Diabetes mellitus is a spectrum of metabolic disorders arising from myriad pathogenic mechanisms, all resulting in hyperglycemia. Both genetic and environmental factors contribute to its pathogenesis, which involves insufficient insulin secretion, reduced responsiveness to endogenous or exogenous insulin, increased glucose production, and/or abnormalities in fat and protein metabolism. The resulting hyperglycemia may lead to both acute symptoms and metabolic abnormalities. Major sources of the morbidity of diabetes are the chronic complications that arise from prolonged hyperglycemia, including retinopathy, neuropathy, nephropathy, and cardiovascular disease. These chronic complications can be mitigated in many patients by sustained control of the blood glucose. There are now a wide variety of treatment options for hyperglycemia that target different processes involved in glucose regulation or dysregulation.
PHYSIOLOGY OF GLUCOSE HOMEOSTASIS
REGULATION OF BLOOD GLUCOSE. The maintenance of glucose homeostasis, termed glucose tolerance, is a highly developed systemic process involving the integration of several major organs (Figure 43–1). Although the actions of insulin are of central importance, webs of inter-organ communication via other hormones, nerves, local factors and substrates, also play a vital role. The pancreatic β cell is central in this homeostatic process, adjusting the amount of insulin secreted very precisely to promote glucose uptake after meals and to regulate glucose output from the liver during fasting.
Figure 43–1 Insulin, glucagon, and glucose homeostasis. A. Fasting State—In healthy humans plasma glucose is maintained in a range from 4.4-5 mM, and fatty acids near 400 µM. In the absence of nutrient absorption from the GI tract, glucose is supplied primarily from the liver and fatty acids from adipose tissue. With fasting, plasma insulin levels are low, and plasma glucagon is elevated, contributing to increased hepatic glycogenolysis and gluconeogenesis; low insulin also releases adipocytes from inhibition, permitting increased lipogenesis. Most tissues oxidize primarily fatty acids during fasting, sparing glucose for use by the CNS. B. Prandial State—During feeding, nutrient absorption causes an increase in plasma glucose, resulting in release of incretins from the gut and neural stimuli that promote insulin secretion. Under the control of insulin, the liver, skeletal muscle, and adipose tissue actively take up glucose. Hepatic glucose production and lipolysis are inhibited, and total body glucose oxidation increases. The brain senses plasma glucose concentrations and provides regulatory inputs contributing to fuel homeostasis. The boldness of the arrows reflects relative intensity of action; adashed line indicates little or no activity.
In the fasting state (Figure 43–1A), the fuel demands of the body are met by the oxidation of fatty acids. The brain does not effectively use fatty acids to meet energy needs and in the fasting state requires glucose for normal function; glucose requirements are ~2 mg/kg/min in adult humans, largely to supply the central nervous system (CNS) with an energy source. Fasting glucose requirements are primarily provided by the liver. Liver glycogen stores provide some of this glucose; conversion of lactate, alanine, and glycerol into glucose accounts for the remainder. The dominant regulation of hepaticglycogenolysis and gluconeogenesis are the pancreatic islet hormones insulin and glucagon. Insulin inhibits hepatic glucose production, and the decline of circulating insulin concentrations in the post-absorptive state (fasting) is permissive for higher rates of glucose output. Glucagon maintains blood glucose concentrations at physiological levels in the absence of exogenous carbohydrate (overnight and in between meals) by stimulating gluconeogenesis and glycogenolysis by the liver. Insulin secretion is stimulated by food ingestion, nutrient absorption, and elevated blood glucose, and insulin promotes glucose, lipid, and protein anabolism (Figure 43–1B). The centrality of insulin in glucose metabolism is emphasized by the fact that all the forms of human diabetes have as a root cause some abnormality of insulin secretion or action.
Pancreatic β cell function is primarily controlled by plasma glucose concentrations. Elevations of blood glucose are necessary for insulin release above basal levels, and other stimuli are relatively ineffective when plasma glucose is in the fasting range (4.4-5.5 mM or 80-100 mg %). These other stimuli include nutrient substrates, insulinotropic hormones released from the GI tract, and autonomic neural pathways. Neural stimuli cause some increase of insulin secretion prior to food consumption. Neural stimulation of insulin secretion occurs throughout the meal and contributes significantly to glucose tolerance. Arrival of nutrient chyme to the intestine leads to the release of insulinotropic peptides from specialized endocrine cells in the intestinal mucosa. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), together termed incretins, are the essential gut hormones contributing to glucose tolerance. They are secreted in proportion to the nutrient load ingested and relay this information to the islet as part of a feed-forward mechanism that allows an insulin response appropriate to meal size. Insulin secretion rates in healthy humans are highest in the early digestive phase of meals, preceding and limiting the peak in blood glucose. This pattern of premonitory insulin secretion is an essential feature of normal glucose tolerance. How to mimic this pattern is one of the key challenges for successful insulin therapy in diabetic patients.
Elevated circulating insulin concentrations lower glucose in blood by inhibiting hepatic glucose production and stimulating the uptake and metabolism of glucose by muscle and adipose tissue. Production of glucose is inhibited half-maximally by an insulin concentration of ~120 pmol/L, whereas glucose utilization is stimulated half-maximally at ~300 pmol/L. Some of the effects of insulin on the liver occur rapidly, within the first 20 min of meal ingestion, whereas stimulation of peripheral glucose uptake may require up to an hour to reach significant rates. Insulin has potent effects to reduce lipolysis from adipocytes, primarily through the inhibition of hormone-sensitive lipase, and increases lipid storage by promoting lipoprotein–lipase synthesis and adipocyte glucose uptake. Insulin also stimulates amino acid uptake and protein synthesis and inhibits protein degradation in muscle and other tissues.
The limited glycogen stores in skeletal muscle are mobilized at the onset of activity but most of the glucose support for exercise comes from hepatic gluconeogenesis. The dominant regulation of hepatic glucose production during exercise comes from EPI and NE. The catecholamines stimulate glycogenolysis and gluconeogenesis, inhibit insulin secretion, and enhance release of glucagon, all contributing to increased hepatic glucose output. In addition, catecholamines promote lipolysis, freeing fatty acids for oxidation in exercising muscle and glycerol for hepatic gluconeogenesis.
PANCREATIC ISLET PHYSIOLOGY AND INSULIN SECRETION. The pancreatic islets comprise 1-2% of the pancreatic volume. The pancreatic islet is a highly vascularized, highly innervated mini-organ containing 5 endocrine cell types: α cells that secrete glucagon, cells that secrete insulin, δ cells that secrete somatostatin, cells that secrete pancreatic polypeptide, and ε cells that secrete ghrelin.
Insulin is initially synthesized as a single polypeptide chain, preproinsulin (110 amino acid), which is processed first to proinsulin and then to insulin and C-peptide (Figure 43–2). This complex and highly regulated process involves the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell. Secretory granules are critical in bringing insulin to the cell surface for exocytosis, and in the cleavage and processing of the prohormone to the final secretion products, insulin and C-peptide. Equimolar quantities of insulin and C-peptide (31 amino acids) are co-secreted. Insulin has a t1/2 of 5-6 min due to extensive hepatic clearance. C-peptide, in contrast, with no known physiological function or receptor, has a t1/2 of ~30 min. The C-peptide is useful in assessment of β cell secretion, and to distinguish endogenous and exogenous hyperinsulinemia (for example in the evaluation of insulin-induced hypoglycemia). The β cell also synthesizes and secretes islet amyloid polypeptide (IAPP) oramylin, a 37–amino acid peptide. IAPP influences GI motility and the speed of glucose absorption. Pramlintide is an agent used in the treatment of diabetes that mimics the action of IAPP.
Figure 43–2 Synthesis and processing of insulin. The initial peptide, preproinsulin (110 amino acids) consists of a signal peptide (SP), B chain, C peptide, and A chain. The SP is cleaved and S-S bonds form as the proinsulin folds. Two prohormone convertases, PC1 and PC2, cleave proinsulin into insulin, C peptide, and 2 dipeptides. Insulin and C peptide are stored in granules and co-secreted in equimolar quantities.
Insulin secretion is tightly regulated to provide stable concentrations of glucose in blood during both fasting and feeding. This regulation is achieved by the coordinated interplay of various nutrients, GI hormones, pancreatic hormones, and autonomic neurotransmitters. Glucose, amino acids (arginine, etc.), fatty acids, and ketone bodies promote the secretion of insulin. Glucose is the primary insulin secretagogue, and insulin secretion is tightly coupled to the extracellular glucose concentration. Insulin secretion is much greater when the same amount of glucose is delivered orally compared to intravenously (incretin effect). Islets are richly innervated by both adrenergic and cholinergic nerves. Stimulation of α2 adrenergic receptors inhibits insulin secretion, whereas β2 adrenergic receptor agonists and vagal nerve stimulation enhance release. In general, any condition that activates the sympathetic branch of the autonomic nervous system (such as hypoxia, hypoglycemia, exercise, hypothermia, surgery, or severe burns) suppresses the secretion of insulin by stimulation of α2 adrenergic receptors. Glucagon and somatostatin inhibit insulin secretion.
The molecular events controlling glucose-stimulated insulin secretion begin with the transport of glucose into the β cell via GLUT, a facilitative glucose transporter, primarily GLUT1 in human β cells (Figure 43–3). Upon entry into the β cell, glucose is quickly phosphorylated by glucokinase (GK; hexokinase IV); this phosphorylation is the rate-limiting step in glucose metabolism in the β cell. GK’s distinctive affinity for glucose leads to a marked increase in glucose metabolism over the range of 5-10 mM glucose, where glucose-stimulated insulin secretion is most pronounced. The glucose-6-phosphate produced by GK activity enters the glycolytic pathway, producing changes in NADPH and the ratio of ADP/ATP. Elevated ATP inhibits an ATP-sensitive K+ channel (KATP channel), leading to cell membrane depolarization. This heteromeric KATP channel consists of an inward rectifying K+ channel (Kir6.2) and a closely associated protein known as the sulfonylurea receptor (SUR). Mutations in the KATP channel are responsible for some types of neonatal diabetes or hypoglycemia. Membrane depolarization then leads to opening of a voltage-dependent Ca2+ channel and increased intracellular Ca2+, resulting in exocytotic release of insulin from storage vesicles. These intracellular events are modulated by changes in cAMP production, amino acid metabolism, and the level of transcription factors. GPCRs for glucagon, GIP, and GLP-1 couple to Gs to stimulate adenylyl cyclase and insulin secretion; receptors for somatostatin and α2 adrenergic agonists couple to Gi to reduce cellular cAMP production and secretion.
