only a few adverse effects have been reported—transient mild headache, flushing, dyspepsia, and some altered color vision. Priapism can occur with these medications, and patients should be advised to seek immediate medical attention if an erection persists for longer than 4 hours. The PDE5 inhibitors potentiate the hypotensive effects of nitrates and their use is contraindicated in patients who are concurrently using organic nitrates in any form. Caution is advised for men who have suffered a heart attack, stroke, or life-threatening arrhythmia within the previous 6 months; men who have resting hypotension or hypertension; and men who have a history of heart failure or have unstable angina. Rarely, a decrease in vision or permanent visual loss has been reported after PDE5 inhibitor use.
Intracorporeal injection of vasoactive medications causes penile engorgement and erection. Medications most commonly used include papaverine alone, papaverine with phentolamine, and alprostadil (prostaglandin E1). Alprostadil injections are relatively painless, but careful instruction is essential to prevent local trauma, priapism, and fibrosis. Intraurethral pellets of alprostadil avoid the problem of injection of the medication.
External vacuum therapy (Erec-Aid System) is a nonsurgical treatment consisting of a suction chamber operated by a hand pump that creates a vacuum around the penis. This draws blood into the penis to produce an erection that is maintained by a specially designed tension ring inserted around the base of the penis and which can be kept in place for up to 20–30 minutes. While this method is generally effective, its cumbersome nature limits its appeal.
In view of the recent development of nonsurgical approaches to therapy of erectile dysfunction, resort to surgical implants of penile prostheses is becoming less common.
The ADA also recommends lowering blood pressure to 140/80 mm Hg or less in patients with diabetes. The systolic target of 130 mm Hg or less is recommended for the younger patient if it can be achieved without undue treatment burden. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized 33,357 persons (age 55 years and older) with hypertension and at least one other coronary artery disease risk factor to receive treatment with chlorthalidone, amlodipine, or lisinopril. Chlorthalidone appeared to be superior to amlodipine and lisinopril in lowering blood pressure, reducing the incidence of cardiovascular events, tolerability, and cost. The study included 12,063 individuals with type 2 diabetes. The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9297 high-risk patients who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor to receive ramipril or placebo for a mean of 5 years. Treatment with ramipril resulted in a 25% reduction of the risk of myocardial infarction, stroke, or death from cardiovascular disease. The mean difference between the placebo and ramipril group was 2.2 mm Hg systolic and 1.4 mm Hg diastolic blood pressure. The reduction in cardiovascular event rate remained significant after adjustment for this small difference in blood pressure. The mechanism underlying this protective effect of ramipril is unknown. Patients with type 2 diabetes who already have cardiovascular disease or microalbuminuria should therefore be considered for treatment with an ACE inhibitor. More clinical studies are needed to address the question of whether patients with type 2 diabetes who do not have cardiovascular disease or microalbuminuria would specifically benefit from ACE inhibitor treatment.
Aspirin at a dose of 81–325 mg daily is effective in reducing cardiovascular morbidity and mortality in patients who have a history of myocardial infarction or stroke (secondary prevention). It is unclear if aspirin prevents primary cardiovascular events in people with diabetes. The current recommendation is to give aspirin to people with diabetes who have a greater than 10% 10-year risk of cardiovascular events. Typically, this includes most diabetic men aged 50 years or older and diabetic women aged 60 years or older with one or more additional risk factors (smoking, hypertension, dyslipidemia, family history of premature cardiovascular disease, or albuminuria). Contraindications for aspirin therapy are patients with aspirin allergy, bleeding tendency, recent gastrointestinal bleeding, or active hepatic disease. Based on the Early Treatment Diabetic Retinopathy Study (ETDRS), there does not appear to be a contraindication to aspirin use to achieve cardiovascular benefit in diabetic patients who have proliferative retinopathy. Aspirin also does not seem to affect the severity of vitreous/preretinal hemorrhages or their resolution.
The incidence of gangrene of the feet in patients with diabetes is 30 times that in age-matched controls. The factors responsible for its development, in addition to peripheral vascular disease, are small vessel disease, peripheral neuropathy with loss of both pain sensation and neurogenic inflammatory responses, and secondary infection. In two-thirds of patients with ischemic gangrene, pedal pulses are not palpable. In the remaining one-third who have palpable pulses, reduced blood flow through these vessels can be demonstrated by plethysmographic or Doppler ultrasound examination. Prevention of foot injury is imperative. Agents that reduce peripheral blood flow such as tobacco should be avoided. Control of other risk factors such as hypertension is essential. Beta-blockers are relatively contraindicated because of presumed negative peripheral hemodynamic consequences but data that support this are lacking. Cholesterol-lowering agents are useful as adjunctive therapy when early ischemic signs are detected and when dyslipidemia is present. Patients should be advised to seek immediate medical care if a diabetic foot ulcer develops. Improvement in peripheral blood flow with endarterectomy and bypass operations is possible in certain patients.
Chronic pyogenic infections of the skin may occur, especially in poorly controlled diabetic patients. Candidal infection can produce erythema and edema of intertriginous areas below the breasts, in the axillas, and between the fingers. It causes vulvovaginitis in women with chronically uncontrolled diabetes who have persistent glucosuria and is a frequent cause of pruritus. While antifungal creams containing miconazole or clotrimazole offer immediate relief of vulvovaginitis, recurrence is frequent unless glucosuria is reduced.
In some patients with type 2 diabetes, poor glycemic control can cause a severe hypertriglycemia, which can present as eruptive cutaneous xanthomas and pancreatitis. The skin lesions appear as yellow morbilliform eruptions 2–5 mm in diameter with erythematous areolae. They occur on extensor surfaces (elbows, knees, buttocks) and disappear after triglyceride levels are reduced.
Necrobiosis lipoidica diabeticorum is usually located over the anterior surfaces of the legs or the dorsal surfaces of the ankles. They are oval or irregularly shaped plaques with demarcated borders and a glistening yellow surface and occur in women two to four times more frequently than in men. Pathologically, the lesions show degeneration of collagen, granulomatous inflammation of subcutaneous tissues and blood vessels, capillary basement membrane thickening and obliteration of vessel lumina. The condition is associated with type 1 diabetes, although it can occur in patients with type 2 diabetes, and also in patients without diabetes. First-line therapy includes topical and subcutaneous corticosteroids. Improving glycemic control may help the condition.
“Shin spots” are not uncommon in adults with diabetes. They are brownish, rounded, painless atrophic lesions of the skin in the pretibial area.
A number of bone and joint complications occur in people with diabetes. Long-standing diabetes can cause progressive stiffness of the hand secondary to contracture and tightening of skin over the joints (diabetic cheiroarthropathy), frozen shoulder (adhesive capsulitis), carpal tunnel syndrome, and Dupuytren contractures. These complications are believed to be due to glycosylation of collagen and perhaps other proteins in connective tissue. There may also be an inflammatory component.
Data on bone mineral density and fracture risk in people with diabetes are contradictory. Patients with type 2 diabetes do appear to be at increased risk for nonvertebral fractures. Women with type 1 diabetes have an increased risk of fracture when compared with women without diabetes. Other factors, such as duration of diabetes, and diabetes complications, such as neuropathy and kidney disease, likely affect both the bone mineral density and fracture risk.
Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of the anterior longitudinal ligaments of the spine and various extraspinal ligaments. It causes stiffness and decreased range of spinal motion. The peripheral joints most commonly affected are the metacarpophalangeal joints, elbows, and shoulders. Diabetes, obesity, hypertension, and dyslipidemia are risk factors for this condition.
Hyperuricemia and acute and tophaceous gout are more common in type 2 diabetes.
Bursitis, particularly of the shoulders and hips occurs more frequently than expected in patients with diabetes.
Chin JA et al. Diabetes mellitus and peripheral vascular disease: diagnosis and management. Clin Podiatr Med Surg. 2014 Jan;31(1):11–26. [PMID: 24296015]
Lingam G et al. Systemic medical management of diabetic retinopathy. Middle East Afr J Ophthalmol. 2013 Oct–Dec;20(4):301–8. [PMID: 24339679]
Singleton JR et al. The diabetic neuropathies: practical and rational therapy. Semin Neurol. 2012 Jul;32(3):196–203. [PMID: 23117944]
Waanders F et al. Current concepts in the management of diabetic nephropathy. Neth J Med. 2013 Nov;71(9):448–58. [PMID: 24218418]
Most patients with diabetes are hospitalized for reasons other than their diabetes. Indeed, up to 10–15% of all hospitalized patients have diabetes. Audits suggest that as many as a 30% of these hospitalized patients have inappropriate management of their diabetes, with such errors as being given metformin where contraindicated, failure to act on high blood glucose levels, omission of diabetes medication, no record of diabetes complications, and inappropriate insulin management or blood glucose monitoring. It is challenging using outpatient oral therapies or insulin regimens in the hospital because patients are not eating as usual; they are often fasting for procedures; clinical events increase adverse reactions associated with diabetes medicines, eg, thiazolidinediones can cause fluid retention and worsen heart failure; metformin should not be used in patients with significant chronic kidney or liver disease, or those getting contrast for radiographic studies. Subcutaneous or intravenous insulin therapy is frequently substituted for other diabetes medicines because the insulin dose can be adjusted to match changing inpatient needs and it is safe to use insulin in patients with heart, kidney, and liver disease.
Surgery represents a stress situation during which most of the insulin antagonists (eg, catecholamines, growth hormone, and corticosteroids) are mobilized. In the diabetic patient, this can lead to a worsening of hyperglycemia and perhaps even ketoacidosis. The aim of medical management of people with diabetes during the perioperative period is to minimize these stress-induced changes. Recommendations for management depend both on the patient’s usual diabetic regimen and on the type of surgery (major or minor) to be done (see also Chapter 3).
For people with diabetes controlled with diet alone, no special precautions must be taken unless diabetic control is markedly disturbed by the procedure. If this occurs, small doses of short-acting insulin as needed will correct the hyperglycemia.
