Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia. Insulin- dependent diabetes mellitus (IDDM; type 1) is caused by destruction of the insulin-producing beta cells of the pancreas by antibodies (autoimmune). Non-insulin-dependent diabetes mellitus (NIDDM; type 2) is due to insufficient production of insulin or insulin resistance. The effects of insulin deficiency are shown in Fig. 18.1, and Table 18.1 lists the signs, symptoms, and complications of diabetes mellitus.
Table 18.1 Signs, Symptoms, and Complications of Diabetes Mellitus
Poor wound healing
Predilection to infection
Increased frequency of urination (polyuria)
Nausea and vomiting
—retinopathy (can cause blindness)
Accelerated atherosclerosis causing strokes, coronary heart disease, and hypertension
Glucose tolerance test
Glucose tolerance is used to test for type 2 diabetes. It involves giving the patient a known oral dose of glucose, following an 8- to 12-hour fasting period, then measuring plasma glucose levels at intervals thereafter to determine how quickly plasma glucose levels fall and homeostasis is regained. Normal fasting plasma glucose levels are < 6.1 mmol. Glucose levels of 6.1 to 7.0 mmol are considered borderline and are indicative of impaired fasting glycemia. Measurements of plasma glucose taken after 2 hours should be < 7.8 mmol. Glucose levels of 7.8 to 11.0 mmol indicate impaired glucose tolerance, and levels of 11.1 mmol or higher allow the diagnosis of diabetes.
Diagnosis of type 1 diabetes
The diagnosis of type 1 diabetes is made by conducting various blood tests:
1. Glycated hemoglobin (AC1) test. This test, which measures the percentage of blood sugar attached to hemoglobin, indicates the patient's average blood sugar levels over the past 2 to 3 months. An AC1 > 6.5% is diagnostic of diabetes. The AC1 has yet to be adopted by the World Health Organization as the gold standard test for diabetes.
2. Random blood sugar level. A random blood test is taken and blood sugar measured. A value of > 200 mg/dL (11.1 mmol/L) is suggestive of diabetes, especially if the patient has associated symptoms.
3. Fasting blood sugar test. The patient fasts overnight, and a blood sample is taken in the morning. A value of > 126 mg/dL (> 7 mmol/L) on two separate occasions allows for a diagnosis of diabetes.
4. Oral glucose tolerance test. (see call-out box below).
If type 1 diabetes is diagnosed, the patient will also be screened for autoantibodies, which are commonly associated with diabetes.
Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes. It mostly occurs in type 1 diabetes but may occur in type 2. In DKA, there is a shortage of insulin, so the body ceases to use carbohydrate as an energy source and starts using fatty acids, which produce ketones (acetoacetic acid, β hydroxybutyric acid, and acetone). Dehydration occurs, followed by acidosis and coma. Signs may include hyperventilation and the breath smelling of ketones (“fruity” smell). DKA usually occurs in known diabetics and can be triggered by illness or inadequate/inappropriate insulin therapy. Treatment involves giving insulin, K+, and fluid replacement.
Ketones provide an alternative source of energy during periods of low glucose after glycogen stores have been consumed. They are formed by the beta oxidation of acetyl coenzyme A (CoA), which is derived from fatty acids, in liver mitochondrial cells. Beta oxidation also yields the reduced form of nicotinamide adenine dinucleotide (NADH) and the hydroquinone form of flavin a denine dinucleotide (FADH2), which then undergoes oxidative phosphorylation, producing adenosine triphosphate (ATP). Acetyl CoA from fatty acid catabolism would normally enter the citric acid cycle, producing energy (via the oxidative phosphorylation of NADH and FADH2). However, in periods of low glucose, oxaloacetate (a citric acid cycle intermediate) is used for gluconeogenesis; thus acetyl CoA is diverted for ketone formation. There are three ketones: acetoacetic acid, β-hydroxybutyric acid, and acetone. Acetone is a result of the spontaneous decarboxylation of acetoacetic acid and is produced in the least quantity of all the ketones. Furthermore, acetone cannot be converted back to acetyl CoA, so it is excreted in urine and exhaled (giving the breath a characteristic “fruity” smell in ketotic states).
Gestational diabetes occurs during pregnancy and resembles type 2 diabetes. It is thought to occur in ~2 to 5% of all pregnancies and may improve or disappear after delivery of the baby. Gestational diabetes can be dangerous for both mother and baby. The baby may have macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. They may also have respiratory distress syndrome after birth due to decreased production of surfactant, a substance that causes maturation of the lungs.
Synthesis. Insulin is produced by the beta cells of the pancreatic islets. Preproinsulin is processed to proinsulin, which is cleaved to form three peptide chains. The A (21 amino acids) and B (30 amino acids) chains of insulin are connected by disulfide bonds and, along with the C peptide, are secreted from the beta cells. The beta cells also secrete amylin, a 37-amino acid peptide.
Mechanism of action. The insulin receptor is a tyrosine kinase receptor that, upon binding insulin, dimerizes, leading to receptor autophosphorylation and the activation of intracellular signaling molecules. The activated receptor initiates a complex cascade that mediates the effects of insulin (Fig. 18.2). Examples include stimulation of the translocation of glucose transporters and increased glycogen synthesis which lowers elevated blood glucose levels. It also stimulates protein synthesis, and lipogenesis.