Figure 43–3 Regulation of insulin secretion from a pancreatic β cell. The pancreatic β cell in a resting state (fasting blood glucose) is hyperpolarized. Glucose, entering via GLUT transporters (primarily GLUT1 in humans, GLUT2 in rodents), is metabolized and elevates cellular ATP, which reduces K+ conductance through the KATP channel; the decreased K+ conductance results in depolarization, leading to Ca2+-dependent exocytosis of stored insulin. The KATP channel, with SUR1 and Kir 6.2 subunits, is the site of action of several classes of drugs: ATP binds to and inhibits Kir 6.2; sulfonylureas and meglitinides bind to and inhibit SUR1; all 3 agents thereby promote insulin secretion. Diazoxide and ADP-Mg2+ (low ATP) bind to and activate SUR1, thereby inhibiting insulin secretion. Incretins enhance insulin secretion.
The pancreatic α cell secretes glucagon, primarily in response to hypoglycemia. Glucagon biosynthesis begins with preproglucagon, which is processed in a cell-specific fashion to several biologically active peptides such as glucagon, GLP-1, and glucagon-like peptide 2 (GLP-2) (see Figure 43–9). In general, glucagon and insulin secretion are regulated in a reciprocal fashion; that is, the agents or processes that stimulate insulin secretion inhibit glucagon secretion. Notable exceptions are arginine and somatostatin: arginine stimulates and somatostatin inhibits the secretion of both hormones.
INSULIN ACTION. The insulin receptor is expressed on virtually all mammalian cell types. Tissues that are critical for regulation of blood glucose are liver, skeletal muscle, fat (see Figure 43–1), and specific regions of the brain and the pancreatic islet. The actions of insulin are anabolic, and insulin signaling is critical for promoting the uptake, use, and storage of the major nutrients: glucose, lipids, and amino acids. Insulin stimulates glycogenesis, lipogenesis, and protein synthesis; it also inhibits the catabolism of these compounds. On a cellular level, insulin stimulates transport of substrates and ions into cells, promotes translocation of proteins between cellular compartments, regulates the action of specific enzymes, and controls gene transcription and mRNA translation. Some effects of insulin (e.g., activation of glucose and ion transport systems, phosphorylation or dephosphorylation of specific enzymes) occur within seconds or minutes; other effects (e.g., those promoting protein synthesis and regulating gene transcription and cell proliferation) manifest over minutes to hours to days. The effects of insulin on cell proliferation and differentiation occur over days.
THE INSULIN RECEPTOR. Insulin action is transmitted through a receptor tyrosine kinase that bears functional similarity to the insulin-like growth factor 1 (IGF-1) receptor. The insulin receptor is composed of linked α/β subunit dimers that are products of a single gene; dimers linked by disulfide bonds form a transmembrane heterotetramer glycoprotein composed of 2 extracellular α-subunits and 2 membrane-spanning β-subunits (Figure 43–4). The number of receptors varies from 40/cell on erythrocytes to 300,000/cell on adipocytes and hepatocytes.
Figure 43–4 Pathways of insulin signaling. The binding of insulin to its plasma membrane receptor activates a cascade of downstream signaling events. Insulin binding activates the intrinsic tyrosine kinase activity of the receptor dimer, resulting in the tyrosine phosphorylation (Y-P) of the receptor’s β subunits and a small number of specific substrates (yellow shapes): the insulin receptor substrate (IRS) proteins, Gab-1 and SHC; within the membrane, a caveolar pool of insulin receptor phosphorylates caveolin (Cav), APS, and Cbl. These tyrosine-phosphorylated proteins interact with signaling cascades via SH2 and SH3 domains to mediate the effects of insulin, with specific effects resulting from each pathway. In target tissues such as skeletal muscle and adipocytes, a key event is the translocation of the Glut4 glucose transporter from intracellular vesicles to the plasma membrane; this translocation is stimulated by both the caveolar and noncaveolar pathways. In the noncaveolar pathway, the activation of PI3K is crucial, and PKB/Akt (anchored at the membrane by PIP3) and/or an atypical form of PKC is involved. In the caveolar pathway, caveolar protein flotillin localizes the signaling complex to the caveola; the signaling pathway involves series of SH2 domain interactions that add the adaptor protein CrkII, the guanine nucleotide exchange protein C3G, and small GTP-binding protein, TC10. The pathways are inactivated by specific phosphoprotein phosphatases (e.g., PTB1B). In addition to the actions shown, insulin also stimulates the plasma membrane Na+, K+-ATPase by a mechanism that is still being elucidated; the result is an increase in pump activity and a net accumulation of K+ in the cell. Abbreviations: APS, adaptor protein with PH and SH2 domains; CAP, Cbl associated protein; CrkII, chicken tumor virus regulator of kinase II; GLUT4, glucose transporter 4; Gab-1, Grb-2 associated binder; MAP kinase, mitogen-activated protein kinase; PDK, phosphoinositide-dependent kinase; PI3 kinase, phosphatidylinositol-3-kinase; PIP3, phosphatidylinositol trisphosphate; PKB, protein kinase B (also called Akt); aPKC, atypical isoform of protein kinase C; Y, tyrosine residue; Y-P, phosphorylated tyrosine residue.
The α-subunits inhibit the inherent tyrosine kinase activity of the β-subunits. Insulin binding to the α-subunits releases this inhibition and allows transphosphorylation of 1 β-subunit by the other, and autophosphorylation at specific sites from the juxtamembrane region to the intracellular tail of the receptor. Activation of the insulin receptor initiates signaling by phosphorylating a set of intracellular proteins such as the insulin receptor substrates (IRS) and Src-homology-2-containing protein (Shc). These IRS interact with effectors that amplify and extend the signaling cascade.
Insulin action on glucose transport depends on the activation of phosphatidylinositol-3-kinase (PI3K). PI3K is activated by interaction with IRS proteins and generates phosphatidylinositol 3,4,5-trisphosphate (PIP3), which regulates the localization and activity of several downstream kinases, including Akt, atypical isoforms of protein kinase C (PKC ζ and λ/τ), and mammalian target of rapamycin (mTOR). The isoform Akt2 appears to control the downstream steps that are important for glucose uptake in skeletal muscle and adipose tissue, and to regulate glucose production in the liver. Substrates of Akt2 coordinate the translocation of the glucose transporter 4 (GLUT4) to the plasma membrane through processes involving actin remodeling and other membrane trafficking systems. Actions of small G-proteins, such as Rac and TC10, have also been implicated in the actin remodeling necessary for GLUT4 translocation. GLUT4 is expressed in insulin-responsive tissues such as skeletal muscle and adipose tissue. In the basal state, most GLUT4 resides in the intracellular space; following activation of insulin receptors, GLUT4 is shifted rapidly and in abundance to the plasma membrane, where it facilitates inward transport of glucose from the circulation. Insulin signaling also reduces GLUT4 endocytosis, increasing the residence time of the protein in the plasma membrane. Following the facilitated diffusion into cells along a concentration gradient, glucose is phosphorylated to glucose-6-phosphate (G-6-P) by hexokinases. Hexokinase II is found in association with GLUT4 in skeletal and cardiac muscle and in adipose tissue. Like GLUT4, hexokinase II is regulated transcriptionally by insulin. G-6-P can be isomerized to G-1-P and stored as glycogen (insulin enhances the activity of glycogen synthase); G-6-P can enter the glycolytic pathway (for ATP production) and the pentose phosphate pathway.
PATHOPHYSIOLOGY AND DIAGNOSIS OF DIABETES MELLITUS
GLUCOSE HOMEOSTASIS AND THE DIAGNOSIS OF DIABETES
Broad categories of glucose homeostasis as defined by the fasting blood glucose or the glucose level following an oral glucose challenge include:
• Normal glucose homeostasis: fasting plasma glucose <5.6 mmol/L (100 mg/dL)
• Impaired fasting glucose (IFG): 5.6-6.9 mmol/L (100-125 mg/dL)
• Impaired glucose tolerance (IGT): glucose level between 7.8 and 11.1 mmol/L (140-199 mg/dL) 120 min after ingestion of 75 g liquid glucose solution
• Diabetes mellitus (see Table 43–1)
Criteria for the Diagnosis of Diabetes
The American Diabetes Association (ADA) and the World Health Organization (WHO) have adopted criteria for the diagnosis of diabetes, based on the fasting blood glucose, the glucose value following an oral glucose challenge, or the level of hemoglobin A1c (HbA1c, or more simply, A1c; exposure of proteins to elevated [glucose] produces nonenzymatic glycation of proteins including Hb. Thus, the level of A1c represents a measure of the average glucose concentration to which the Hb has been exposed) (see Table 43–1). The diagnostic criteria have recently been changed to also include an A1c value ≥6.5%. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), or an A1c of 5.7-6.4% portend a markedly increased risk of progressing to type 2 diabetes, and are associated with increased risk of cardiovascular disease.
The 4 categories of diabetes include type 1 diabetes, type 2 diabetes, other forms of diabetes, and gestational diabetes (Table 43–2). Although hyperglycemia is common to all forms of diabetes, the pathogenic mechanisms leading to diabetes are quite distinct.
Different Forms of Diabetes Mellitus
SCREENING FOR DIABETES AND CATEGORIES OF INCREASED RISK OF DIABETES. Many individuals with type 2 diabetes are asymptomatic at the time of diagnosis, and diabetes is often found on routine blood testing for nonglucose-related reasons. The ADA recommends widespread screening for type 2 diabetes of these individuals with the following features:
• >45 years of age, or
• Body mass index >25 kg/m2 with 1 of these additional risk factors: hypertension, low high-density lipoprotein, family history of type 2 diabetes, high-risk ethnic group (African American, Latino, Native American, Asian American, and Pacific Islander), abnormal glucose testing (IFG, IGT, A1c of 5.7-6.4%), cardiovascular disease, and women with polycystic ovary syndrome or who have previously delivered a large infant
Earlier diagnosis and treatment of type 2 diabetes should delay diabetes-related complications and reduce the burden of the disease. A number of interventions including pharmacological agents and lifestyle modification are effective. Screening for type 1 diabetes is not currently recommended.
PATHOGENESIS OF TYPE 1 DIABETES. Type 1 diabetes accounts for 5-10% of diabetes and results from autoimmune-mediated destruction of the β cells of the islet leading to total or near total insulin deficiency. Prior terminology included juvenile-onset diabetes mellitus or insulin-dependent diabetes mellitus. Type 1 diabetes resulting from autoimmune β cell destruction can occur at any age. Individuals with type 1 diabetes and their families have an increased prevalence of autoimmune diseases such as Addison disease, Graves and Hashimoto disease, pernicious anemia, vitiligo, and celiac sprue. The concordance of type 1 diabetes in genetically identical twins is 40-60%, indicating a significant genetic component. The major genetic risk (40-50%) is conferred by HLA class II genes encoding HLA-DR and HLA-DQ (and possibly other genes with the HLA locus). However, there clearly is a critical interaction of genetics and an environmental or infectious agent. Most individuals with type 1 diabetes (-75%) do not have a family member with type 1 diabetes, and the genes conferring genetic susceptibility are found in a significant fraction of the nondiabetic population.