Patients taking oral agents should not take them on the day of surgery. If there is significant hyperglycemia, small doses of short-acting insulin are given as needed. If this approach does not provide adequate control, an insulin infusion should be started in the manner indicated below. The oral agents can be restarted once the patient is eating normally after the operation. It is important to order a postoperative serum creatinine level to ensure adequate kidney function prior to restarting metformin therapy.
Patients taking insulin represent the only serious challenge to management of diabetes when surgery is necessary. However, with careful attention to changes in the clinical or laboratory picture, glucose control can be managed successfully. The protocol used to control the glucose depends on the kind of diabetes (type 1 or type 2); whether it is minor surgery (lasting < 2 hours and patient eating afterwards) or major surgery (lasting > 2 hours, with invasion of a body cavity, and patient not eating afterwards); and the preoperative insulin regimen (basal bolus or premixed insulin twice a day or premeal bolus only or regular insulin before meals and NPH at bedtime). Patients with type 1 diabetes must be receiving some insulin to prevent the development of diabetic ketoacidosis. Many patients with type 2 diabetes who are taking insulin do well perioperatively without insulin for a few hours. Ideally, patients with diabetes should undergo surgery early in the morning. Table 27–10 summarizes the approach for these patients.
Table 27–10. Recommendations for management of insulin-treated diabetes during surgery.
One insulin infusion method adds 10 units of regular insulin to 1 L of 5% dextrose in 0.45% saline, and this is infused intravenously at a rate of 100–180 mL/h. This gives the patient 1–1.8 units of insulin per hour which, except in the most severe cases, generally keeps the blood glucose within the range of 100–250 mg/dL (5.5–13.9 mmol/L). The infusion may be continued for several days, if necessary. Perioperatively, plasma glucose or blood glucose should be determined every 2–4 hours to be sure metabolic control is adequate. If it is not, adjustments in the ratio of insulin to dextrose in the intravenous solution can be made.
An alternative method consists of separate infusions of insulin and glucose delivered by pumps to permit independent adjustments of each infusion rate, depending on hourly variation of blood glucose values. There are a number of different algorithms available for insulin infusions (see http://www.hospitalmedicine.org).
After surgery, when the patient has resumed an adequate oral intake, subcutaneous administration of insulin can be resumed and intravenous administration of insulin and dextrose can be stopped 30 minutes after the first subcutaneous dose. Insulin needs may vary in the first several days after surgery because of continuing postoperative stresses and because of variable caloric intake. In this situation, multiple doses of short-acting insulin plus some long-acting basal insulin, guided by blood glucose determinations, can keep the patient in acceptable metabolic control.
In the intensive care units (ICUs), glucose levels are controlled most frequently using insulin infusions. Patients receiving total parenteral nutrition can have insulin added to the bag. Standard total parenteral nutrition contains 25% dextrose so an infusion rate of 50 mL/h delivers 12.5 g of dextrose per hour.
On the general surgical and medical wards, most patients are treated with subcutaneous insulin regimens. Limited cross-sectional and prospective studies suggest that the best glucose control is achieved on a combination of basal and bolus regimen with 50% of daily insulin needs provided by intermediate- or long-acting insulins. Standardized order sets prompt medical personnel to write more physiologic insulin orders; they can reduce errors; and they often include algorithms for recognition and treatment of hypoglycemia (see http://ucsfinpatientdiabetes.pbworks.com for examples).
The morbidity and mortality in diabetic patients is twice that of nondiabetic patients. Those with new-onset hyperglycemia (ie, those without a preadmission diagnosis of diabetes) have even higher mortality—almost eightfold that of nondiabetic patients in one study. These observations have led to the question of whether tight glycemic control in the hospital improves outcomes.
A prospective trial in surgical ICU patients (Leuven 1 study) reported that aggressive treatment of hyperglycemia (defined as blood glucose > 110 mg/dL [6.1 mmol/L]) reduced mortality and morbidity. Only a small number of persons in this study (204 of 1548) had a diagnosis of diabetes preoperatively, and so this study suggests that controlling hyperglycemia per se (independent of a diagnosis of diabetes) was beneficial. The benefits, however, were principally seen in patients who were in the ICU for longer than 5 days, and it is unclear whether the benefits also apply to most surgical patients who stay in the ICU for only 1 to 2 days.
The same investigators performed a similar prospective trial among 1200 medical ICU patients (Leuven 2 study) and reported that aggressive treatment of hyperglycemia reduced morbidity (decreased acquired kidney injury and increased early weaning from mechanical ventilation) but not mortality. Again, as in the surgical ICU study, only a small number of persons (16.9%) had a diagnosis of diabetes at admission.
The findings of the Leuven studies, however, have not been confirmed by other prospective studies. Two other ICU-based studies (Glucontrol and VISEP) that attempted to confirm the findings were unable to do so. Both studies were stopped prematurely, however. The Glucontrol study was stopped because an interim analysis (falsely) suggested increased mortality in the test group; and the VISEP study was stopped because of seven-fold increase in hypoglycemic events in the intensively treated group. A large multicenter, multinational study (NICE-SUGAR) recruited 6104 surgical and medical ICU patients with hyperglycemia (20% had diabetes) and randomized them to tight control (blood glucose levels of 81–108 mg/dL [4.5–6 mmol/L]) or less tight control (glucose levels < 180 mg/dL [< 10 mmol/L]). The tight group achieved blood glucose levels of 115 ± 18 mg/dL (6.4 ± 1.0 mmol/L) and the conventional group, 144 ± 23 mg/dL (8 ± 1.3 mmol/L). There were more deaths (829 versus 751 deaths) in the tight glucose control group compared with the less tight glucose control group (P = 0.02). The excess deaths in the intensive group were due to cardiovascular events. The intensively treated group also had more cases of severe hypoglycemia (206 versus 15 cases).
A study on tight intraoperative glycemic control during cardiac surgery also failed to show any benefit; if anything, the intensively treated group had more events. The United Kingdom Glucose Insulin in Stroke Trial (GIST-UK) failed to show beneficial effect of tight glycemic control in stroke patients; however, the investigators acknowledged that, because of slow recruitment, the study was underpowered.
Thus, based on the evidence available, ICU patients with diabetes and new-onset hyperglycemia with blood glucose levels above 180 mg/dL (10 mmol/L) should be treated with insulin, aiming for target glucose levels between 140 mg/dL (7.8 mmol/L) and 180 mg/dL (10 mmol/L). In the ICU setting, aiming for blood glucose levels close to 100 mg/dL (5.6 mmol/L) is not beneficial and may even be harmful. When patients leave the ICU, target glucose values between 100 mg/dL (5.6 mmol/L) and 180 mg/dL (10 mmol/L) may be appropriate, although this view is based on clinical observations rather than conclusive evidence.
Tight glycemic control with normal HbA1c levels is very important during pregnancy. Early in pregnancy, poor control increases the risk of spontaneous abortion and congenital malformations. Late in pregnancy, poor control can result in polyhydramnios, preterm labor, stillbirth, and fetal macrosomia with its associated problems. Diabetes complications can impact both maternal and fetal health. Diabetic retinopathy can first develop during pregnancy or retinopathy that is already present can worsen. Diabetic women with microalbuminuria can have worsening albuminuria during pregnancy and are at higher risk for preeclampsia. Patients who have preexisting kidney failure (prepregnancy creatinine clearance < 80 mL/min) are at high risk for further decline in kidney function during the pregnancy, and this may not reverse after delivery. Diabetic gastroparesis can severely exacerbate the nausea and vomiting of pregnancy and some patients may require fluid and nutritional support.
Although there is evidence that glyburide is safe during pregnancy, the current practice is to control diabetes with insulin therapy. Every effort should be made, utilizing multiple injections of insulin or a continuous infusion of insulin by pump, to maintain near-normalization of fasting and preprandial blood glucose values while avoiding hypoglycemia. The fast-acting insulin analogs insulin aspart and insulin lispro can be used, but data on using the long-acting insulin analogs are limited. A small study using insulin glargine in 32 pregnancies did not reveal any problems. There are no data on insulin detemir use in pregnancy. NPH is currently the preferred intermediate insulin for basal coverage during pregnancy.
Unless there are fetal or maternal complications, diabetic women should be able to carry the pregnancy to full-term, delivering at 38 to 41 weeks. Induction of labor before 39 weeks may be considered if there is concern about increasing fetal weight. See Chapter 19 for further details.
Ballas J et al. Management of diabetes in pregnancy. Curr Diab Rep. 2012 Feb;12(1):33–42. [PMID: 22139557]
Kansagara D et al. Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med. 2011 Feb 15;154(4):268–82. [PMID: 21320942]
The DCCT showed that the previously poor prognosis for as many as 40% of patients with type 1 diabetes is markedly improved by optimal care. DCCT participants were generally young and highly motivated and were cared for in academic centers by skilled diabetes educators and endocrinologists who were able to provide more attention and services than are usually available. Improved training of primary care providers may be beneficial.
For type 2 diabetes, the UKPDS documented a reduction in microvascular disease with glycemic control, although this was not apparent in the obese subgroup. Cardiovascular outcomes were not improved by glycemic control, although antihypertensive therapy showed benefit in reducing the number of adverse cardiovascular complications as well as in reducing the occurrence of microvascular disease among hypertensive patients. In patients with visceral obesity, successful management of type 2 diabetes remains a major challenge in the attempt to achieve appropriate control of hyperglycemia, hypertension, and dyslipidemia. Once safe and effective methods are devised to prevent or manage obesity, the prognosis of type 2 diabetes with its high cardiovascular risks should improve considerably.
In addition to poorly understood genetic factors relating to differences in individual susceptibility to development of long-term complications of hyperglycemia, it is clear that in both types of diabetes, the diabetic patient’s intelligence, motivation, and awareness of the potential complications of the disease contribute significantly to the ultimate outcome.