Uses. To lower elevated blood glucose levels in type 1 diabetes mellitus, as well as some cases of type 2 diabetes mellitus.
Insulin is produced by recombinant DNA techniques.
Pharmacokinetics. Short half-life (5–10 min).
Fig. 18.1 Effects of insulin deficiency.
Insulin deficiency causes hyperglycemia. In muscle, glucose uptake is impaired and protein catabolism is increased. Additionally, the uptake of glucose into fat is reduced, glucose conversion to fat is inhibited, and lipolysis is stimulated. The amino acids produced are transported in the blood to the liver, where they are converted to ketone bodies and lipoproteins. Gluconeogenesis is stimulated in the liver, leading to more glucose being transported to the blood than is taken up by the liver. Glucose conversion to glycogen is also inhibited. In the kidneys, glucose is secreted when their capacity to reabsorb glucose is exceeded, along with ketones, water, and electrolytes. (CoA, coenzyme A.)
Fig. 18.2 Signal transduction: insulin.
The insulin receptor is a glycoprotein consisting of two alpha chains, located on the outside of the cell, and two beta chains that are membrane bound and reach into the cytosol. Insulin binds to the exterior alpha chains, which phosphorylates part of the internal beta chains. This activates tyrosine kinase, which then phosphorylates tyrosine groups of a peptide (insulin receptor substrate), which in turn triggers further phosphorylation and dephosphorylation reactions, leading to the physiological effects of insulin. (ADP, adenosine diphosphate; ATP, adenosine triphosphate.)
– Increased transport of glucose into fat and muscle, increased muscle, and hepatic glycogen synthesis
– Increased K+ uptake into cells
– Decreased lipolysis and increased triglyceride synthesis
– Decreased protein catabolism, increased amino acid transport, and ribosomal protein synthesis
– Decreased hepatic glucose production (gluconeogenesis)
– Decreased glucagon secretion
Note: The overall effect of insulin is to control hyperglycemia and keto acid formation.
Insulin and K+ balance
K+ is an important ion in the body, with 98% being intracellular. The ratio of intra-cellular to extracellular K+ determines cell membrane potential. Immediate K+ balance is controlled by intracellular and extracellular potassium exchange driven by the Na+-K+-ATPase pump. This is controlled by insulin and β2 receptors. Long-term K+ balance is controlled by renal excretion. In hyperkalemic (high-K+) states, glucose and insulin are used to drive K+ into cells by increasing the activity of the Na+-K+-ATPase pump.
Side effects. Hypoglycemia is the most common adverse effect in patients with well- controlled diabetes. This may be caused by any of the following factors:
– Wrong dose
– Exercise inappropriate for the dose of insulin (exercise increases glucose uptake by insulin-independent mechanisms)
– Not eating at a regular time or eating insufficient amounts
– Drugs enhancing insulin-induced hypoglycemia include anabolic steroids, captopril, ethyl alcohol, and salicylates.
– Beta-adrenergic-blocking drugs that may mask symptoms of hypoglycemia and delay the onset of treatment. These drugs also impair counter-regulatory responses.
– Allergic reactions and localized atrophy are less common with newer, single-component insulin preparations.
Hypoglycemia should be treated with oral glucose (tablets or gel) to relieve the symptoms. Patients and their families may be instructed in the use of a glucagon emergency kit for treating severe hypoglycemic reactions.
Modified Insulin Preparations
Insulin preparations have been developed to delay absorption of insulin and prolong its action, but they act in the same way as regular insulin and have the same side effects. Table 18.2 provides a summary of the pharmacokinetic properties of different insulin preparations, and Fig. 18.3 describes two different approaches to insulin replacement.
Fig. 18.3 Methods of insulin replacement.
In intensified insulin therapy, long-acting insulin is administered late in the evening to generate a basal level. A fast-acting insulin is then injected before meals, the dose being dependent on blood glucose concentration measurement and the meal-dependent demand. This approach allows the patient flexibility in meal times and insulin injection. In conventional insulin therapy, a fixed-dosage schedule is maintained. Insulin (a combination of regular insulin and insulin suspension) is injected in the morning and evening, and carbohydrate ingestion is synchronized with this.
Fast-acting Insulins: Insulin Lispro, Insulin Aspart, and Insulin Glulisine
– Insulin lispro differs from human insulin by inversion of the B-chain amino acids proline and lysine at positions 28 and 29, respectively.
– Insulin aspart differs from human insulin by replacement of the proline at position 28 (B chain) by aspartic acid.
– Insulin glulisine is formulated by substituting an asparagine for lysine at position 3 and glutamic acid for lysine at position 29 of the B chain.
Intermediate-acting Insulin: Neutral Protamine Hagedorn (NPH) Insulin
NPH insulin is produced by combining insulin with the positively charged polypeptide protamine.
Long-acting Insulin: Insulin Detemir and Insulin Glargine
– Insulin detemir is produced by covalently binding myristic acid to lysine 29 and omitting lysine 30 on the B chain.