Genetically susceptible individuals are thought to have a normal β cell number or mass until β cell–directed autoimmunity develops and β cell loss begins. The initiating or triggering stimulus for the autoimmune process is not known, but most favor exposure to viruses (enterovirus, etc.) or other ubiquitous environmental agents. The β cell destruction is cell mediated, and there is also evidence that infiltrating cells produce local inflammatory agents such as TNF-α, IFN-γ, and IL-1, all of which can lead to β cell death. The β cell destruction occurs over a period of months to years and when >80% of the β cells are destroyed, hyperglycemia ensues and the clinical diagnosis of type 1 diabetes is made. Most patients report several weeks of polyuria and polydipsia, fatigue, and often abrupt and significant weight loss. Some adults with the phenotypic appearance of type 2 diabetes (obese, not insulin-requiring initially) have islet cell autoantibodies suggesting autoimmune-mediated β cell destruction and are diagnosed as expressing latent-autoimmune diabetes of adults (LADA).
PATHOGENESIS OF TYPE 2 DIABETES. The condition is best thought of as a heterogeneous syndrome of dysregulated glucose homeostasis associated with impaired insulin secretion and action. Overweight or obesity is a common correlate of type 2 diabetes that occurs in -80% of affected individuals. For the vast majority of persons developing type 2 diabetes, there is no clear inciting incident; rather, the condition is thought to develop gradually over years with progression through identifiable prediabetic stages. Type 2 diabetes results when there is insufficient insulin action to maintain plasma glucose levels in the normal range. Insulin action is the composite effect of plasma insulin concentrations (determined by islet β cell function) and insulin sensitivity of key target tissues (liver, skeletal muscle, and adipose tissue). These sites of regulation are all impaired to variable extents in patients with type 2 diabetes (Figure 43–5). The etiology of type 2 diabetes has a strong genetic component. It is a heritable condition with a relative 4-fold increased risk of disease for persons having a diabetic parent or sibling, increasing to 6-fold if both parents have type 2 diabetes. Although more than 20 genetic loci with clear associations to type 2 diabetes have been identified through recent genome-wide association studies, the contribution of each is relatively small.
Figure 43–5 Pathophysiology of type 2 diabetes mellitus. Graphs show data from diabetic and -nondiabetic patients, comparing postprandial insulin and glucagon secretion and hepatic glucose production, and the sensitivities of muscle glucose use and adipocyte lipolysis to insulin.
Impaired β Cell Function. In persons with type 2 diabetes, the sensitivity of the β cell to glucose is impaired, and there is also a loss of responsiveness to other stimuli such as insulinotropic GI hormones and neural signaling. This results in delayed secretion of insufficient amounts of insulin, allowing the blood glucose to rise dramatically after meals, and failure to restrain liver glucose release during fasting. The absolute mass of β cells also is greatly reduced in type 2 diabetes patients. Progressive reduction of β cell mass and function explains the natural history of type 2 diabetes in most patients who require steadily increasing therapy to maintain glucose control.
Type 2 diabetic patients frequently have elevated levels of fasting insulin, a result of their higher fasting glucose levels and insulin resistance. Another factor contributing to apparently high insulin levels early in the course of the disease is the presence of increased amounts of proinsulin. Proinsulin, the precursor to insulin, is inefficiently processed in the diabetic islet. Whereas healthy subjects have only 2-4% of total circulating insulin as proinsulin, type 2 diabetic patients can have 10-20% of the measurable plasma insulin in this form. Proinsulin has a considerably attenuated effect for lowering blood glucose compared to insulin.
Insulin Resistance. Insulin sensitivity is measured as the amount of glucose cleared from the blood in response to a dose of insulin. The failure of normal amounts of insulin to elicit the expected response is referred to as insulin resistance. There is inherent variability of insulin sensitivity among cells, tissues, and individuals. Insulin sensitivity is affected by many factors including age, body weight, physical activity levels, illness, and medications. Nonetheless, persons with type 2 diabetes or glucose intolerance have reduced responses to insulin and can easily be distinguished from groups with normal glucose tolerance.
The major insulin-responsive tissues are skeletal muscle, adipose tissue, and liver. Insulin resistance in muscle and fat is generally marked by a decrease in transport of glucose from the circulation. Hepatic insulin resistance generally refers to a blunted ability of insulin to suppress glucose production. Insulin resistance in adipocytes causes increased rates of lipolysis and release of fatty acids into the circulation, which can contribute to insulin resistance in liver and muscle, hepatic steatosis, and dyslipidemia. The sensitivity of humans to the effects of insulin administration is inversely related to the amount of fat stored in the abdominal cavity; more visceral adiposity leads to more insulin resistance. Intracellular lipid or its by-products may have direct effects to impede insulin signaling. Enlarged collections of adipose tissue, visceral or otherwise, are often infiltrated with macrophages and can become sites of chronic inflammation. Adipocytokines, secreted from adipocytes and immune cells, including TNF-α, IL-6, resistin, and retinol-binding protein 4, can also cause systemic insulin resistance.
Sedentary persons are more insulin resistant than active ones, and physical training can improve insulin sensitivity. Physical activity can decrease the risk of developing diabetes and improve glycemic control in persons who have diabetes. Insulin resistance is more common in the elderly; within populations, insulin sensitivity decreases linearly with age. At the cellular level, insulin resistance involves blunted steps in the cascade from the insulin receptor tyrosine kinase to translocation of GLUT4 transporters, but the molecular mechanisms are incompletely defined. There have been >75 different mutations in the insulin receptor discovered, most of which cause significant impairment of insulin action. These mutations affect insulin receptor number, movement to and from the plasma membrane, binding, and phosphorylation. Mutations involving the insulin binding domains of the extracellular α-chain cause the most severe syndromes. Insulin sensitivity is under genetic control but it is unclear whether insulin-resistant individuals have mutations in specific components of the insulin signaling cascade or whether they have a complement of signaling effectors that operate at the lower range of normal. Regardless, it is apparent that insulin resistance clusters in families and is a major risk factor for the development of diabetes.
Dysregulated Hepatic Glucose Metabolism. In type 2 diabetes, hepatic glucose output is excessive in the fasting state and inadequately suppressed after meals. Abnormal secretion of the islet hormones, both insufficient insulin and excessive glucagon, accounts for a significant portion of dysregulated hepatic glucose metabolism in type 2 diabetes. Increased concentrations of glucagon, especially in conjunction with hepatic insulin resistance, can lead to excessive hepatic gluconeogenesis and glycogenolysis and abnormally high fasting glucose concentrations. The liver is resistant to insulin action in type 2 diabetes. This contributes to the reduced potency of insulin to suppress hepatic glucose production and promote hepatic glucose uptake and glycogen synthesis after meals. Despite ineffective insulin effects on hepatic glucose metabolism, the lipogenic effects of insulin in the liver are maintained and even accentuated by fasting hyperinsulinemia. This contributes to hepatic steatosis and further worsening of insulin resistance.
PATHOGENESIS OF OTHER FORMS OF DIABETES. Mutations in key genes involved in glucose homeostasis cause monogenic diabetes, which is inherited in an autosomal dominant fashion. These fall in 2 broad categories: diabetes onset in the immediate neonatal period (<6 months of age) and diabetes in children or adults. Some forms of neonatal diabetes are caused by mutations in the SUR or its accompanying inward rectifying K+ channel and mutations in the insulin gene. Monogenic diabetes beyond the first year of life may appear clinically similar to type 1 or type 2 diabetes. In other instances, young individuals (adolescence to young adulthood) may have monogenic forms of diabetes known as maturity onset diabetes of the young (MODY). Phenotypically, these individuals are not obese and are not insulin resistant, or they may initially have modest hyperglycemia. The most common causes are mutations in key islet-enriched transcription factors or glucokinase. Most individuals with MODY are treated similarly to those with type 2 diabetes.
Diabetes may also be the result of other pathological processes such as acromegaly and Cushing disease (see Table 43–2). A number of medications promote hyperglycemia or lead to diabetes by either impairing insulin secretion or insulin action (Table 43–3).
Some Drugs That May Promote Hyperglycemia or Hypoglycemia
DIABETES-RELATED COMPLICATIONS. Diabetes can cause metabolic derangements or acute complications, such as the life-threatening metabolic disorders of diabetic ketoacidosis and hyperglycemic hyperosmolar state. These require hospitalization for insulin administration, rehydration with intravenous fluids, and careful monitoring of electrolytes and metabolic parameters. Chronic complications of diabetes are commonly divided into microvascular and macrovascular complications. Microvascular complications occur only in individuals with diabetes and include retinopathy, nephropathy, and neuropathy. Macrovascular complications occur more frequently in individuals with diabetes but are not diabetes specific (e.g., increased atherosclerosis-related events such as myocardial infarction and stroke). In the U.S., diabetes is the leading cause of blindness in adults, the leading reason for renal failure requiring dialysis or renal transplantation, and the leading cause of nontraumatic lower extremity amputations. Fortunately, most of these diabetes-related complications can be prevented, delayed, or reduced by near normalization of the blood glucose on a consistent basis. How chronic hyperglycemia causes these complications is unclear. For microvascular complications, current hypothesis are that hyperglycemia leads to advanced glycosylation end products (AGEs), increased glucose metabolism via the sorbitol pathway, increased formation of diacylglycerol leading to PKC activation, and increased flux through the hexosamine pathway. Growth factors such as vascular endothelial growth factor α may be involved in diabetic retinopathy and TGF-β in diabetic nephropathy.
THERAPY OF DIABETES
GOALS OF THERAPY. The goals of therapy for diabetes are to alleviate the symptoms related to hyperglycemia (fatigue, polyuria, etc.) and to prevent or reduce the acute and chronic complications of diabetes.
Glycemic control is assessed using both short-term (blood glucose self-monitoring) and long-term metrics (A1c, fructosamine). Using capillary blood glucose measurements, the patient assesses capillary blood glucose on a regular basis (fasting, before meals, or postprandially) and reports these values to the diabetes management team. A1c reflects glycemic control over the prior 3 months; glycosylated albumin (fructosamine) is a measure of glycemic control over the preceding 2 weeks. The term comprehensive diabetes care describes optimal therapy, which involves more than glucose management and includes aggressive treatment of abnormalities in blood pressure and lipids and detection and management of diabetes-related complications (Figure 43–6). Table 43–4 shows the ADA-recommended treatment goals for comprehensive diabetes care, for glucose, blood pressure, and lipids. A summary of available pharmacologic agents for the treatment of diabetes is at the end of this chapter (see Table 43–8).
Figure 43–6 Components of comprehensive diabetes care.
Goals of Therapy in Diabetes
Comparison of Agents Used for Treatment of Diabetes
NONPHARMACOLOGIC ASPECTS OF DIABETES THERAPY. The patient with diabetes should be educated about nutrition, exercise, and medications aimed at lowering the plasma glucose. In type 1 diabetes, matching caloric intake and insulin dosing is very important. In type 2 diabetes, the diet is directed at weight loss and reducing blood pressure and atherosclerotic risk. Remarkably, bariatric surgery also rapidly improves glucose tolerance and can prevent or reverse type 2 diabetes.