When to Refer
American Association of Diabetes Educators http://www.aadenet.org/
American Diabetes Association http://www.diabetes.org/home
American Diabetes Association. Standards of Medical Care in Diabetes—2013. Diabetes Care. 2013 Jan;36(Suppl 1):S11–66. [PMID: 23264422]
American Dietetic Association http://www.eatright.org
Juvenile Diabetes Foundation http://www.jdf.org/index.html
Coma may be due to a variety of causes not directly related to diabetes. Certain causes directly related to diabetes require differentiation: (1) Hypoglycemic coma resulting from excessive doses of insulin or oral hypoglycemic agents. (2) Hyperglycemic coma associated with either severe insulin deficiency (diabetic ketoacidosis) or mild to moderate insulin deficiency (hyperglycemic hyperosmolar state). (3) Lactic acidosis associated with diabetes, particularly in diabetics stricken with severe infections or with cardiovascular collapse.
ESSENTIALS OF DIAGNOSIS
Hyperglycemia > 250 mg/dL (13.9 mmol/L).
Acidosis with blood pH < 7.3.
Serum bicarbonate < 15 mEq/L.
Serum positive for ketones.
Diabetic ketoacidosis may be the initial manifestation of type 1 diabetes or may result from increased insulin requirements in type 1 diabetes patients during the course of infection, trauma, myocardial infarction, or surgery. It is a life-threatening medical emergency with a mortality rate just under 5% in individuals under 40 years of age, but with a more serious prognosis in the elderly, who have mortality rates over 20%. The National Data Group reports an annual incidence of five to eight episodes of diabetic ketoacidosis per 1000 diabetic persons. Ketoacidosis may develop in patients with type 2 diabetes when severe stress such as sepsis or trauma is present. Diabetic ketoacidosis has been found to be one of the more common serious complications of insulin pump therapy, occurring in approximately 1 per 80 patient-months of treatment. Many patients who monitor capillary blood glucose regularly ignore urine ketone measurements, which would signal the possibility of insulin leakage or pump failure before serious illness develops. Poor compliance, either for psychological reasons or because of inadequate education, is one of the most common causes of diabetic ketoacidosis, particularly when episodes are recurrent.
The appearance of diabetic ketoacidosis is usually preceded by a day or more of polyuria and polydipsia associated with marked fatigue, nausea, and vomiting. If untreated, mental stupor ensues that can progress to coma. Drowsiness is fairly common but frank coma only occurs in about 10% of patients. On physical examination, evidence of dehydration in a stuporous patient with rapid deep breathing anda “fruity” breath odor of acetone would strongly suggest the diagnosis. Hypotension with tachycardia indicates profound fluid and electrolyte depletion, and mild hypothermia is usually present. Abdominal pain and even tenderness may be present in the absence of abdominal disease. Conversely, cholecystitis or pancreatitis may occur with minimal symptoms and signs.
(Table 27–11.) Typically, the patient with moderately severe diabetic ketoacidosis has a plasma glucose of 350–900 mg/dL (19.4–50 mmol/L), serum ketones at a dilution of 1:8 or greater, hyperkalemia (serum potassium level of 5–8 mEq/L), slight hyponatremia (serum sodium of approximately 130 mEq/L), hyperphosphatemia (serum phosphate level of 6–7 mg/dL [1.9–2.3 mmol/L]), and elevated blood urea nitrogen and serum creatinine levels. Acidosis may be severe (pH ranging from 6.9 to 7.2, and serum bicarbonate ranging from 5 mEq/L to 15 mEq/L); Pco2 is low (15–20 mm Hg) related to hyperventilation. Fluid depletion is marked, typically about 100 mL/kg.
Table 27–11. Laboratory diagnosis of coma in diabetic patients.
The hyperkalemia occurs despite total body potassium depletion because of the shift of potassium from the intracellular to extracellular spaces that occurs in systemic acidosis. The average total body potassium deficit resulting from osmotic diuresis, acidosis, and gastrointestinal losses is about 3–5 mEq/kg. Similarly, despite the elevated serum phosphate, total body phosphate is generally depleted. Serum sodium is generally reduced due to loss of sodium ions (7–10 mEq/kg) by polyuria and vomiting and because severe hyperglycemia shifts intracellular water into the interstitial compartment. There is some controversy about the correction factor for the serum sodium in the presence of hyperglycemia. Many guidelines recommend a correction factor, whereby the serum sodium concentration decreases by 1.6 mEq/L for every 100 mg/dL (5.56 mmol/L) rise in plasma glucose above normal, but there is evidence that the decrease may be greater when patients have more severe hyperglycemia (greater than 400 mg/dL or 22.2 mmol/L) and/or volume depletion. One group has suggested (based on short-term exposure of normal volunteers to markedly elevated glucose levels) that, when the serum glucose is greater than 200 mg/dL (11.1 mmol/L), the serum sodium concentration decreases by at least 2.4 mEq/L. Serum osmolality can be directly measured by standard tests of freezing point depression or can be estimated by calculating the molarity of sodium, chloride, and glucose in the serum. A convenient method of estimating effective serum osmolality is as follows (normal values in humans are 280–300 mosm/kg):
These calculated estimates are usually 10–20 mosm/kg lower than values measured by standard cryoscopic techniques. Central nervous system depression or coma occurs when the effective serum osmolality exceeds 320–330 mosm/L. Coma in a diabetic patient with a lower osmolality should prompt a search for cause of coma other than hyperosmolality (see Chapter 21).
Blood urea nitrogen and serum creatinine are invariably elevated because of dehydration. In some automated creatinine assays, serum creatinine can be falsely elevated by nonspecific chromogenicity of keto acids and glucose. Most laboratories, however, now routinely eliminate this interference.
Ketoacidemia represents the effect of insulin lack at multiple enzyme loci. Insulin lack associated with elevated levels of growth hormone, catecholamines, and glucagon contributes to increases in lipolysis from adipose tissue and in hepatic ketogenesis. In addition, reduced ketolysis by insulin-deficient peripheral tissues contributes to the ketoacidemia. The only true “keto” acid present is acetoacetic acid which, along with its by-product acetone, is measured by nitroprusside reagents (Acetest and Ketostix). The sensitivity for acetone, however, is poor, requiring over 10 mmol/L, which is seldom reached in the plasma of ketoacidotic patients—although this detectable concentration is readily achieved in urine. Thus, in the plasma of ketotic patients, only acetoacetate is measured by these reagents. The more prevalent beta-hydroxybutyric acid has no ketone group and is therefore not detected by conventional nitroprusside tests. This takes on special importance in the presence of circulatory collapse during diabetic ketoacidosis, wherein an increase in lactic acid can shift the redox state to increase beta-hydroxybutyric acid at the expense of the readily detectable acetoacetic acid. Bedside diagnostic reagents are then unreliable, suggesting no ketonemia in cases where beta-hydroxybutyric acid is a major factor in producing the acidosis. Combined glucose and ketone meter (Precision Xtra, Nova Max Plus) that measure blood beta-hydroxybutyrate concentration on capillary blood are now available. Many clinical laboratories also offer direct blood beta-hydroxybutyrate measurement.
Elevation of serum amylase is common but often represents salivary as well as pancreatic amylase. Thus, in this setting, an elevated serum amylase is not specific for acute pancreatitis. Serum lipase may be useful if the diagnosis of acute pancreatitis is being seriously considered. Leukocytosis as high as 25,000/mcL with a left shift may occur with or without associated infection. The presence of an elevated or even a normal temperature would suggest the presence of an infection, since patients with diabetic ketoacidosis are generally hypothermic if uninfected.
Patients with mild diabetic ketoacidosis are alert and have pH levels between 7.25 and 7.30; those with moderate ketoacidosis have pH levels between 7.0 and 7.24 and are either alert or little drowsy; and those with severe ketoacidosis are stuporose and have a pH < 7.0. Those with mild ketoacidosis can be treated in the emergency department, but those with moderate or severe ketoacidosis require admission to the ICU or step-down unit. Therapeutic goals are to restore plasma volume and tissue perfusion, reduce blood glucose and osmolality toward normal, correct acidosis, replenish electrolyte losses, and identify and treat precipitating factors. Gastric intubation is recommended in the comatose patient to prevent vomiting and aspiration that may occur as a result of gastric atony, a common complication of diabetic ketoacidosis. An indwelling catheter may also be necessary. In patients with preexisting cardiac or renal failure or those in severe cardiovascular collapse, a central venous pressure catheter or a Swan-Ganz catheter should be inserted to evaluate the degree of hypovolemia and to monitor subsequent fluid administration.
A comprehensive flow sheet that includes vital signs, serial laboratory data, and therapeutic interventions (eg, fluids, insulin) should be meticulously maintained by the clinician responsible for the patient’s care. Plasma glucose should be recorded hourly and electrolytes and pH at least every 2–3 hours during the initial treatment period. Bedside glucose meters should be used to titrate the insulin therapy. The patient should not receive sedatives or opioids in order to avoid masking signs and symptoms of impeding cerebral edema.
In most patients, the fluid deficit is 4–5 L. Initially, 0.9% saline solution is the solution of choice to help reexpand the contracted vascular volume and should be started in the emergency department as soon as the diagnosis is established. The saline should be infused rapidly to provide 1 L/h over the first 1–2 hours. After the first 2 L of fluid have been given, the intravenous infusion should be at the rate of 300–400 mL/h. Use 0.9% (“normal”) saline unless the serum sodium is> 150 mEq/L, when 0.45% (“half normal”) saline solution should be used. The volume status should be very carefully monitored. Failure to give enough volume replacement (at least 3–4 L in 8 hours) to restore normal perfusion is one of the most serious therapeutic short-comings adversely influencing satisfactory recovery. Excessive fluid replacement (more than 5 L in 8 hours) may contribute to acute respiratory distress syndrome or cerebral edema. When blood glucose falls to approximately 250 mg/dL (13.9 mmol/L), the fluids should be changed to a 5% glucose-containing solution to maintain serum glucose in the range of 250–300 mg/dL (13.9–16.7 mmol/L). This will prevent the development of hypoglycemia and will also reduce the likelihood of cerebral edema, which could result from too rapid decline of blood glucose.