– Insulin glargine is produced by replacing the asparagine residue at position 21 of the A chain with glycine and adding two arginine residues to the C terminus of the B chain.
18.2 Oral Hypoglycemic Drugs
Uses. Oral hypoglycemic agents are used in the treatment of type 2 diabetes mellitus, although diet and exercise are the primary treatments for this condition. These agents are ineffective in type 1 diabetes mellitus.
Cholporamide, Tolazamide, Tolbutamide, Glimepiride, Glipizide, Glyburide, and Glibenclamide
– First-generation agents: Chlorpropamide, Tolazamide, and Tolbutamide
– Second-generation agents: Glimepiride, Glipizide, Glyburide, and Glibenclamide
Mechanism of action. These agents block ATP-sensitive K+ channels on the surface of pancreatic beta cells. This causes membrane depolarization and increased insulin secretion (Fig. 18.4).
– Chlorpropamide may cause water retention because of augmentation of antidiuretic hormone action.
Mechanism of action
– Decreases hepatic gluconeogenesis and absorption of glucose from the gastrointestinal (GI) tract
– Increases insulin sensitivity of skeletal muscle and adipose tissue
Note: Metformin does not increase the release of pancreatic insulin; therefore, the risk of hypoglycemia is less than that found for the sulfonylurea agents.
– GI disturbances, including diarrhea
Fig. 18.4 Oral antidiabetics.
Blood glucose concentration depends on the inflow of glucose (mainly from the liver and intestines), and the outflow from the blood into tissues. Metformin and acarbose both inhibit glucose inflow into the blood, and sulfonylureas and thiazolidinedione derivatives positively affect the outflow of glucose into tissues by stimulating insulin secretion and increasing insulin sensitivity, respectively. (PPAR, peroxisome proliferator–activated receptor.)
Acarbose and Miglitol
Mechanism of action. These agents are competitive reversible inhibitors of intestinal α-glucosidase, which normally hydrolyzes oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides. They cause delayed absorption of carbohydrates, thereby blunting postprandial hyperglycemia (Fig. 18.2).
Pharmacokinetics. These agents are not absorbed systemically.
– High incidence of GI pain, discomfort, flatulence, and diarrhea
Pioglitazone and Rosiglitazone
Mechanism of action. These agents increase insulin sensitivity in tissues, for example, muscle, adipose tissue, and the liver (Fig. 18.2).
– Weight gain
Nateglinide, and Repaglinide
Mechanism of action. Meglitinides block ATP-sensitive K+ channels in pancreatic beta cells, leading to membrane depolarization and increased insulin release.
Mechanism of action. Pramlintide is a synthetic analogue of amylin, a neuroendocrine hormone synthesized by pancreatic beta cells. It mimics amylin effects to delay gastric emptying and to prevent the postprandial rise in plasma glucagon. This improves postprandial glucose control. It may also increase satiety, leading to decreased caloric intake and weight loss.
Pharmacokinetics. It is given by subcutaneous injection with every meal to reduce post-prandial hyperglycemia.
– Type 1 or type 2 diabetes mellitus
– Mild nausea that decreases over time
Glucagon-like peptide 1 (GLP-1) Agonists
Mechanism of action. GLP-1 is a hormone secreted from intestinal L cells in response to nutrient ingestion. It acts on the GLP-1 receptor to stimulate glucose-dependent insulin release and inhibit glucagon secretion. Exenatide is a 39-amino acid peptide that acts as an agonist at the GLP-1 receptor. It lowers blood glucose by mimicking the actions of GLP-1.
Pharmacokinetics. It is given by subcutaneous injection within 60 minutes before a meal.
Uses. Exenatide is used as an adjunctive agent to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, or both.
Dipeptidyl peptidase 4 (DPP-4) Inhibitors
Mechanism of action. DPP-4 is the enzyme that rapidly metabolizes endogenously released GLP-1 in the intestine, terminating its effects. Sitagliptin inhibits the degradation of GLP-1 by DPP-4. It thus enhances the action of GLP-1 to increase insulin release and decrease glucagon levels.
– Management of type 2 diabetes in combination with metformin and thiazolidinediones
18.3 Antihypoglycemic Drugs
In patients with diabetes who are taking insulin, hypoglycemia may occur from insufficient caloric intake or sudden, excessive physical exertion or an excess of injected insulin. Primary therapy is to raise the glucose level in the blood. In emergency situations, glucagon raises blood glucose levels by increasing the release of glucose from the liver into blood.
Glucagon is a polypeptide produced by the alpha cells of the pancreas.
Mechanism of action. Glucagon binds to G-protein coupled receptors, mainly in the liver. Signal transduction occurs by means of increased cyclic adenosine monophosphate (cAMP), leading to stimulation of gluconeogenesis and glycogenolysis in the liver and an increase in blood glucose.
Pharmacokinetics. Glucagon is available as an emergency kit that contains freeze-dried glucagon as a powder and a 1 mL syringe of glycerin. The glycerin is mixed with the glucagon powder prior to injection and may be given intravenously, intramuscularly, or subcutaneously.
– Hypoglycemic emergency
– Nausea and vomiting