Insulin is the mainstay for treatment of virtually all type 1 and many type 2 diabetes patients. Insulin may be administered intravenously, intramuscularly, or subcutaneously. Long-term treatment relies predominantly on subcutaneous injection. Subcutaneous administration of insulin delivered into the peripheral circulation can lead to near-normal glycemia but differs from physiological secretion of insulin in 2 major ways:
• The absorption kinetics do not reproduce the rapid rise and decline of endogenous insulin in response to glucose following intravenous or oral administration.
• Injected insulin is delivered into the peripheral circulation instead of being released into the portal circulation. Thus, the portal/peripheral insulin concentration is not physiological, and this may alter the influence of insulin on hepatic metabolic processes.
INSULIN PREPARATION AND CHEMISTRY. Human insulin, produced by recombinant DNA technology, is soluble in aqueous solution. Doses and concentration of clinically used insulin preparations are expressed in international units. One unit of insulin is defined as the amount required to reduce the blood glucose concentration in a fasting rabbit to 45 mg/dL (2.5 mM). Commercial preparations of insulin are supplied in solution or suspension at a concentration of 100 units/mL, which is ~3.6 mg insulin per milliliter (0.6 mM) and termed U-100. Insulin also is available in a more concentrated solution (500 units/mL or U-500) for patients who are resistant to the hormone.
INSULIN FORMULATIONS. Preparations of insulin are classified according to their duration of action into short-acting and long-acting (Table 43–5).
Properties of Insulin Preparations
Within the short-acting acting category, some distinguish the very rapid-acting insulins (aspart, glulisine, lispro) from regular insulin. Likewise, some distinguish formulations with a longer duration of action (detemir, glargine) from NPH insulin. Two approaches are used to modify the absorption and pharmacokinetic profile of insulin. The first approach is based on formulations that slow the absorption following subcutaneous injection. The other approach is to alter the amino acid sequence or protein structure of human insulin so that it retains its ability to bind the insulin receptor, but its behavior in solution or following injection is either accelerated or prolonged in comparison to native or regular insulin (Figure 43–7). There is wide variability in the kinetics of insulin action between and even within individuals. The time to peak hypoglycemic effect and insulin levels can vary by 50%, due in part, by large variations in the rate of subcutaneous absorption.
Figure 43–7 Insulin analogs. Modifications of native insulin can alter its pharmacoki-netic profile. Reversing amino acids 28 and 29 in the B chain (lispro) or substituting Asp for Pro28B (aspart) gives analogs with reduced tendencies for molecular self-association that are faster acting. Altering Asp3B to Lys and Lys29B to Glu produces an insulin (glulisine) with a more rapid onset and a shorter duration of action. Substituting Gly for Asn21A and lengthening the B chain by adding Arg31 and Arg32 produces a derivative (glargine) with reduced solubility at pH 7.4 that is, consequently, absorbed more slowly and acts over a longer period of time. Deleting Thr30B and adding a myristoyl group to the ε-amino group of Lys29B (detemir) enhances reversible binding to albumin, thereby slowing transport across vascular endothelium to tissues and providing prolonged action.
Short-Acting Regular Insulin. Native or regular insulin molecules associate as hexamers in aqueous solution at a neutral pH and this aggregation slows absorption following subcutaneous injection. Regular insulin should be injected 30-45 min before a meal. Regular insulin also may be given intravenously or intramuscularly.
Short-Acting Insulin Analogs. These analogs are absorbed more rapidly from subcutaneous sites than regular insulin (see Figures 43–7 and 43–8; see Table 43–5). Insulin analogs should be injected <15 min before a meal.
Figure 43–8 Commonly used insulin regimens. Panel A shows administration of a long-acting insulin like glargine (detemir could also be used but often requires twice-daily administration) to provide basal insulin and a pre-meal short-acting insulin analog (see Table 43–5). Panel B shows a less intensive insulin regimen with BID injection of NPH insulin providing basal insulin and regular insulin or an insulin analog providing meal-time insulin coverage. Only 1 type of shorting-acting insulin would be used. Panel C shows the insulin level attained following subcutaneous insulin (short-acting insulin analog) by an insulin pump programmed to deliver different basal rates. At each meal, an insulin bolus is delivered. B, breakfast; L, lunch; S, supper; HS, bedtime. Upward arrow shows insulin administration at mealtime. (Copyright 2008 American Diabetes Association. From Kaufman FR, ed. Medical Management of Type 1 Diabetes, 5th ed. Modified with permission from the American Diabetes Association.)
Insulin lispro (HUMALOG) is identical to human insulin except at positions B28 and B29. Unlike regular insulin, lispro dissociates into monomers almost instantaneously following injection. This property results in the characteristic rapid absorption and shorter duration of action compared with regular insulin. The prevalence of hypoglycemia is reduced with lispro; and glucose control, as assessed by A1c, is modestly but significantly improved (0.3-0.5%).
Insulin aspart (NOVOLOG) is formed by the replacement of proline at B28 with aspartic acid, reducing self-association. Like lispro, insulin aspart dissociates rapidly into monomers following injection. Insulin aspart and insulin lispro have similar effects on glucose control and hypoglycemia frequency, with lower rates of nocturnal hypoglycemia as compared with regular insulin.
Insulin glulisine (APIDRA) is formed when glutamic acid replaces lysine at B29, and lysine replaces asparagine at B3; these substitutions result in a reduction in self-association and rapid dissociation into active monomers. The time–action profile of insulin glulisine is similar to that of insulin aspart and insulin lispro.
Long-Acting Insulins. Neutral protamine hagedorn (NPH; insulin isophane) is a suspension of native insulin complexed with zinc and protamine in a phosphate buffer. This produces a cloudy or whitish solution in contrast to the clear appearance of other insulin solutions. This formulation dissolves more gradually when injected subcutaneously and thus its duration of action is prolonged. NPH insulin is usually given either once a day (at bedtime) or twice a day in combination with short-acting insulin.
Insulin glargine (LANTUS) is a long-acting analog of human insulin. Two arginine residues are added to the C terminus of the B chain, and an asparagine molecule in position 21 on the A chain is replaced with glycine. Insulin glargine is a clear solution with a pH of 4.0, which stabilizes the insulin hexamer. When injected into the neutral pH of the subcutaneous space, aggregation occurs, resulting in prolonged, but predictable, absorption from the injection site. Owing to insulin glargine’s acidic pH, it cannot be mixed with short-acting insulin preparations that are formulated at a neutral pH. Glargine has a sustained peakless absorption profile, and provides a better once-daily 24-h insulin coverage than NPH insulin. Clinical trial data suggest that glargine has a lower risk of hypoglycemia, particularly overnight compared to NPH insulin. Glargine may be administered at any time during the day with equivalent efficacy and does not accumulate after several injections. The site of administration does not influence the time–action profile of glargine.
Insulin detemir (LEVEMIR) is an insulin analog modified by the addition of a saturated fatty acid to the ε amino group of LysB29, yielding a myristoylated insulin. When insulin detemir is injected subcutaneously, it binds to albumin via its fatty acid chain. Clinical studies in patients with type 1 diabetes have demonstrated that when insulin detemir is administered twice a day, it has a smoother time–action profile and produces a reduced prevalence of hypoglycemia than NPH insulin. The absorption profiles of glargine and detemir insulin are similar, but detemir often requires twice-daily administration.
Other Insulin Formulations. Stable combinations of NPH and regular insulin in proportions of 70:30 combinations are available, as are combinations of lispro protamine/lispro (50/50 and 75/25) and aspart protamine/aspart (70/30) (see Table 43–5).
INSULIN DELIVERY. Most insulin is injected subcutaneously. Pen devices containing prefilled regular, lispro, NPH, glargine, premixed lispro protamine-lispro, or premixed aspart protamine-aspart have proven to be popular with many diabetic patients. Jet injector systems that enable patients to receive subcutaneous insulin injections without a needle are available. Intravenous infusions of insulin are useful in patients with ketoacidosis or when requirements for insulin may change rapidly, such as during the perioperative period, during labor and delivery, and in intensive care situations.
Continuous Subcutaneous Insulin Infusion (CSII). Short-acting insulins are the only form of the hormone used in subcutaneous infusion pumps. A number of pumps are available for CSII therapy. Insulin pumps provide a constant basal infusion of insulin and have the option of different infusion rates during the day and night to help avoid the dawn phenomenon (rise in blood glucose that occurs just prior to awakening from sleep) and bolus injections that are programmed according to the size and nature of a meal. Selection of the most appropriate patients is extremely important for success with CSII. Pump therapy is capable of producing a more physiological profile of insulin replacement during exercise (where insulin production is decreased) and therefore less hypoglycemia than do traditional subcutaneous insulin injections.
FACTORS THAT AFFECT INSULIN ABSORPTION. Factors that determine the rate of absorption of insulin after subcutaneous administration include the site of injection, the type of insulin, subcutaneous blood flow, smoking, regional muscular activity at the site of the injection, the volume and concentration of the injected insulin, and depth of injection (insulin has a more rapid onset of action if delivered intramuscularly rather than subcutaneously). Increased subcutaneous blood flow (brought about by massage, hot baths, or exercise) increases the rate of absorption. The abdomen currently is the preferred site of injection in the morning because insulin is absorbed 20-30% faster from that site than from the arm. Rotation of insulin injection sites traditionally has been advocated to avoid lipohypertrophy or lipoatrophy. In a small group of patients, subcutaneous degradation of insulin has been observed, and this has necessitated the injection of large amounts of insulin for adequate metabolic control.
INSULIN DOSING AND REGIMENS. A number of commonly used dosage regimens that include mixtures of insulin given in 2 or more daily injections are depicted in Figure 43–8.
In most patients, insulin-replacement therapy includes long-acting insulin (basal) and a short-acting insulin to provide postprandial needs. In a mixed population of type 1 diabetes patients, the average dose of insulin is usually 0.6-0.7 units/kg body weight per day, with a range of 0.2-1 units/kg/day. Obese patients generally and pubertal adolescents require more (~1-2 units/kg/day) because of resistance of peripheral tissues to insulin. Patients who require less insulin than 0.5 units/kg/day may have some endogenous production of insulin or may be more sensitive to the hormone because of good physical conditioning. The basal dose is usually 40-50% of the total daily dose with the remainder as prandial or pre-meal insulin. The insulin dose at mealtime should reflect the anticipated carbohydrate intake. A supplemental scale of short-acting insulin is added to the prandial insulin dose to allow correction of the BG. Insulin administered as a single daily dose of long-acting insulin, alone or in combination with short-acting insulin, is rarely sufficient to achieve euglycemia. More complex regimens that include multiple injections of long-acting or short-acting insulin are needed to reach this goal. In all patients, careful monitoring of therapeutic end points directs the insulin dose used. This approach is facilitated by self-monitoring of glucose and measurements of A1c. In patients who have gastroparesis or loss of appetite, injection of a short-acting analog postprandially, based on the amount of food actually consumed, may provide smoother glycemic control.