Immediately after initiation of fluid replacement, regular insulin should be given intravenously in a loading dose of 0.1 unit/kg as a bolus to prime the tissue insulin receptors. Following the initial bolus, intravenous doses of insulin as low as 0.1 unit/kg/h are continuously infused or given hourly as an intramuscular injection; this is sufficient to replace the insulin deficit in most patients. A prospective randomized study showed that a bolus dose is not required if patients are given hourly insulin infusion at 0.14 unit/kg. Replacement of insulin deficiency helps correct the acidosis by reducing the flux of fatty acids to the liver, reducing ketone production by the liver, and also improving removal of ketones from the blood. Insulin treatment reduces the hyperosmolality by reducing the hyperglycemia. It accomplishes this by increasing removal of glucose through peripheral utilization as well as by decreasing production of glucose by the liver. This latter effect is accomplished by direct inhibition of gluconeogenesis and glycogenolysis as well as by lowered amino acid flux from muscle to liver and reduced hyperglucagonemia.
The insulin dose should be “piggy-backed” into the fluid line so the rate of fluid replacement can be changed without altering the insulin delivery rate. If the plasma glucose level fails to fall at least 10% in the first hour, a repeat loading dose (0.1 or 0.14 unit/kg) is recommended. The availability of bedside glucometers and of laboratory instruments for rapid and accurate glucose analysis (Beckman or Yellow Springs glucose analyzer) has contributed much to achieving optimal insulin replacement. Rarely, a patient with immune insulin resistance is encountered, and this requires doubling the insulin dose every 2–4 hours if hyperglycemia does not improve after the first two doses of insulin. The insulin dose should be adjusted to lower the glucose concentration by about 50–70 mg/dL (2.8–3.9 mmol/L).
Total body potassium loss from polyuria and vomiting may be as high as 200 mEq. However, because of shifts of potassium from cells into the extracellular space as a consequence of acidosis, serum potassium is usually normal to slightly elevated prior to institution of treatment. As the acidosis is corrected, potassium flows back into the cells, and hypokalemia can develop if potassium replacement is not instituted. If the patient is not uremic and has an adequate urinary output, potassium chloride in doses of 10–30 mEq/h should be infused during the second and third hours after beginning therapy as soon as the acidosis starts to resolve. Replacement should be started sooner if the initial serum potassium is inappropriately normal or low and should be delayed if serum potassium fails to respond to initial therapy and remains above 5 mEq/L, as in cases of chronic kidney disease. Occasionally, a patient may present with a serum potassium level < 3.5 mEq/L, in which case insulin therapy should be delayed until the potassium level is corrected to > 3.5 mEq/L. An ECG can be of help in monitoring the patient’s potassium status: High peaked T waves are a sign of hyperkalemia, and flattened T waves with U waves are a sign of hypokalemia. Foods high in potassium content should be prescribed when the patient has recovered sufficiently to take food orally. Tomato juice has 14 mEq of potassium per 240 mL, and a medium-sized banana provides about 10 mEq.
The use of sodium bicarbonate in management of diabetic ketoacidosis has been questioned since clinical benefit was not demonstrated in one prospective randomized trial and because of the following potentially harmful consequences: (1) development of hypokalemia from rapid shift of potassium into cells if the acidosis is overcorrected; (2) tissue anoxia from reduced dissociation of oxygen from hemoglobin when acidosis is rapidly reversed (leftward shift of the oxygen dissociation curve); and (3) cerebral acidosis resulting from lowering of cerebrospinal fluid pH. It must be emphasized, however, that these considerations are less important when very severe acidosis exists. Therefore, it is recommended that bicarbonate be administered to diabetic patients in ketoacidosis if the arterial blood pH is 7.0 or less, with careful monitoring to prevent overcorrection. One or two ampules of sodium bicarbonate (one ampule contains 44 mEq/50 mL) should be added to 1 L of 0.45% saline. (Note: Addition of sodium bicarbonate to 0.9% saline would produce a markedly hypertonic solution that could aggravate the hyperosmolar state already present.) This should be administered rapidly (over the first hour). It can be repeated until the arterial pH reaches 7.1, but it should not be given if the pH is 7.1 or greater since additional bicarbonate would increase the risk of rebound metabolic alkalosis as ketones are metabolized. Alkalosis shifts potassium from serum into cells, which could precipitate a fatal cardiac arrhythmia.
Phosphate replacement is seldom required in treating diabetic ketoacidosis. However, if severe hypophosphatemia of < 1 mg/dL (< 0.32 mmol/L) develops during insulin therapy, a small amount of phosphate can be replaced per hour as the potassium salt. Correction of hypophosphatemia helps restore the buffering capacity of the plasma, thereby facilitating renal excretion of hydrogen. It also corrects the impaired oxygen dissociation from hemoglobin by regenerating 2,3-diphosphoglycerate. However, three randomized studies in which phosphate was replaced in patients with diabetic ketoacidosis did not show any apparent clinical benefit from phosphate administration. Moreover, attempts to use potassium phosphate as the sole means of replacing potassium have led to a number of reported cases of severe hypocalcemia with tetany. To minimize the risk of inducing tetany from too-rapid replacement of phosphate, the average deficit of 40–50 mmol of phosphate should be replaced intravenously at a rate no > 3–4 mmol/h in a 60–70-kg person. A stock solution (Abbott) provides a mixture of 1.12 g KH2PO4 and 1.18 g K2HPO4 in a 5-mL single-dose vial (this equals 22 mmol of potassium and 15 mmol of phosphate). One-half of this vial (2.5 mL) should be added to 1 L of either 0.45% saline or 5% dextrose in water. Two liters of this solution, infused at a rate of 400 mL/h, will correct the phosphate deficit at the optimal rate of 3 mmol/h while providing 4.4 mEq of potassium per hour. (Additional potassium should be administered as potassium chloride to provide a total of 10–30 mEq of potassium per hour, as noted above.) If the serum phosphate remains below 2.5 mg/dL (0.8 mmol/L) after this infusion, a repeat 5-hour infusion can be given.
Because of the considerable loss of keto acids in the urine during the initial phase of therapy, substrate for subsequent regeneration of bicarbonate is lost and correction of the total bicarbonate deficit is hampered. A portion of the bicarbonate deficit is replaced with chloride ions infused in large amounts as saline to correct the dehydration. In most patients, as the ketoacidosis clears during insulin replacement, a hyperchloremic, low-bicarbonate pattern emerges with a normal anion gap. This is a relatively benign condition that reverses itself over the subsequent 12–24 hours once intravenous saline is no longer being administered. Using a balanced electrolyte solution similar to serum in chloride concentration and pH during resuscitation instead of normal saline has been reported to prevent the hyperchloremic acidosis.
Antibiotics are prescribed as indicated. Cholecystitis and pyelonephritis may be particularly severe in these patients.
Once the diabetic ketoacidosis is controlled and the patient is awake and able to eat, subcutaneous insulin therapy can be initiated. The patient with type 1 diabetes may have persistent significant tissue insulin resistance and may require a total daily insulin dose of approximately 0.6 units/kg. The amount of insulin required in the previous 8 hours can also be helpful in estimating the initial insulin doses. Half the total daily dose can be given as a long-acting basal insulin and the other half as short-acting insulin premeals. The patient should receive subcutaneous basal insulin and rapid-acting insulin analog with the first meal and the insulin infusion discontinued an hour later. The overlap of the subcutaneous insulin action and insulin infusion is necessary to prevent relapse of the diabetic ketoacidosis. The increased insulin resistance is only present for a few days, and it is important to reduce both the basal and bolus insulins to avoid hypoglycemia. A patient with new-onset type 1 diabetes usually still has significant beta cell function and may not need any basal insulin and only very low doses of rapid-acting insulin before meals after recovery from the ketoacidosis. Patients with type 2 diabetes and diabetes ketoacidosis due to severe illness may initially require insulin therapy but can often transition back to oral agents during outpatient follow-up.
Low-dose insulin infusion and fluid and electrolyte replacement combined with careful monitoring of patients’ clinical and laboratory responses to therapy have dramatically reduced the mortality rates of diabetic ketoacidosis to < 5%. However, this complication remains a significant risk in the aged who have mortality rates > 20% and in patients in profound coma in whom treatment has been delayed. Acute myocardial infarction and infarction of the bowel following prolonged hypotension worsen the outlook. A serious prognostic sign is end-stage chronic kidney disease, and prior kidney dysfunction worsens the prognosis considerably because the kidney plays a key role in compensating for massive pH and electrolyte abnormalities. Symptomatic cerebral edema occurs primarily in the pediatric population. Risk factors for its development include severe baseline acidosis, rapid correction of hyperglycemia, and excess volume administration in the first 4 hours. Onset of headache or deterioration in mental status during treatment should lead to consideration of this complication. Intravenous mannitol at a dosage of 1–2 g/kg given over 15 minutes is the mainstay of treatment. Excess crystalloid infusion can precipitate pulmonary edema. Acute respiratory distress syndrome is a rare complication of treatment of diabetic ketoacidosis.
After recovery and stabilization, patients should be instructed on how to recognize the early symptoms and signs of ketoacidosis. Urine ketones or capillary blood beta-hydroxybutyrate should be measured in patients with signs of infection or in insulin pump-treated patients when capillary blood glucose remains unexpectedly and persistently high. When heavy ketonuria and glycosuria persist on several successive examinations, supplemental rapid acting insulin should be administered and liquid foods such as lightly salted tomato juice and broth should be ingested to replenish fluids and electrolytes. The patient should be instructed to contact the clinician if ketonuria persists, and especially if there is vomiting and inability to keep down fluids. Recurrent episodes of severe ketoacidosis often indicate poor compliance with the insulin regimen, and these patients will require intensive counseling.
Savage MW et al. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabet Med. 2011 May;28(5):508–15. [PMID: 21255074]
HYPERGLYCEMIC HYPEROSMOLAR STATE
ESSENTIALS OF DIAGNOSIS
Hyperglycemia > 600 mg/dL (33.3 mmol/L).
Serum osmolality > 310 mosm/kg.
No acidosis; blood pH above 7.3.
Serum bicarbonate > 15 mEq/L.
Normal anion gap (< 14 mEq/L)
This second most common form of hyperglycemic coma is characterized by severe hyperglycemia in the absence of significant ketosis, with hyperosmolality and dehydration. It occurs in patients with mild or occult diabetes, and most patients are typically middle-aged to elderly. Accurate figures are not available as to its true incidence, but from data on hospital discharges it is rarer than diabetic ketoacidosis even in older age groups. Underlying chronic kidney disease or heart failure is common, and the presence of either worsens the prognosis. A precipitating event such as infection, myocardial infarction, stroke, or recent operation is often present. Certain medications such as phenytoin, diazoxide, corticosteroids, and diuretics have been implicated in its pathogenesis, as have procedures associated with glucose loading such as peritoneal dialysis.
A partial or relative insulin deficiency may initiate the syndrome by reducing glucose utilization of muscle, fat, and liver while inducing hyperglucagonemia and increasing hepatic glucose output. With massive glycosuria, obligatory water loss ensues. If a patient is unable to maintain adequate fluid intake because of an associated acute or chronic illness or has suffered excessive fluid loss, marked dehydration results. As the plasma volume contracts, kidney function becomes impaired, limiting the urinary glucose losses and exacerbating the hyperglycemia. Severe hyperosmolality develops that causes mental confusion and finally coma. It is not clear why ketosis is virtually absent under these conditions of insulin insufficiency, although reduced levels of growth hormone may be a factor, along with portal vein insulin concentrations sufficient to restrain ketogenesis.
Onset may be insidious over a period of days or weeks, with weakness, polyuria, and polydipsia. The lack of features of ketoacidosis may retard recognition of the syndrome and delay therapy until dehydration becomes more profound than in ketoacidosis. Reduced intake of fluid is not an uncommon historical feature, due to either inappropriate lack of thirst, nausea, or inaccessibility of fluids to elderly, bedridden patients. Lethargy and confusion develop as serum osmolality exceeds 310 mosm/kg, and convulsions and coma can occur if osmolality exceeds 320–330 mosm/kg. Physical examination confirms the presence of profound dehydration in a lethargic or comatose patient without Kussmaul respirations.
(Table 27–11.) Severe hyperglycemia is present, with blood glucose values ranging from 800 mg/dL to 2400 mg/dL (44.4 mmol/L to 133.2 mmol/L). In mild cases, where dehydration is less severe, dilutional hyponatremia as well as urinary sodium losses may reduce serum sodium to 120–125 mEq/L, which protects to some extent against extreme hyperosmolality. However, as dehydration progresses, serum sodium can exceed 140 mEq/L, producing serum osmolality readings of 330–440 mosm/kg. Ketosis and acidosis are usually absent or mild. Prerenal azotemia is the rule, with serum urea nitrogen elevations over 100 mg/dL (35.7 mmol/L) being typical.
Fluid replacement is of paramount importance in treating nonketotic hyperglycemic coma. The onset of hyperosmolarity is more insidious in elderly people without ketosis than in younger individuals with high serum ketone levels, which provide earlier indicators of severe illness (vomiting, rapid deep breathing, acetone odor, etc). Consequently, diagnosis and treatment are often delayed until fluid deficit has reached levels of 6–10 L.
If hypovolemia is present as evidenced by hypotension and oliguria, fluid therapy should be initiated with 0.9% saline. In all other cases, 0.45% saline appears to be preferable as the initial replacement solution because the body fluids of these patients are markedly hyperosmolar. As much as 4–6 L of fluid may be required in the first 8–10 hours. Careful monitoring of the patient is required for proper sodium and water replacement. Once blood glucose reaches 250 mg/dL (13.9 mmol/L), fluid replacement should include 5% dextrose in either water, 0.45% saline solution, or 0.9% saline solution. The rate of dextrose infusion should be adjusted to maintain glycemic levels of 250–300 mg/dL (13.9–16.7 mmol/L) in order to reduce the risk of cerebral edema. An important end point of fluid therapy is to restore urinary output to 50 mL/h or more.
Less insulin may be required to reduce the hyperglycemia in nonketotic patients as compared to those with diabetic ketoacidotic coma. In fact, fluid replacement alone can reduce hyperglycemia considerably by correcting the hypovolemia, which then increases both glomerular filtration and renal excretion of glucose. An initial insulin dose of 0.1 unit/kg is followed by an insulin infusion of 0.1 units/kg/h (or just an infusion of 0.14 units/kg/h without a bolus), which is titrated to lower blood glucose levels by 50–70 mg/dL per hour (2.8–3.9 mmol/L/h). Once the patient has stabilized and the blood glucose falls to around 250 mg/dL (13.9 mmol/L), insulin can be given subcutaneously.
With the absence of acidosis, there may be no initial hyperkalemia unless associated end-stage chronic kidney disease is present. This results in less severe total potassium depletion than in diabetic ketoacidosis, and less potassium replacement is therefore needed. However, because initial serum potassium is usually not elevated and because it declines rapidly as a result of insulin’s effect on driving potassium intracellularly, it has been recommended that potassium replacement be initiated earlier than in ketotic patients, assuming that no chronic kidney disease or oliguria is present. Potassium chloride (10 mEq/L) can be added to the initial bottle of fluids administered if the patient’s serum potassium is not elevated.
If severe hypophosphatemia (serum phosphate < 1 mg/dL [<0.32 mmol/L]) develops during insulin therapy, phosphate replacement can be given as described for ketoacidotic patients (at 3 mmol/h).
The severe dehydration and low output state may predispose the patient to complications such as myocardial infarction, stroke, pulmonary embolism, mesenteric vein thrombosis, and disseminated intravascular coagulation. Fluid replacement remains the primary approach to the prevention of these complications. Low-dose heparin prophylaxis is reasonable but benefits of routine anticoagulation remain doubtful. Rhabdomyolysis is a recognized complication and should be looked for and treated.
The overall mortality rate of hyperglycemic hyperosmolar state coma is more than ten times that of diabetic ketoacidosis, chiefly because of its higher incidence in older patients, who may have compromised cardiovascular systems or associated major illnesses and whose dehydration is often excessive because of delays in recognition and treatment. (When patients are matched for age, the prognoses of these two hyperglycemic emergencies are reasonably comparable.) When prompt therapy is instituted, the mortality rate can be reduced from nearly 50% to that related to the severity of coexistent disorders.
After the patient is stabilized, the appropriate form of long-term management of the diabetes must be determined. Insulin treatment should be continued for a few weeks but patients usually recover sufficient endogenous insulin secretion to make a trial of diet or diet plus oral agents worthwhile. When the episode occurs in a patient who has known diabetes, then education of the patient and caregivers should be instituted. They should be taught how to recognize situations (nausea and vomiting, infection) that predispose to recurrence of the hyperglycemic, hyperosmolar state, as well as detailed information on how to prevent the escalating dehydration that culminates in hyperosmolar coma (small sips of sugar-free liquids, increase in usual hypoglycemic therapy, or early contact with the clinician).
Nyenwe EA et al. Evidence-based management of hyperglycemic emergencies in diabetes mellitus. Diabetes Res Clin Pract. 2011 Dec;94(3):340–51. [PMID: 21978840]
ESSENTIALS OF DIAGNOSIS
Severe acidosis with hyperventilation.
Blood pH below 7.30.
Serum bicarbonate < 15 mEq/L.
Anion gap > 15 mEq/L.
Absent serum ketones.
Serum lactate > 5 mmol/L
Lactic acidosis is characterized by accumulation of excess lactic acid in the blood. Normally, the principal sources of this acid are the erythrocytes (which lack enzymes for aerobic oxidation), skeletal muscle, skin, and brain. Conversion of lactic acid to glucose and its oxidation principally by the liver but also by the kidneys represent the chief pathways for its removal. Overproduction of lactic acid (tissue hypoxia), deficient removal (hepatic failure), or both (circulatory collapse) can cause accumulation. Lactic acidosis is not uncommon in any severely ill patient suffering from cardiac decompensation, respiratory or hepatic failure, septicemia, or infarction of bowel or extremities. Lactic acidosis in patients with diabetes mellitus is uncommon but occasionally occurs in metformin-treated patients (see above) and it still must be considered in the acidotic diabetic patient, especially if the individual is seriously ill. Most cases of metformin-associated lactic acidosis occur in patients in whom there were contraindications to the use of metformin, in particular kidney failure.
The main clinical feature of lactic acidosis is marked hyperventilation. When lactic acidosis is secondary to tissue hypoxia or vascular collapse, the clinical presentation is variable, being that of the prevailing catastrophic illness. However, in the idiopathic, or spontaneous, variety, the onset is rapid (usually over a few hours), blood pressure is normal, peripheral circulation is good, and there is no cyanosis.
Plasma bicarbonate and blood pH are quite low, indicating the presence of severe metabolic acidosis. Ketones are usually absent from plasma and urine or at least not prominent. The first clue may be a high anion gap (serum sodium minus the sum of chloride and bicarbonate anions [in mEq/L] should be no> 15). A higher value indicates the existence of an abnormal compartment of anions. If this cannot be clinically explained by an excess of keto acids (diabetes), inorganic acids (uremia), or anions from medication overdosage (salicylates, methyl alcohol, ethylene glycol), then lactic acidosis is probably the correct diagnosis. (See also Chapter 21.) In the absence of azotemia, hyperphosphatemia may be a clue to the presence of lactic acidosis for reasons that are not clear. The diagnosis is confirmed by demonstrating, in a sample of blood that is promptly chilled and separated, a plasma lactic acid concentration of 5 mmol/L or higher (values as high as 30 mmol/L have been reported). Normal plasma values average 1 mmol/L, with a normal lactate/pyruvate ratio of 10:1. This ratio is greatly exceeded in lactic acidosis.1
Aggressive treatment of the precipitating cause of lactic acidosis is the main component of therapy, such as ensuring adequate oxygenation and vascular perfusion of tissues. Empiric antibiotic coverage for sepsis should be given after culture samples are obtained in any patient in whom the cause of the lactic acidosis is not apparent.