ADVERSE EVENTS. Hypoglycemia is the major risk that must be weighed against benefits of efforts to normalize glucose control. Insulin treatment of both type 1 and type 2 diabetes is associated with modest weight gain. Although uncommon, allergic reactions to recombinant human insulin may still occur as a result of reaction to the small amounts of aggregated or denatured insulin in preparations, to minor contaminants, or because of sensitivity to a component added to insulin in its formulation (protamine, Zn2+, etc.). Atrophy of subcutaneous fat at the site of insulin injection (lipoatrophy) was a rare side effect of older insulin preparations. Lipohypertrophy (enlargement of subcutaneous fat depots) has been ascribed to the lipogenic action of high local concentrations of insulin.
INSULIN TREATMENT OF KETOACIDOSIS AND OTHER SPECIAL SITUATIONS. Intravenous administration of insulin is most appropriate in patients with ketoacidosis or severe hyperglycemia with a hyperosmolar state. Insulin infusion inhibits lipolysis and gluconeogenesis completely and produces near-maximal stimulation of glucose uptake. In most patients with diabetic ketoacidosis, blood glucose concentrations will fall by -10% per hour; the acidosis is corrected more slowly. As treatment proceeds, it often is necessary to administer glucose along with the insulin to prevent hypoglycemia but to allow clearance of all ketones. Patients with nonketotic hyperglycemic hyperosmolar state may be more sensitive to insulin than are those with ketoacidosis. Appropriate replacement of fluid and electrolytes is an integral part of the therapy in both situations because there is always a major deficit. A long-acting insulin should be administered subcutaneously before the insulin infusion is discontinued.
TREATMENT OF DIABETES IN CHILDREN OR ADOLESCENTS. Diabetes is one of the most common chronic diseases of childhood, and rates of type 1 diabetes in American youth are estimated at 1 in 300. An unfortunate corollary of the growing rates of obesity over the past 3 decades is an increase in the numbers of children and adolescents with non-autoimmune, or type 2, diabetes. Current estimates are that 15-20% of new cases of pediatric diabetes may be type 2 diabetes; rates vary by ethnicity, with disproportionately high rates in Native Americans, African Americans, and Latinos. Current practice is for more intensive, physiologically based insulin replacement with a goal of tight glucose control achieved with combinations of basal and prandial insulin replacement. The primary limiting factor of more aggressive insulin therapy is hypoglycemia. Diabetic patients <5 years old have increased rates of severe hypoglycemia with seizures and coma, and may suffer permanent cognitive dysfunction as a result of repeated episodes of low blood glucose. Older children and adolescents do not seem to have demonstrable cognitive impairment related to hypoglycemia; good glycemic control is associated with better mental function. The standard for insulin treatment now includes multiple dose regimens with 3-5 injections per day or CSII. Split/mixed regimens using NPH and regular insulin have been increasingly supplanted by regimens using insulin analogs because they offer more flexibility in dosing and meal patterns. Similarly, CSII is used with increasing frequency in the pediatric diabetic population and in older children and adolescents.
Because of the association of type 2 diabetes with obesity in the pediatric age group, lifestyle management is the recommended first step in therapy. Goals of reducing body weight and increasing physical activity are broadly recommended. The only medication currently approved by the FDA specifically for medical treatment of type 2 diabetes is metformin. Metformin is approved for children as young as 10 years of age and is available in a liquid formulation (100 mg/mL). Insulin is the typical second line of therapy after metformin; basal insulin can be added to oral agent therapy or multiple daily injections can be used when simpler regimens are not successful. Weight gain is a more significant problem than hypoglycemia with insulin treatment in pediatric type 2 diabetes.
MANAGEMENT OF DIABETES IN HOSPITALIZED PATIENTS. Hyperglycemia is common in hospitalized patients. Prevalence estimates of elevated blood glucose among inpatients with and without a prior diagnosis of diabetes range between 20% and 100% for patients treated in intensive care units (ICUs) and 30% and 83% outside the ICU. Stress of illness has been associated with insulin resistance, possibly the result of counterregulatory hormone secretion, cytokines, and other inflammatory mediators. Food intake is often variable due to concurrent illness or preparation for diagnostic testing. Medications used in the hospital, such as glucocorticoids or dextrose-containing intravenous solutions, can exacerbate tendencies toward hyperglycemia. Finally fluid balance and tissue perfusion can affect the absorbance of subcutaneous insulin and the clearance of glucose. Therapy of hyperglycemia in hospitalized patients needs to be adjusted for these variables.
Emerging data indicate that hyperglycemia portends poor outcomes in hospitalized patients. The ADA currently suggests these blood glucose targets: 140-180 m/dL (7.8-10.0 mM) in critically ill patients and random glucose of 180 mg/dL (10 mM) or pre-meal glucose of 140 mg/dL (7.8 mM) in noncritically ill patients. Insulin is the cornerstone of treatment of hyperglycemia in hospitalized patients. For critically ill patients and those with variable blood pressure, edema, and tissue perfusion, intravenous insulin is the treatment of choice. Oral agents have a limited place in treatment of hyperglycemic patients in the hospital because of slow onset of action, insufficient potency, need for intact GI function, and side effects. Intravenous administration of insulin also is well suited to the treatment of diabetic patients during the perioperative period and during childbirth.
INSULIN SECRETAGOGUES AND ORAL HYPOGLYCEMIC AGENTS
A variety of sulfonylureas, meglitinides, GLP-1 agonists, and inhibitors of dipeptidyl peptidase-4 (DPP-4) are used as secretagogues to stimulate insulin release (Table 43–6).
Properties of Insulin Secretagogues
KATP CHANNEL MODULATORS: SULFONYLUREAS
First-generation sulfonylureas (tolbutamide, tolazamide, and chlorpropamide) are rarely used now in the treatment of type 2 diabetes. The second, more potent generation of hypoglycemic sulfonylureas includes glyburide (glibenclamide; DIABETA, others), glipizide (GLUCOTROL, others), and glimepiride (AMARYL, others). Some are available in an extended-release (glipizide) or a micronized (glyburide) formulation.
MECHANISM OF ACTION. Sulfonylureas stimulate insulin release by binding to a specific site on the β cell KATP channel complex (SUR) and inhibiting its activity. KATP channel inhibition causes cell membrane depolarization and the cascade of events leading to insulin secretion (see Figure 43–3). The acute administration of sulfonylureas to type 2 diabetes patients increases insulin release from the pancreas. With chronic administration, circulating insulin levels decline to those that existed before treatment, but despite this reduction in insulin levels, reduced plasma glucose levels are maintained. The absence of acute stimulatory effects of sulfonylureas on insulin secretion during chronic treatment is attributed to downregulation of cell surface receptors for sulfonylureas on the pancreatic β cell.
ADME. Sulfonylureas are effectively absorbed from the GI tract. Food and hyperglycemia can reduce absorption. Sulfonylureas in plasma are largely (90-99%) bound to protein, especially albumin. The volumes of distribution of most of the sulfonylureas are ~0.2 L/kg. Although their half-lives are short (3-5 h), their hypoglycemic effects are evident for 12-24 h, and they often can be administered once daily. The liver metabolizes all sulfonylureas, and the metabolites are excreted in the urine. Thus, sulfonylureas should be administered with caution to patients with either renal or hepatic insufficiency.
ADVERSE EFFECTS AND DRUG INTERACTIONS. Sulfonylureas may cause hypoglycemic reactions, including coma. Weight gain of 1-3 kg is a common side effect of improving glycemic control with sulfonylurea treatment. Less frequent side effects include nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions. Rarely, patients treated with these drugs develop an alcohol-induced flush similar to that caused by disulfiram or hyponatremia.
The hypoglycemic effect of sulfonylureas may be enhanced by various mechanisms (decreased hepatic metabolism or renal excretion, displacement from protein-binding sites). Some drugs (sulfonamides, clofibrate, and salicylates) displace the sulfonylureas from binding proteins, thereby transiently increasing the concentration of free drug. Ethanol may enhance the action of sulfonylureas and cause hypoglycemia. Hypoglycemia may be more frequent in patients taking a sulfonylurea and 1 of these agents: androgens, anticoagulants, azole antifungals, chloramphenicol, fenfluramine, fluconazole, gemfibrozil, H2 antagonists, magnesium salts, methyldopa, MAO inhibitors, probenecid, sulfinpyrazone, sulfonamides, tricyclic antidepressants, and urinary acidifiers. Other drugs may decrease the glucose-lowering effect of sulfonylureas by increased hepatic metabolism, increased renal excretion, or inhibiting insulin secretion (β blockers, Ca2+ channel blockers, cholestyramine, diazoxide, estrogens, hydantoins, isoniazid, nicotinic acid, phenothiazines, rifampin, sympathomimetics, thiazide diuretics, and urinary alkalinizers).
DOSAGE FORMS AVAILABLE. Treatment is initiated at lower end of the dose range and titrated upward based on the patient’s glycemic response. Some have a longer duration of action and can be prescribed in a single daily dose (glimepiride), whereas others are formulated as extended-release or micronized formulations to extend their duration of action (see Table 43–6). Sulfonylureas such as glipizide or glimepiride appear safer in elderly individuals with type 2 diabetes.
THERAPEUTIC USES. Sulfonylureas are used to treat hyperglycemia in type 2 diabetes. Of properly selected patients, 50-80% respond to this class of agents. All members of the class appear be equally efficacious. A significant number of patients who respond initially later cease to respond to the sulfonylurea and develop unacceptable hyperglycemia (secondary failure). This may occur as a result of a change in drug metabolism or more likely from a progression of β cell failure. Some individuals with neonatal diabetes or MODY-3 respond to these agents. Contraindications to the use of these drugs include type 1 diabetes, pregnancy, lactation, and, for the older preparations, significant hepatic or renal insufficiency.
KATP CHANNEL MODULATORS: NONSULFONYLUREAS
REPAGLINIDE. Repaglinide (PRANDIN) is an oral insulin secretagogue of the meglitinide class (see Table 43–6). Like sulfonylureas, it stimulates insulin release by closing KATPchannels in pancreatic β cells.
The drug is absorbed rapidly from the GI tract, and peak blood levels are obtained within 1 h. The t1/2 is ~1 h. These features allow for multiple preprandial use. Repaglinide is metabolized primarily by the liver (CYP3A4) to inactive derivatives. Because a small proportion (~10%) is metabolized by the kidney, dosing of the drug in patients with renal insufficiency also should be performed cautiously. The major side effect of repaglinide is hypoglycemia. Repaglinide also is associated with a decline in efficacy (secondary failure) after initially improving glycemic control. Certain drugs may potentiate the action of repaglinide by displacing it from plasma protein binding sites (β blockers, chloramphenicol, coumarins, MAOIs, NSAIDs, probenecid, salicylates, and sulfonamide) or altering its metabolism (gemfibrozil, itraconazole, trimethoprim, cyclosporine, simvastatin, clarithromycin).