Alkalinization with intravenous sodium bicarbonate to keep the pH above 7.2 has been recommended by some in the emergency treatment of lactic acidosis; as much as 2000 mEq in 24 hours has been used. However, there is no evidence that the mortality rate is favorably affected by administering bicarbonate, and its use remains controversial. Hemodialysis may be useful in cases where large sodium loads are poorly tolerated and in cases associated with metformin toxicity.
The mortality rate of spontaneous lactic acidosis is high. The prognosis in most cases is that of the primary disorder that produced the lactic acidosis.
Lalau JD. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf. 2010 Sep 1;33(9):727–40. [PMID: 20701406]
THE HYPOGLYCEMIC STATES
Spontaneous hypoglycemia in adults is of two principal types: fasting and postprandial. Symptoms begin at plasma glucose levels in the range of 60 mg/dL (3.3 mmol/L) and impairment of brain function at approximately 50 mg/dL (2.8 mmol/L). Fasting hypoglycemia is often subacute or chronic and usually presents with neuroglycopenia as its principal manifestation; postprandial hypoglycemia is relatively acute and is often heralded by symptoms of neurogenic autonomic discharge (sweating, palpitations, anxiety, tremulousness).
Differential Diagnosis (Table 27–12)
Table 27–12. Common causes of hypoglycemia in adults.1
Fasting hypoglycemia may occur in certain endocrine disorders, such as hypopituitarism, Addison disease, or myxedema; in disorders related to liver malfunction, such as acute alcoholism or liver failure; and in instances of end-stage chronic kidney disease, particularly in patients requiring dialysis. These conditions are usually obvious, with hypoglycemia being only a secondary feature. When fasting hypoglycemia is a primary manifestation developing in adults without apparent endocrine disorders or inborn metabolic diseases from childhood, the principal diagnostic possibilities include: (1) hyperinsulinism, due to either pancreatic B cell tumors, iatrogenic or surreptitious administration of insulin or sulfonylurea and (2) hypoglycemia due to extrapancreatic tumors.
Postprandial (reactive) hypoglycemia may be seen after gastrointestinal surgery and is particularly associated with the dumping syndrome after gastrectomy and Roux-en-Y gastric bypass surgery. Occult diabetes very occasionally present with postprandial hypoglycemia. Rarely, it occurs with islet cell hyperplasia—the so-called noninsulinoma pancreatogenous hypoglycemia syndrome.
Alcohol-related hypoglycemia is due to hepatic glycogen depletion combined with alcohol-mediated inhibition of gluconeogenesis. It is most common in malnourished alcohol abusers but can occur in anyone who is unable to ingest food after an acute alcoholic episode followed by gastritis and vomiting.
Immunopathologic hypoglycemia is an extremely rare condition in which anti-insulin antibodies or antibodies to insulin receptors develop spontaneously. In the former case, the mechanism appears to relate to increasing dissociation of insulin from circulating pools of bound insulin. When antibodies to insulin receptors are found, most patients do not have hypoglycemia but rather severe insulin-resistant diabetes and acanthosis nigricans. However, during the course of the disease in these patients, certain anti-insulin receptor antibodies with agonist activity mimicking insulin action may develop, producing severe hypoglycemia.
HYPOGLYCEMIA DUE TO PANCREATICB CELL TUMORS
ESSENTIALS OF DIAGNOSIS
Hypoglycemic symptoms—frequently neuroglycopenic (confusion, blurred vision, diplopia, anxiety, convulsions).
Immediate recovery upon administration of glucose.
Blood glucose < 45 mg/dL (2.5 mmol/L) with a serum insulin level of 6 microunit/mL or more.
Fasting hypoglycemia in an otherwise healthy, well-nourished adult is rare and is most commonly due to an adenoma of the islets of Langerhans. Ninety percent of such tumors are single and benign, but multiple adenomas can occur as well as malignant tumors with functional metastases. Adenomas may be familial, and multiple adenomas have been found in conjunction with tumors of the parathyroids and pituitary (MEN type 1 [MEN 1]). Over 99% of them are located within the pancreas and less than 1% in ectopic pancreatic tissue.
The most important prerequisite to diagnosing an insulinoma is simply to consider it, particularly in relatively healthy-appearing persons who have fasting hypoglycemia associated with some degree of central nervous system dysfunction such as confusion or abnormal behavior. A delay in diagnosis can result in unnecessary treatment for psychomotor epilepsy or psychiatric disorders and may cause irreversible brain damage. In long-standing cases, obesity can result as a consequence of overeating to relieve symptoms.
The so-called Whipple triad is characteristic of hypoglycemia regardless of the cause. It consists of (1) a history of hypoglycemic symptoms, (2) an associated fasting blood glucose of 45 mg/dL (2.5 mmol/L) or less, and (3) immediate recovery upon administration of glucose. The hypoglycemic symptoms in insulinoma often develop in the early morning or after missing a meal. Occasionally, they occur after exercise. They typically begin with evidence of central nervous system glucose lack and can include blurred vision or diplopia, headache, feelings of detachment, slurred speech, and weakness. Personality and mental changes vary from anxiety to psychotic behavior, and neurologic deterioration can result in convulsions or coma. Sweating and palpitations may not occur.
Hypoglycemic unawareness is very common in patients with insulinoma. They adapt to chronic hypoglycemia by increasing their efficiency in transporting glucose across the blood-brain barrier, which masks awareness that their blood glucose is approaching critically low levels. Counterregulatory hormonal responses as well as neurogenic symptoms such as tremor, sweating, and palpitations are therefore blunted during hypoglycemia. If lack of these warning symptoms prevents recognition of the need to eat to correct the problem, patients can lapse into severe hypoglycemic coma. However, symptoms and normal hormone responses during experimental insulin-induced hypoglycemia have been shown to be restored after successful surgical removal of the insulinoma. Presumably with return of euglycemia, adaptive effects on glucose transport into the brain are corrected, and thresholds of counterregulatory responses and neurogenic autonomic symptoms are therefore restored to normal.
B cell adenomas do not reduce secretion of insulin in the presence of hypoglycemia, and the critical diagnostic test is to demonstrate inappropriately elevated serum insulin, proinsulin, and C-peptide levels at a time when plasma glucose level is below 45 mg/dL.
The diagnostic criteria for insulinoma after a 72-hour fast are listed in Table 27–13. Other causes of hyperinsulinemic hypoglycemia must be considered, including factitious administration of insulin or sulfonylureas. Factitious use of insulin will result in suppression of endogenous insulin secretion and low C-peptide levels. An elevated circulating proinsulin level in the presence of fasting hypoglycemia is characteristic of most B cell adenomas and does not occur in factitious hyperinsulinism. Thus, C-peptide levels (by immunochemiluminometric assays [ICMA]) of > 200 pmol/L and proinsulin levels (by RIA) of > 5 pmol/L are characteristic of insulinomas. In patients with insulinoma, plasma beta-hydroxybutyrate levels are suppressed to 2.7 mmol/L or less. No single hormone measurement (insulin, proinsulin, C-peptide) is 100% sensitive and specific for the diagnosis of insulinoma, and insulinoma cases have been reported with insulin levels below 3 microunits/mL (ICMA assay) or proinsulin level below 5 pmol/L. Therefore, the diagnosis should be based on multiple biochemical parameters.
Table 27–13. Diagnostic criteria for insulinoma after a 72-hour fast.
In patients with epigastric distress, a history of renal calculi, or menstrual or erectile dysfunction, a serum calcium, gastrin, or prolactin level may be useful in screening for MEN 1 associated with insulinoma.
If the history is consistent with episodic spontaneous hypoglycemia, patients should be given a home blood glucose monitor and advised to monitor blood glucose levels at the time of symptoms and before consumption of carbohydrates, if this can be done safely. Patients with insulinomas frequently report fingerstick blood glucose levels between 40 mg/dL (2.2 mmol/L) and 50 mg/dL (2.8 mmol/L) at the time of symptoms. The diagnosis, however, cannot be made based on a fingerstick blood glucose. It is necessary to have a low laboratory glucose concomitantly with elevated plasma insulin, proinsulin, and C-peptide levels and a negative sulfonylurea screen. When patients give a history of symptoms after only a short period of food withdrawal or with exercise, then an outpatient assessment can be attempted. The patient should be brought by a family member to the office after an overnight fast and observed in the office. Activity such as walking should be encouraged and fingerstick blood glucose measured repeatedly during observation. If symptoms occur or fingerstick blood glucose is below 50 mg/dL (2.8 mmol/L) then samples for plasma glucose, insulin, C-peptide, proinsulin, sulfonylurea screen, serum ketones, and antibodies to insulin should be sent. If outpatient observation does not result in symptoms or hypoglycemia and if the clinical suspicion remains high, then the patient should undergo an inpatient supervised 72-hour fast. A suggested protocol for the supervised fast is shown in Table 27–14.
Table 27–14. Suggested hospital protocol for supervised fast in diagnosis of insulinoma.
In 30% of patients with insulinoma, the blood glucose levels often drop below 45 mg/dL (2.5 mmol/L) after an overnight fast, but some patients require up to 72 hours to develop symptomatic hypoglycemia. However, the term “72-hour fast” is actually a misnomer in most cases since the fast should be immediately terminated as soon as symptoms appear and laboratory confirmation of hypoglycemia is available. In normal male subjects, the blood glucose does not fall below 55–60 mg/dL (3.1–3.3 mmol/L) during a 3-day fast. In contrast, in normal premenopausal women who have fasted for only 24 hours, the plasma glucose may fall normally to such an extent that it can reach values as low as 35 mg/dL (1.9 mmol/L). In these cases, however, the women are not symptomatic, presumably owing to the development of sufficient ketonemia to supply energy needs to the brain. Insulinoma patients, on the other hand, become symptomatic when plasma glucose drops to subnormal levels, since inappropriate insulin secretion restricts ketone formation. Moreover, the demonstration of a nonsuppressed insulin level ≥ 6 microunit/mL using a RIA assay (> 3 microunit/mL using an ICMA assay) in the presence of hypoglycemia suggests the diagnosis of insulinoma. If hypoglycemia does not develop in a male patient after fasting for up to 72 hours—and particularly when this prolonged fast is terminated with a period of moderate exercise—insulinoma must be considered an unlikely diagnosis.
Stimulation with pancreatic B cell secretagogues such as tolbutamide, glucagon, or leucine has been devised to demonstrate exaggerated and prolonged insulin secretion in the presence of insulinomas. However, because insulin-secreting tumors have a wide range of granule content and degrees of differentiation, they are variably responsive to these secretagogues; and a negative response does not necessarily rule out an insulinoma. For these reasons, stimulation tests are not recommended in the diagnostic work-up of insulinoma.
An oral glucose tolerance test is of no value in the diagnosis of insulin secreting tumors. HbA1c levels may be low but there is considerable overlap with normal patients and no particular value is diagnostic.
After the diagnosis of insulinoma has been unequivocally made by clinical and laboratory findings, studies to localize the tumor should be initiated. The focus of attention should be directed to the pancreas since that is where virtually all insulinomas originate.
Because of the small size of these tumors (averaging 1.5 cm in diameter in one large series), imaging studies do not necessarily identify all of them. A pancreatic dual phase helical CT scan with thin section can identify 82–94% of the lesions. MRI scans with gadolinium can be helpful in detecting a tumor in 85% of cases. One case report suggests that diffusion-weighted MRI can be useful for detecting and localizing small insulinomas, especially for those with no hypervascular pattern. The imaging study used will depend on local availability and local radiologic skill. If the imaging study is normal, then an endoscopic ultrasound should be performed. In experienced hands, about 80–90% of tumors can be detected with this procedure. Fine-needle aspiration of the identified lesion can be attempted to confirm the presence of a neuroendocrine tumor. If the tumor is not identified or the imaging result is equivocal, then the patient should undergo selective calcium-stimulated angiography, which has been reported to localize the tumor to a particular region of the pancreas approximately about 90% of the time. In this test, angiography is combined with injections of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric arteries, and insulin levels are measured in the hepatic vein effluent. The procedure is performed after an overnight fast. Calcium gluconate 10% solution diluted to a volume of 5 mL with 0.95% saline is bolused into the selected artery at a dose of 0.0125 mmol calcium/kg (0.005 mmol calcium/kg for obese patients). Small samples of blood (5 mL) are taken from the hepatic effluent at times 0, 30, 60, 90, 120, and 180 seconds after the calcium injection. Fingerstick blood glucose levels are measured at intervals and a dextrose infusion is maintained throughout the procedure to prevent hypoglycemia. Calcium stimulates insulin release from insulinomas but not normal islets, and so a step-up from baseline in insulin levels at 30 or 60 seconds (twofold or greater) regionalizes the source of the hyperinsulinism to the head of the pancreas for the gastroduodenal artery, the uncinate process for the superior mesenteric artery, and the body and tail of the pancreas for the splenic artery calcium infusions. A less than twofold elevation of insulin in the 120-second sample may represent effects of recirculating calcium and is not considered a positive localization. In a single insulinoma, the response is in one artery alone unless the tumor resides in an area fed by two arteries or if there are multiple insulinomas (eg, in MEN 1). Patients who have diffuse islet hyperplasia (the noninsulinoma pancreatogenous hypoglycemia syndrome) will have positive responses in multiple arteries. Because diazoxide may interfere with this test, it should be discontinued for at least 48–72 hours before sampling. Patients should be closely monitored during the procedure to avoid hypoglycemia (as well as hyperglycemia, which could affect insulin gradients). These studies combined with careful intraoperative ultrasonography and palpation by a surgeon experienced in insulinoma surgery identifies up to 98% of tumors.
The treatment of choice for insulin-secreting tumors is surgical resection. While waiting for surgery, patients should be given oral diazoxide. Divided doses of 300–400 mg/d usually suffice although an occasional patient may require up to 800 mg/d. Side effects include edema due to sodium retention, gastric irritation, and mild hirsuitism. Hydrochlorothiazide, 25–50 mg daily, can be used to counteract the sodium retention and edema as well potentiate diazoxide’s hyperglycemic effect.
Tumor resection should be performed by a surgeon with experience in removing pancreatic B cell tumors. In patients with a single benign adenoma, 90–95% have a successful cure at the first surgical attempt when intraoperative ultrasound is used by a skilled surgeon. Diazoxide should be administered on the day of the surgery because it reduces the risk of hypoglycemia during surgery. Typically, it does not mask the glycemic rise indicative of surgical cure. Blood glucose should be monitored throughout surgery, and 5% or 10% dextrose infusion should be used to maintain euglycemia. In cases where the diagnosis has been established but no adenoma is located after careful palpation and use of intraoperative ultrasound, it is no longer advisable to blindly resect the body and tail of the pancreas, since a nonpalpable tumor missed by ultrasound is most likely embedded within the fleshy head of the pancreas that is left behind with subtotal resections. Most surgeons prefer to close the incision and schedule a selective arterial calcium stimulation with hepatic venous sampling to locate the tumor site prior to a repeat operation. Laparoscopy using ultrasound and enucleation has been successful with a single tumor of the body or tail of the pancreas, but open surgery remains necessary for tumors in the head of the pancreas.
In patients with inoperable functioning islet cell carcinoma and in approximately 5–10% of MEN 1 cases when subtotal removal of the pancreas has failed to produce cure, diazoxide is the treatment of choice. Frequent carbohydrate feedings (every 2 to 3 hours) can also be helpful although weight gain may become a problem. If patients are unable to tolerate diazoxide because of gastrointestinal upset, hirsutism, or edema, the calcium channel blocker verapamil may be beneficial in view of its inhibitory effect on insulin release from insulinoma cells. Octreotide, a potent long-acting synthetic octapeptide analog of somatostatin, has been used to inhibit release of hormones from a number of endocrine tumors. A dose of 50 mcg of octreotide injected subcutaneously twice daily has been tried in cases where surgery failed to remove the source of hyperinsulinism. However, its effectiveness is limited since its affinity for somatostatin receptors of the pancreatic B cell is very much less than for those of the anterior pituitary somatotrophs for which it was originally designed as treatment for acromegaly. When hypoglycemia persists after attempted surgical removal of the insulinoma and if diazoxide or verapamil is poorly tolerated or ineffective, multiple small feedings may be the only recourse. Streptozocin can decrease insulin secretion in islet cell carcinomas and increase survival. With selective arterial administration, effective cytotoxic doses have been achieved without undue renal toxicity that characterized early experience. Benign tumors appear to respond poorly, if at all.
Cryer PE et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009 Mar;94(3):709–28. [PMID: 19088155]
Mathur A et al. Insulinoma. Surg Clin North Am. 2009 Oct;89 (5):1105–21. [PMID: 19836487]
NONISLET CELL TUMOR HYPOGLYCEMIA
These rare causes of hypoglycemia include mesenchymal tumors such as retroperitoneal sarcomas, hepatocellular carcinomas, adrenocortical carcinomas, and miscellaneous epithelial-type tumors. The tumors are frequently large and readily palpated or visualized on CT scans or MRI.
In many cases the hypoglycemia is due to the expression and release of an incompletely processed insulin-like growth factor 2 (IGF-2) by the tumor. This immature form of the IGF-II molecule (pro-IGF-2 or “big IGF-2”) binds IGF-binding protein-3 (IGFBP-3) but not to the acid-labile subunit. As a consequence, this pro-IGF-II remains active and binds to insulin receptors in muscle to promote glucose transport and to insulin receptors in liver and kidney to reduce glucose output. It also binds to receptors for IGF-1 in the pancreatic B cell to inhibit insulin secretion and in the pituitary to suppress growth hormone release. With the reduction of growth hormone, there is a consequent lowering of IGF-1 levels as well as IGFBP-3 and acid-labile subunit.
The diagnosis is supported by laboratory documentation of serum insulin levels below 5 microunit/mL with plasma glucose levels of 45 mg/dL (2.5 mmol/L) or lower. Values for growth hormone and IGF-1 are also decreased. Levels of IGF-2 may be increased but often are “normal” in quantity, despite the presence of the immature, higher-molecular-weight form of IGF-2, which can only be detected by special laboratory techniques.
Not all the patients with nonislet cell tumor hypoglycemia have elevated pro-IGF-II. Ectopic insulin production has been described in bronchial carcinoma, ovarian carcinoma, and small cell carcinoma of the cervix. Hypoglycemia due to IgF-1 released from a metastatic large cell carcinoma of the lung has also been reported.
The prognosis for these tumors is generally poor, and surgical removal should be attempted when feasible. Dietary management of the hypoglycemia is the mainstay of medical treatment, since diazoxide is usually ineffective.
Bodnar TW et al. Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab. 2013 Dec 10. [Epub ahead of print] [PMID: 24423303]
de Groot JW et al. Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases. Endocr Relat Cancer. 2007 Dec;14(4):979–93. [PMID: 18045950]
Hypoglycemia sometimes develops in patients who have undergone gastric surgery (eg, gastrectomy, vagotomy, pyloroplasty, gastrojejunostomy, Nissan fundoplication, Bilroth II procedure and Roux-en-Y), especially when they consume foods containing high levels of carbohydrates. This late dumping syndrome occurs about 1–3 hours after a meal and is a result of rapid delivery of high concentration of carbohydrates in the proximal small bowel and rapid absorption of glucose. The hyperinsulinemic response to the high carbohydrate load causes hypoglycemia. The symptoms include lightheadedness, sweating, confusion and even loss of consciousness after eating a high carbohydrate meal. It is possible that gastrointestinal hormones such as GLP-1 play a role in the hyperinsulinemic response. The incidence of secondary dumping syndrome declined with the advent of medical therapy for peptic ulcer disease. There has been resurgence of cases, however, with the popularity of Roux-en-Y gastric bypass surgery for the treatment of morbid obesity. Patients typically complain of symptoms that are more severe after consumption of large amounts of readily absorbable carbohydrates. In terms of documenting hypoglycemia, it is reasonable to request the patient to consume a meal that leads to symptoms during everyday life. An oral glucose tolerance test is not recommended because many normal persons have false-positive test results. There have been case reports of insulinoma and noninsulinoma pancreatogenous hypoglycemia syndrome in patients with hypoglycemia post Roux-en-Y surgery. It is unclear how often this occurs. A careful history may identify patients who have a history of hypoglycemia with exercise or meals, and these individuals may require a formal 72-hour fast to rule out an insulinoma.