NATEGLINIDE. Nateglinide (STARLIX) is an orally effective insulin secretagogue. Nateglinide stimulates insulin secretion by blocking KATP channels in pancreatic β cells. Nateglinide promotes a more rapid but less sustained secretion of insulin than other available oral antidiabetic agents. The drug’s major therapeutic effect is reducing postprandial glycemic elevations in type 2 diabetes patients.
Nateglinide is most effective when administered in a dose of 120 mg, 1-10 min before a meal. It is metabolized primarily by hepatic CYPs (2C9, 70%; 3A4, 30%) and should be used cautiously in patients with hepatic insufficiency. About 16% of an administered dose is excreted by the kidney as unchanged drug. Some drugs reduce the glucose-lowering effect of nateglinide (corticosteroids, rifamycins, sympathomimetics, thiazide diuretics, thyroid products); others (alcohol, NSAIDs, salicylates, MAOIs, and nonselective β blockers) may increase the risk of hypoglycemia with nateglinide. Nateglinide therapy may produce fewer episodes of hypoglycemia than other currently available oral insulin secretagogues including repaglinide. As with sulfonylureas and repaglinide, secondary failure occurs.
AMPK AND PPARG ACTIVATORS
METFORMIN. Metformin (GLUCOPHAGE, others) is the only member of the biguanide class of oral hypoglycemic drugs available for use today.
Mechanism of Action. Metformin increases the activity of the AMP-dependent protein kinase (AMPK). AMPK is activated by phosphorylation when cellular energy stores are reduced. Activated AMPK stimulates fatty acid oxidation, glucose uptake, and nonoxidative metabolism, and it reduces lipogenesis and gluconeogenesis. The net result of these actions is increased glycogen storage in skeletal muscle, lower rates of hepatic glucose production, increased insulin sensitivity, and lower blood glucose levels.
The molecular mechanism by which metformin activates AMPK is not known; it may be indirect, possibly via reduction of intracellular energy stores. Metformin has little effect on blood glucose in normoglycemic states, does not affect the release of insulin or other islet hormones, and rarely causes hypoglycemia. However, even in persons with only mild hyperglycemia, metformin lowers blood glucose by reducing hepatic glucose production and increasing peripheral glucose uptake. This effect is at least partially mediated by reducing insulin resistance at key target tissues. Table 43–7 compares metformin and thiazolidinediones (glitazones).
Comparison of Metformin and Thiazolidinediones
Metformin is absorbed primarily from the small intestine. The drug does not bind to plasma proteins, and is excreted unchanged in the urine. It has a t1/2 in the circulation of ~2 h. The transport of metformin into cells is mediated in part by organic cation transporters OCT 1 and OCT 2.
THERAPEUTIC USES AND DOSAGE. Metformin, currently the most commonly used oral agent for type 2 diabetes, is generally accepted as the first-line treatment for this condition. Metformin is effective as monotherapy and in combination therapy. Fixed-dose combinations of metformin in conjunction with glipizide, glyburide, pioglitazone, repaglinide, rosiglitazone, and sitagliptin are available. Metformin is available as an immediate-release form. The currently recommended dosing is 0.5-1.0 g twice daily, with a maximum dose of 2550 mg. A sustained-release preparation is available for once-daily dosing; the maximum dose is 2 g.
Metformin has superior or equivalent efficacy of glucose lowering compared to other oral agents used to treat diabetes, and reduces diabetes-related complications in patients with type 2 diabetes. Metformin does not typically cause weight gain and in some cases causes weight reduction. Metformin is not effective in the treatment of type 1 diabetes. In persons with IGT, treatment with metformin delays the progression to diabetes. Metformin has been used as a treatment for infertility in women with the polycystic ovarian syndrome. Although not formally approved for this purpose, metformin has demonstrable effects to improve ovulation and menstrual cyclicity and reduce circulating androgens and hirsutism.
ADVERSE EFFECTS; INTERACTIONS. The most common side effects (10-25%) of metformin are GI: nausea, indigestion, abdominal cramps or bloating, diarrhea, or some combination of these. Metformin has direct effects on GI function including glucose and bile salt absorption. Use of metformin is associated with 20-30% lower blood levels of vitamin B12. Most GI adverse effects of metformin abate over time with continued use, and can be minimized by starting at low doses and gradually titrating to a target dose over several weeks, and by having patients take it with meals.
Metformin has been associated with lactic acidosis, mostly reported in patients with concurrent conditions that can cause poor tissue perfusion such as sepsis, myocardial infarction, and congestive heart failure; recent analyses of this association have raised doubts as to whether the association of lactic acidosis with metformin is causal. Renal failure is a comorbidity reported in patients having lactic acidosis associated with metformin use, and decreased glomerular filtration rates are thought to increase plasma metformin levels by reducing clearance of drug from the circulation (e.g., when creatinine clearance drops below 50 mL/min). It is important to assess renal function before starting metformin and to monitor function at least annually. Metformin should be discontinued preemptively in situations where renal function could decline precipitously, such as before radiographic procedures that use contrast dyes and during admission to hospital for severe illness. Metformin should not be used in severe pulmonary disease, decompensated heart failure, severe liver disease, or chronic alcohol abuse. Cationic drugs that are eliminated by renal tubular secretion have the potential for interaction with metformin by competing for common renal tubular transport systems. Adjustment of metformin is recommended in patients who are taking cationic medications such as cimetidine, furosemide, and nifedipine.
Thiazolidinediones are ligands for the PPART receptor, a pair of nuclear hormone receptors that are involved in the regulation of genes related to glucose and lipid metabolism. Two thiazolidinediones are currently available to treat patients with type 2 diabetes, rosiglitazone (AVANDIA) and pioglitazone (ACTOS). Table 43–7 compares thiazolidinediones and metformin.
Mechanism of Action; Pharmacological Effects. Thiazolidinediones activate PPARγ receptors. PPARγ is expressed primarily in adipose tissue with lesser expression in cardiac, skeletal, and smooth muscle cells, islet β cells, macrophages, and vascular endothelial cells. The endogenous ligands for PPARγ include small lipophilic molecules such as oxidized linoleic acid, arachidonic acid, and the prostaglandin metabolite 15d-PGJ2; rosiglitazone and pioglitazone are synthetic ligands for PPARγ. Ligand binding to PPARγ. causes heterodimer formation with the retinoid X receptor and interaction with PPAR response elements on specific genes. The principal response to PPARγ activation is adipocyte differentiation. PPARγ activity also promotes uptake of circulating fatty acids into fat cells and shifts of lipid stores from extra-adipose to adipose tissue. One consequence of the cellular responses to PPARγ activation is increased tissue sensitivity to insulin.
Pioglitazone and rosiglitazone are insulin sensitizers and increase insulin-mediated glucose uptake by 30-50% in patients with type 2 diabetes. Although adipose tissue seems to be the primary target for PPARγ agonists, both clinical and preclinical models support a role for skeletal muscle, the major site for insulin-mediated glucose disposal, in the response to thiazolidinediones. In addition to promoting glucose uptake into muscle and adipose tissue, the thiazolidinediones reduce hepatic glucose production and increase hepatic glucose uptake. It is not clear whether thiazolidinedione-induced improvement of insulin resistance is due to direct effects on key target tissues (skeletal muscle and liver), indirect effects mediated by secreted products of adipocytes (e.g., adiponectin), or some combination of these.
Thiazolidinediones also affect lipid metabolism. Treatment with rosiglitazone or pioglitazone reduces plasma levels of fatty acids by increasing clearance and reducing lipolysis. These drugs also cause a shift of triglyceride stores from nonadipose to adipose tissues, and from visceral to subcutaneous fat depots. In clinical trials, pioglitazone reduces plasma triglycerides by 10-15%, and raises HDL cholesterol levels. However, randomized clinical trials demonstrated a questionable benefit of pioglitazone, and no effect of rosiglitazone on major events related to atherosclerosis.
ADME. Both agents are absorbed within 2-3 h, and bioavailability is unaffected by food. The thiazolidinediones are metabolized by the liver and may be administered to patients with renal insufficiency, but should not be used if there is active hepatic disease. Rifampin induces hepatic CYPs and causes a significant decrease in plasma concentrations of rosiglitazone and pioglitazone; gemfibrozil impedes metabolism of the thiazolidinediones and can increase plasma levels by γ2-fold. Prudence suggests reducing the doses of the thiazolidinediones when they are used in conjunction with gemfibrozil.
Therapeutic Uses and Dosage. Rosiglitazone and pioglitazone are dosed once daily. The starting dose of rosiglitazone is 4 mg and should not exceed 8 mg daily. The starting dose of pioglitazone is 15-30 mg, up to a maximum of 45 mg daily. Thiazolidinediones enhance insulin action on liver, adipose tissue, and skeletal muscle, confer improvements in glycemic control in persons with type 2 diabetes, and cause average reductions in A1c of 0.5-1.4%. Thiazolidinediones require the presence of insulin for pharmacological activity and are not indicated to treat type 1 diabetes. Both pioglitazone and rosiglitazone are effective as monotherapy and as additive therapy to metformin, sulfonylureas, or insulin. The onset of action of thiazolidinediones is relatively slow; maximal effects on glucose homeostasis develop gradually over the course of 1-3 months.
ADVERSE EFFECTS AND DRUG INTERACTIONS. The most common adverse effects of the thiazolidinediones are weight gain and edema. Thiazolidinediones cause an increase in body adiposity and an average weight gain of 2-4 kg over the first year of treatment. The use of insulin with thiazolidinedione treatment roughly doubles the incidence of edema and amount of weight gain, compared with either drug alone. Macular edema has been reported in patients using both rosiglitazone and pioglitazone, usually in association with more general fluid retention. Beyond regular retinal exams, diabetic patients taking thiazolidinediones should be observed for visual changes.
Exposure to these drugs over several years in clinical trials has been associated with an increased incidence of heart failure (up to 2-fold). This has generally been attributed to the effect of the drugs to cause plasma volume expansion in type 2 diabetic patients who have significantly increased risk for heart failure. There does not appear to be an acute effect of pioglitazone or rosiglitazone to reduce myocardial contractility or ejection fraction. The use of thiazolidinediones in diabetic patients without a history of heart failure, or with compensated heart failure, can be initiated, but monitoring for signs and symptoms of congestive heart failure is important, especially when insulin is also used. Thiazolidinediones should not be used in patients with moderate to severe heart failure. Recent evidence suggests that rosiglitazone, but not pioglitazone, increases the risk of cardiovascular events (myocardial infarction, stroke). The FDA requires that new prescriptions for rosiglitazone be issued under a risk evaluation and mitigation strategy and be limited to patients whose diabetes could not be adequately controlled by other medications (including pioglitazone).
Treatment with thiazolidinediones has been associated with increased risk of bone fracture in women and with a small but consistent reduction in the hematocrit. Pioglitazone and rosiglitazone are associated with a lowering of transaminases, probably reflective of reductions in hepatic steatosis; thus, thiazolidinediones should be withheld from patients with clinically apparent liver disease and liver function be monitored intermittently during treatment.
Incretins are GI hormones that are released after meals and stimulate insulin secretion. The best known incretins are GLP-1 and GIP. GIP is not effective for stimulating insulin release and lowering blood glucose in persons with type 2 diabetes, whereas GLP-1 is effective. Consequently, the GLP-1 signaling system has been a successful drug target.
Both GLP-1 and glucagon are products derived from preproglucagon, a 180–amino acid precursor with 5 separately processed domains (Figure 43–9). Given intravenously to diabetic subjects in supraphysiologic amounts, GLP-1 stimulates insulin secretion, inhibits glucagon release, delays gastric emptying, reduces food intake, and normalizes fasting and postprandial insulin secretion. The insulinotropic effect of GLP-1 is glucose-dependent in that insulin secretion at fasting glucose concentrations, even with high levels of circulating GLP-1, is minimal. GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-4), with a plasma t1/2 of 1-2 min; thus, the natural peptide, itself, is not a useful therapeutic agent. Two broad strategies have been taken to applying GLP-1 to therapeutics, the development of injectable, DPP-4 resistant peptide agonists of the GLP-1 receptor, and the creation of small molecule inhibitors of DPP-4 (Figure 43–10; see Table 43–6).
Figure 43–9 Processing of proglucagon to glucagon, GLP-1, GLP-2, and GRPP. Proglucagon is synthesized in islet α cells, intestinal enteroendocrine cells (L cells), and a subset of neurons in the hindbrain. In α cells, prohormone processing is primarily by proconvertase 2, releasing glucagon, glicentin-related pancreatic polypeptide (GRPP), and a major proglucagon fragment, containing the 2 glucagon-like peptides (GLPs). In L cells and neurons, proglucagon cleavage is mostly through proconvertase 1/3, giving glicentin, oxyntomodulin, GLP-1, and GLP-2. STN, solitary tract nucleus.
Figure 43–10 Pharmacological effects of DDP-4 inhibition. DPP-4, an ectoenzyme located on the luminal side of capillary endothelial cells metabolizes the incretins, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), by removing the 2 N-terminal amino acids. The target for DPP-4 cleavage is a proline or alanine residue in the second position of the primary peptide sequence. The truncated metabolites GLP-1[9-36] and GIP[3-42] are the major forms of the incretins in plasma and are inactive as insulin secretagogues. Treatment with a DPP-4 inhibitor increases the concentrations of intact GLP-1 and GIP.
GLP-1 RECEPTOR AGONISTS. Two GLP-1 receptor agonists that have been approved for treatment diabetic patients in the U.S. Exendin-4, a naturally occurring 39-amino acid reptilian peptide and GLP-1 homolog, is a potent GLP-1 receptor agonist that shares many of the physiological and pharmacological effects of GLP-1. It is not metabolized by DPP-4 and so has a plasma t1/2 of 2-3 h following subcutaneous injection. Exendin-4 causes glucose-dependent insulin secretion, delayed gastric emptying, lower glucagon levels, and reduced food intake.
Exenatide (BYETTA), synthetic exendin-4, is approved for use as monotherapy and as adjunctive therapy for type 2 diabetes patients not achieving glycemic targets with other drugs.
In clinical trials, exenatide, alone or in combination with metformin, sulfonylurea, or thiazolidinedione, was associated with improved glycemic control, as reflected in an ~1% decrease in A1c, and weight loss that averaged 2.5-4 kg.
Liraglutide is also a GLP-1 receptor agonist. Structurally, liraglutide is nearly identical to native GLP-1, with Lys34 to Arg substitution and addition of a α-glutamic acid spacer coupled to a C16 fatty acyl group.
The fatty acid side chain permits binding to albumin and other plasma proteins and accounts for an extended t1/2 permitting once-daily administration. The pharmacodynamic profile of liraglutide mimics GLP-1 and exenatide, and in clinical trials liraglutide caused both improvement in glycemic control and weight loss. In a single comparative trial, liraglutide reduced A1c -30% more than exenatide. Liraglutide is indicated for adjunctive therapy in patients not achieving glycemic control with metformin, sulfonylurea, their combination, or metformin/thiazolidinedione.
MECHANISM OF ACTION. All GLP-1 receptor agonists share a common mechanism, activation of the GLP-1 receptor. GLP-1 receptors are expressed by β cells, cells in the peripheral and central nervous systems, the heart and vasculature, kidney, lung, and GI mucosa. Binding of agonists to the GLP-1 receptor activates the cyclic AMP-PKA pathway and several GEFs (guanine nucleotide exchange factors). GLP-1 receptor activation also initiates signaling via PKC and PI3K and alters the activity of several ion channels. In β cells, the end result of these actions is increased insulin biosynthesis and exocytosis in a glucose-dependent manner (see Figure 43–3).
ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION, AND DOSING. Exenatide is given as a subcutaneous injection twice daily, typically before meals. Exenatide is rapidly absorbed, reaches peak concentrations in ~2 h, undergoes little metabolism in the circulation, and has a volume of distribution of nearly 30 L. Clearance of the drug occurs primarily by glomerular filtration, with tubular proteolysis and minimal reabsorption. Exenatide is marketed as a pen that delivers 5 or 10 µg; dosing is typically started at the lower amount and increased as needed.
Liraglutide is given as a subcutaneous injection once daily. Peak levels occur in 8-12 h and the elimination t1/2 is 12-14 h. There is little renal or intestinal excretion of liraglutide, and clearance is primarily through the metabolic pathways of large plasma proteins. Liraglutide is supplied in a pen injector that delivers 0.6, 1.2, or 1.8 mg of drug; the low dose is for treatment initiation, with elevation to the higher doses based on clinical response.
ADVERSE EFFECTS AND DRUG INTERACTIONS. Intravenous or subcutaneous administration of GLP-1 causes nausea and vomiting; the doses above which GLP-1 causes GI side effects are higher than those needed to regulate blood glucose. Nonetheless, up to 40-50% of subjects report nausea at the initiation of therapy. The GI side effects of these drugs wane over time. Activation of the GLP-1 receptor can delay gastric emptying, and GLP-1 agonists may alter the pharmacokinetics of drugs that require rapid GI absorption, such as oral contraceptives and antibiotics. In the absence of other diabetes drugs that cause low blood glucose, hypoglycemia associated with GLP-1 agonist treatment is rare. The combination of exenatide or liraglutide with sulfonylurea drugs causes an increased rate of hypoglycemia compared to sulfonylurea treatment alone. Because of its reliance on renal clearance, exenatide should not be given to persons with moderate to severe renal failure (creatinine clearance <30 mL/min). Based on surveillance data, there is a possible association of exenatide treatment with pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis.
DPP-4 is a serine protease that is widely distributed throughout the body, expressed as an ectoenzyme on endothelial cells, on the surface of T-lymphocytes, and in a circulating form. DPP-4 cleaves the two N-terminal amino acids from peptides with a proline or alanine in the second position. It seems to be especially critical for the inactivation of GLP-1 and GIP. DPP-4 inhibitors increase the AUC of GLP-1 and GIP when their secretion is by a meal (see Figure 43–10). Several agents provide nearly complete and long-lasting inhibition of DPP-4, thereby increasing the proportion of active GLP-1 from 10-20% of total circulating GLP-1 immunoreactivity to nearly 100%. Sitagliptin (JANUVIA), saxagliptin(ONGLYZA), linagliptin (TRADJENTA), and alogliptin (NESINA) are available in the U.S.; vildagliptin, is available in the E.U.
MECHANISMS OF ACTION; EFFECTS. Sitagliptin and alogliptin are competitive inhibitors of DPP-4; vildagliptin and saxagliptin bind the enzyme covalently. All 4 drugs can be given in doses that lower measurable activity of DPP-4 by >95% for 12 h. This causes a greater than 2-fold elevation of plasma concentrations of active GIP and GLP-1 and is associated with increased insulin secretion, reduced glucagon levels, and improvements in both fasting and postprandial hyperglycemia. Inhibition of DPP-4 does not appear to have direct effects on insulin sensitivity, gastric motility, or satiety, nor does chronic treatment with DPP-4 inhibitors affect body weight. DPP-4 inhibitors, used as monotherapy in type 2 diabetic patients, reduced A1c levels by an average ~0.8%. These compounds are also effective for chronic glucose control when added to the treatment of diabetic patients receiving metformin, thiazolidinediones, sulfonylureas, and insulin. The effects of DPP-4 inhibitors in combination regimens appear to be additive. The recommended dose of sitagliptin is 100 mg once daily. The recommended dose of saxagliptin is 5 mg once daily.
ADME. DPP-4 inhibitors are absorbed effectively from the small intestine. They circulate in primarily in unbound form and are excreted largely unchanged in the urine. Both sitagliptin and saxagliptin are excreted renally, and lower doses should be used in patients with reduced renal function. Sitagliptin has minimal metabolism by hepatic microsomal enzymes. Saxagliptin is metabolized by CYP3A4/5 to an active metabolite. The dose saxagliptin should be lowered to 2.5 mg daily when coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).
ADVERSE EFFECTS; DRUG INTERACTIONS. There are no consistent adverse effects that have been noted in clinical trials with any of the DPP-4 inhibitors. DPP-4 is expressed on lymphocytes; in the immunology literature, the enzyme is referred to as CD26. This area bears scrutiny as more patients are treated with these compounds.
OTHER HYPOGLYCEMIC AGENTS
ALPHA GLUCOSIDASE INHIBITORS
α-Glucosidase inhibitors reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of α-glucosidase in the intestinal brush border. These drugs also increase the release of the glucoregulatory hormone GLP-1 into the circulation, which may contribute to their glucose-lowering effects. The drugs in this class are acarbose(PRECOSE, others), miglitol (GLYSET), and voglibose.
DOSING; ADME. Dosing of acarbose and miglitol are similar. Both are provided as 25, 50, or 100 mg tablets that are taken before meals. Treatment should start with lower doses and be titrated as indicated by balancing postprandial glucose, A1c, and GI symptoms. Acarbose is minimally absorbed; the small amount of drug reaching the systemic circulation is cleared by the kidney. Miglitol absorption is saturable, with 50-100% of any dose entering the circulation. Miglitol is cleared almost entirely by the kidney, and dose reductions are recommended for patients with creatinine clearance <30 mL/min.
ADVERSE EFFECTS AND DRUG INTERACTIONS. The most prominent adverse effects are malabsorption, flatulence, diarrhea, and abdominal bloating. Mild to moderate elevations of hepatic transaminases have been reported with acarbose, but symptomatic liver disease is very rare. Cutaneous hypersensitivity has been described but is also rare. Hypoglycemia has been described when α-glucosidase inhibitors are added to insulin or an insulin secretagogue. Acarbose can decrease the absorption of digoxin and miglitol can decrease the absorption of propranolol and ranitidine. Alpha glucosidase inhibitors are contraindicated in patients with stage 4 renal failure.