Treatment for secondary dumping includes dietary modification, but this may be difficult to sustain. Patients can try more frequent meals with smaller portions of less rapidly digested carbohydrates. Alpha-glucosidase therapy may be a useful adjunct to a low carbohydrate diet. Octreotide 50 mcg administered subcutaneously two or three times a day 30 minutes prior to each meal has been reported to improve symptoms due to late dumping syndrome. Various surgical procedures to delay gastric emptying have been reported to improve symptoms but long-term efficacy studies are lacking.
In a very small number of patients with organic hyperinsulinism, islet cell hyperplasia is present rather than an adenoma. This condition is referred to as noninsulinoma pancreatogenous hypoglycemia syndrome. These patients typically have documented hyperinsulinemic hypoglycemia after meals but not with fasting up to 72 hours. The patients have a positive response to calcium-stimulated angiography. A gradient-guided partial pancreatectomy leads to clinical remission, and the pathology of the pancreas shows evidence of islet cell hyperplasia and nesidioblastosis. These patients do not have mutations in the pancreatic islet beta-cell ATP-sensitive potassium channel inward rectifier (Kir 6.2) and the sulfonylurea receptor-1 (SUR1) genes, which have been reported in children with familial hyperinsulinemic hypoglycemia.
Patients have symptoms suggestive of increased sympathetic activity, including anxiety, weakness, tremor, sweating or palpitations after meals. Physical examination and laboratory tests are normal. Previously, many of these patients underwent a 5-hour oral glucose tolerance test and the detection of glucose levels in the 50–60 mg/dL (2.8–3.3 mmol/L) range was thought to be responsible for the symptoms; the recommended treatment was dietary modification. It is now recognized that at least 10% of normal patients who do not have any symptoms have nadir glucose levels < 50 mg/dL (2.8 mmol/L) during a 4- to 6-hour oral glucose tolerance test. In a study comparing responses to oral glucose tolerance test with a mixed meal tolerance test, none of the patients who had plasma glucose levels < 50 mg/dL on oral glucose had low glucose values with the mixed meal. Thus, it is not recommended that these patients with symptoms suggestive of increased sympathetic activity undergo either a prolonged oral glucose tolerance test or a mixed meal test. Instead, the patients should be given home blood glucose monitors (with memories) and instructed to monitor fingerstick glucose levels at the time of symptoms. Only patients who have symptoms when their fingerstick blood glucose is low (< 50 mg/dL) and who have resolution of symptoms when the glucose is raised by eating rapidly released carbohydrate need additional evaluation. Patients who do not have evidence for low glucose levels at time of symptoms are generally reassured by their findings. Counseling and support should be the mainstays in therapy, with dietary manipulation only an adjunct.
This condition is characterized by a delay in early insulin release from pancreatic B cells, resulting in initial exaggeration of hyperglycemia during a glucose tolerance test. In response to this hyperglycemia, an exaggerated insulin release produces a late hypoglycemia 4–5 hours after ingestion of glucose. These patients are often obese and frequently have a family history of diabetes mellitus.
Patients with this type of postprandial hypoglycemia often respond to reduced intake of refined sugars with multiple, spaced, small feedings high in dietary fiber. In the obese, treatment is directed at weight reduction to achieve ideal weight. These patients should be considered to have prediabetes or early diabetes (type 1 or 2) and advised to have periodic medical evaluations.
Patients with autoimmune hypoglycemia have early postprandial hyperglycemia followed by hypoglycemia 3–4 hours later. The hypoglycemia is attributed to a dissociation of insulin-antibody immune complexes, releasing free insulin.
The disorder is associated with methimazole treatment for Graves disease, although it can also occur in patients treated with various other sulfhydryl-containing medications (captopril, penicillamine) as well as other drugs such as hydralazine, isoniazid, and procainamide. In addition, it has been reported in patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and polymyositis as well as in multiple myeloma and other plasma cell dyscrasias where paraproteins or antibodies cross-react with insulin. There is also an association with the HLA class II alleles (DRB1*0406, DQA1*0301, and DQB1*0302). These alleles are 10 to 20 times more common in Japanese and Korean populations, which explains why the disorder has been reported mostly in Japanese patients.
High titers of insulin autoantibodies, usually IgG class, can be detected. Insulin, proinsulin, and C-peptide levels may be elevated, but the results may be erroneous because of the interference of the insulin antibodies with the immunoassays for these peptides.
In most cases, the hypoglycemia is transient and usually resolves spontaneously within 3–6 months of diagnosis, particularly when the offending medications are stopped. The most consistent therapeutic benefit in management of this syndrome has been achieved by dietary treatment with small, frequent low-carbohydrate meals. Prednisone (30–60 mg orally daily) has been used to lower the titer of insulin antibodies.
Kellogg TA et al. Postgastric bypass hyperinsulinemic hypoglycemia syndrome: characterization and response to a modified diet. Surg Obes Relat Dis. 2008 Jul–Aug;4(4):492–9. [PMID: 18656831]
Lupsa BC et al. Autoimmune forms of hypoglycemia. Medicine (Baltimore). 2009 May;88(3):141–53. [PMID: 19440117]
Factitious hypoglycemia may be difficult to document. A suspicion of self-induced hypoglycemia is supported when the patient is associated with the health professions or has access to insulin or sulfonylurea medications taken by a diabetic member of the family. The triad of hypoglycemia, high immunoreactive insulin, and suppressed plasma C peptide immunoreactivity is pathognomonic of exogenous insulin administration. Insulin and C peptide is secreted in a 1:1 molar ratio. A large fraction of the endogenous insulin is cleared by the liver whereas C peptide, which is cleared by the kidney, has a lower metabolic clearance rate. For this reason, the molar ratio of insulin and C peptide in a hypoglycemic patient should be < 1.0 in cases of insulinoma and is > 1.0 in cases of exogenous insulin administration. When sulfonylureas, repaglinide and nateglinide are suspected as a cause of factitious hypoglycemia, a plasma level of these medications to detect their presence may be required to distinguish laboratory findings from those of insulinoma.
HYPOGLYCEMIA DUE TO INSULIN RECEPTOR ANTIBODIES
Hypoglycemia due to insulin receptor autoantibodies is also an extremely rare syndrome; most cases have occurred in women often with a history of autoimmune disease. Almost all of these patients have also had episodes of insulin-resistant diabetes and acanthosis nigricans. Their hypoglycemia may be either fasting or postprandial and is often severe and is attributed to an agonistic action of the antibody on the insulin receptor. Balance between the antagonistic and agonistic effects of the antibodies determines whether insulin-resistant diabetes or hypoglycemia occurs. Hypoglycemia was found to respond to corticosteroid therapy but not to plasmapheresis or immunosuppression.
Kim CH et al. Autoimmune hypoglycemia in a type 2 diabetic patient with anti-insulin and insulin receptor antibodies. Diabetes Care. 2004 Jan;27(1):288–9. [PMID: 14694017]
A number of medications apart from the sulfonylureas can occasionally cause hypoglycemia. Common offenders include the fluoroquinolones such as gatifloxacin and levofloxacin, pentamidine, quinine, ACE inhibitors, salicylates and beta-adrenergic blocking agents. The fluoroquinolones, particularly gatifloxacin, has been associated with both hypoglycemia and hyperglycemia. It is thought that the drug acts on the ATP sensitive potassium channels in the beta cell. Hypoglycemia is an early event, and hyperglycemia occurs several days into therapy. Intravenous pentamidine is cytotoxic to beta cells and causes acute hyperinsulinemia and hypoglycemia followed by insulinopenia and hyperglycemia. Fasting patients taking noncardioselective beta-blockers can have an exaggerated hypoglycemic response to starvation. The beta-blockade inhibits fatty acids and gluconeogenesis substrate release and reduces plasma glucagon response. Therapy with ACE inhibitors increases the risk of hypoglycemia in patients who are taking insulin or sulfonylureas presumably because these drugs increase sensitivity to circulating insulin by increasing blood flow to the muscle.
Ethanol-associated hypoglycemia may be due to hepatic depletion of NADH and altered NADH:NAD ratio. This in turn limits conversion of lactate to pyruvate, the main substrate for hepatic gluconeogenesis. With prolonged starvation, glycogen reserves become depleted within 18–24 hours and hepatic glucose output becomes totally dependent on gluconeogenesis. Under these circumstances, a blood concentration of ethanol as low as 45 mg/dL (9.8 mmol/L) can induce profound hypoglycemia by blocking gluconeogenesis. Neuroglycopenia in a patient whose breath smells of alcohol may be mistaken for alcoholic stupor. Prevention consists of adequate food intake during ethanol ingestion. Therapy consists of glucose administration to replenish glycogen stores until gluconeogenesis resumes.
When sugar-containing soft drinks are used as mixers to dilute alcohol in beverages (gin and tonic, rum and cola), there seems to be a greater insulin release than when the soft drink alone is ingested and a tendency for more of a late hypoglycemic overswing to occur 3–4 hours later. Prevention would consist of avoiding sugar mixers while ingesting alcohol and ensuring supplementary food intake to provide sustained absorption.
Vue MH et al. Drug-induced glucose alterations part 1: drug-induced hypoglycemia. Diabetes Spectrum. 2011 Aug; 24 (3):171–7.
1In collecting samples, it is essential to rapidly chill and separate the blood in order to remove red cells, whose continued glycolysis at room temperature is a common source of error in reports of high plasma lactate. Frozen plasma remains stable for subsequent assay.