THERAPEUTIC USES. α-Glucosidase inhibitors are indicated as adjuncts to diet and exercise in type 2 diabetic patients not reaching glycemic targets. They can also be used in combination with other oral antidiabetic agents and/or insulin. In clinical studies α-glucosidase inhibitors reduce A1c by 0.5-0.8%, fasting glucose by ~1 mM and postprandial glucose by 2.0-2.5 mM. These agents do not cause weight gain or have significant effects on plasma lipids.
Islet amyloid polypeptide (IAPP, amylin), is a 37–amino acid peptide produced in the pancreatic β cell and secreted with insulin. A synthetic form of amylin with several amino acid modifications to improve bioavailability, pramlintide (SYMLIN), has been developed as a drug for the treatment of diabetes; pramlintide may affect its actions via the amylin receptor in specific regions of the hindbrain. Activation of the amylin receptor causes reductions in glucagon release, delayed gastric emptying, and satiety.
ADME; DOSING. Pramlintide is administered as a subcutaneous injection prior to meals. Pramlintide is not extensively bound by plasma proteins and has a t1/2 of 50 min. Metabolism and clearance is primarily by the kidney. The doses in patients with type 1 diabetes start at 15 µg and are titrated upward to a maximum of 60 μg; in type 2 diabetes the starting dose is 60 µg and the maximum is 120 µg. Because of differences in the pH of the solutions, pramlintide should not be administered in the same syringe as insulin.
ADVERSE EFFECTS; DRUG INTERACTIONS. The most common adverse effects are nausea and hypoglycemia. Although pramlintide alone does not lower blood glucose, addition to insulin at mealtimes has been noted to cause increased rates of hypoglycemia, occasionally severe. It is currently recommended that prandial insulin doses be reduced 30-50% at the time of pramlintide initiation and then retitrated. Because of its effects on GI motility, pramlintide is contraindicated in patients with gastroparesis or other disorders of motility. Pramlintide is a pregnancy Category C drug. Pramlintide can be used in persons with moderate renal disease (creatinine clearance >20 mL/min).
THERAPEUTIC USES. Pramlintide is approved for treatment of types 1 and 2 diabetes as an adjunct in patients who take insulin with meals. Pramlintide is now being evaluated as a drug for weight loss in nondiabetic persons.
BILE ACID BINDING RESINS
The only bile acid sequestrant specifically approved for the treatment of type 2 diabetes is colesevelam (WELCHOL).
MECHANISM OF ACTION. The mechanism by which bile acid binding and removal from enterohepatic circulation lowers blood glucose has not been established. Bile acid sequestrants could reduce intestinal glucose absorption, although there is no direct evidence of this. Bile acids also act as signaling molecules through nuclear receptors, some of which may act as glucose sensors.
ADME. Colesevelam is provided as a powder for oral solution and as 625-mg tablets; typical usage is 3 tablets twice daily before lunch and dinner or 6 tablets prior to the patient’s largest meal. The drug’s distribution is limited to the GI tract.
ADVERSE EFFECTS AND DRUG INTERACTIONS. Common side effects of colesevelam are gastrointestinal, with constipation, dyspepsia, abdominal pain, and nausea affecting up to 10% of treated patients. Like other bile acid binding resins, colesevelam can increase plasma triglycerides in persons with an inherent tendency to hypertriglyceridemia and should be used cautiously in patients with plasma triglycerides >200 mg/dL. Colesevelam can interfere with the absorption of commonly used agents (e.g., phenytoin, warfarin, verapamil, glyburide, L-thyroxine, and ethinyl estradiol, and fat-soluble vitamins). Colesevelam is a pregnancy Category B drug that has no contraindications in patients with renal or liver disease.
THERAPEUTIC USES. The bile acid binding resin colesevelam, approved for treatment of hypercholesterolemia, may be used for treatment of type 2 diabetes as an adjunct to diet and exercise. In clinical trials, colesevelam reduced A1c by 0.5% when added to metformin, sulfonylurea, or insulin treatment in type 2 diabetic patients.
A formulation of bromocriptine (CYCLOSET), a dopamine receptor agonist, is approved for the treatment of type 2 diabetes but is not yet available in the U.S. Bromocriptine is an established treatment for Parkinson disease and hyperprolactinemia (see Chapters 13, 22, and 38). Effects of bromocriptine on blood glucose are modest and may reflect an action in the CNS.
COMBINED PHARMACOLOGICAL APPROACHES TO TYPE 2 DIABETES
PROGRESSIVE MANAGEMENT OF TYPE 2 DIABETES
There are several useful algorithms or flow charts for the treatment of type 2 diabetes (Figure 43–11). There are a number of pathways or combination of drugs that are used for treatment of type 2 diabetes if the glucose control does not reach the therapeutic target. Table 43–8 summarizes available pharmacological agents for the treatment of diabetes.
Figure 43–11 Treatment algorithm for management of type 2 diabetes mellitus. Patients diagnosed with type 2 diabetes, either by fasting glucose, oral glucose tolerance testing, or A1c measurement, should have diabetes education that includes instruction on medical nutrition therapy and physical activity. Most patients newly diagnosed with type 2 diabetes have had subclinical or undiagnosed diabetes for many years previously and should be evaluated for diabetic complications (retinal exam, test for excess protein or albumin excretion in the urine, and clinical evaluation for peripheral neuropathy and vascular insufficiency); common comorbidities (hypertension and dyslipidemia) should be treated. Metformin is the consensus first line of therapy and should be started at the time of diagnosis. Failure to reach the glycemic target, generally A1c <7% within 3-4 months, should prompt the addition of a second oral agent. Reinforce lifestyle interventions at every visit and check A1c every 3 months. Treatment may escalate to metformin plus 2 oral agents or metformin plus insulin, if necessary.
In the absence of prolonged fasting, healthy humans almost never have blood glucose levels <3.5 mM. This is due to a highly adapted neuroendocrine counterregulatory system that prevents acute hypoglycemia, a hazardous and potentially lethal situation. The 2 major clinical scenarios for hypoglycemia are:
• Treatment of diabetes
• Inappropriate production of endogenous insulin or an insulin-like substance by a pancreatic islet tumor (insulinoma) or a non-islet tumor
Hypoglycemia in the first scenario can occur either in the fasting or fed state, whereas in the second scenario, hypoglycemia occurs almost exclusively in the fasting or postabsorptive state. Some drugs not used for the treatment of diabetes promote hypoglycemia (see Table 43–3).
The most common and serious adverse event related to diabetes therapy is hypoglycemia. Although an adverse reaction to a number of oral therapies, it is most pronounced and serious with insulin therapy. Hypoglycemia may result from an inappropriately large dose, from a mismatch between the time of peak delivery of insulin and food intake, or from superimposition of additional factors that increase sensitivity to insulin (e.g., adrenal or pituitary insufficiency) or that increase insulin-independent glucose uptake (e.g., exercise). Hypoglycemia is the major risk that always must be weighed against benefits of efforts to normalize glucose control.
The first physiological response to hypoglycemia is a reduction of endogenous insulin secretion, which occurs at a plasma glucose level of ~70 mg/dL (3.9 mM); thereafter, the counterregulatory hormones (EPI, glucagon, growth hormone, cortisol, and NE) are released. Symptoms of hypoglycemia are first discerned at a plasma glucose level of 60-80 mg/dL (3.3-4.4 mM). Sweating, hunger, paresthesias, palpitations, tremor, and anxiety, principally of autonomic origin, usually are seen first. Difficulty in concentrating, confusion, weakness, drowsiness, a feeling of warmth, dizziness, blurred vision, and loss of consciousness (i.e., most important neuroglycopenic symptoms) usually occur at lower plasma glucose levels than do autonomic symptoms.
In patients with type 1 and type 2 diabetes of longer duration, the glucagon secretory response to hypoglycemia becomes deficient. Diabetic patients thus become dependent on EPI for counterregulation, and if this mechanism becomes deficient, the incidence of severe hypoglycemia increases. Severe hypoglycemia can lead to convulsions and coma. With the ready availability of home glucose monitoring, hypoglycemia can be documented in most patients who experience suggestive symptoms. Hypoglycemia that occurs during sleep may be difficult to detect but should be suspected from a history of morning headaches, night sweats, or symptoms of hypothermia. Mild-to-moderate hypoglycemia may be treated simply by ingestion of glucose (15 g of carbohydrate). When hypoglycemia is severe, it should be treated with intravenous glucose or an injection of glucagon.
AGENTS USED TO TREAT HYPOGLYCEMIA
Glucagon is a single-chain polypeptide of 29 amino acids now produced by recombinant DNA technology. Glucagon interacts with a GPCR on the plasma membrane of target cells that signals through Gs. The primary effects of glucagon on the liver are mediated by cAMP. Glucagon is used to treat severe hypoglycemia, particularly in diabetic patients when the patient cannot safely consume oral glucose and intravenous glucose is not available.
For hypoglycemic reactions, 1 mg is administered intravenously, intramuscularly, or subcutaneously. After the initial response to glucagon, patients should be given glucose or urged to eat to prevent recurrent hypoglycemia. Nausea and vomiting are the most frequent adverse effects.
Diazoxide (PROGLYCEM) is an antihypertensive, antidiuretic benzothiadiazine derivative with potent hyperglycemic actions when given orally. Hyperglycemia results primarily from inhibition of insulin secretion. Diazoxide interacts with the KATP channel on the β cell membrane and either prevents its closing or prolongs the open time; this effect is opposite to that of the sulfonylureas (see Figure 43–3).
The usual oral dose is 3-8 mg/kg per day in adults and children and 8 to 15 mg/kg per day in infants and neonates. The drug can cause nausea and vomiting and thus usually is given in divided doses with meals. Diazoxide circulates largely bound to plasma proteins and has a t1/2 of ~48 h. Diazoxide has a number of adverse effects, including retention of Na+ and fluid, hyperuricemia, hypertrichosis, thrombocytopenia, and leucopenia, which sometimes limit its use. Despite these side effects, the drug may be useful in patients with inoperable insulinomas and in children with neonatal hyperinsulinism.
OTHER PANCREATIC ISLET HORMONES
SOMATOSTATIN. Somatostatin (SST) is produced by δ cells of the pancreatic islet, cells of the GI tract, and in the CNS. Somatostatin, a 14–amino acid or a 28–amino acid peptide molecule, acts through a family of 5 GPCRs, SSTR1-5. SST inhibits a wide variety of endocrine and exocrine secretions, including TSH and GH from the pituitary, gastrin, motilin, VIP, glicentin, and insulin, glucagon, and pancreatic polypeptide from the pancreatic islet. The physiological role of somatostatin has not been defined precisely, but its short t1/2 (3-6 min) prevents its use therapeutically. Longer-acting analogs such as octreotide (SANDOSTATIN) and lanreotide (SOMATULINE) are useful for treatment of carcinoid tumors, glucagonomas, VIPomas, and acromegaly (see Chapter 38). Gallbladder abnormalities (stones and biliary sludge) occur frequently with chronic use of the somatostatin analogs, as do GI symptoms.