Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 41. Pancreatic Hormones, Antidiabetic Agents, & Glucagon

Pancreatic Hormones, Antidiabetic Agents, & Glucagon: Introduction

In the endocrine pancreas, the islets of Langerhans contain at least 4 types of endocrine cells, including A (alpha, glucagon producing), B (beta, insulin, and amylin producing), D (delta, somatostatin producing), and F (pancreatic polypeptide producing). Of these, the B (insulin-producing) cells are the most numerous.

The most common pancreatic disease requiring pharmacologic therapy is diabetes mellitus, a deficiency of insulin production or effect. Diabetes is treated with several parenteral formulations of insulin and oral or parenteral noninsulin antidiabetic agents. Glucagon, a hormone that affects the liver, cardiovascular system, and gastrointestinal tract, can be used to treat severe hypoglycemia.

High-Yield Terms to Learn

-Glucosidase An enzyme in the gastrointestinal tract that converts complex starches and oligosaccharides to monosaccharides; inhibited by acarbose and miglitol Beta (B) cells in the islets of LangerhansInsulin-producing cells in the endocrine pancreas Hypoglycemia Dangerously lowered serum glucose concentration; a toxic effect of high insulin concentrations and the secretagogue class of oral antidiabetic drugs Lactic acidosis Acidemia due to excess serum lactic acid; can result from excess production or decreased metabolism of lactic acid Type 1 diabetes mellitus A form of chronic hyperglycemia caused by immunologic destruction of pancreatic beta cells Type 2 diabetes mellitus A form of chronic hyperglycemia initially caused by resistance to insulin; often progresses to insulin deficiency

Diabetes Mellitus

Two major forms of diabetes mellitus have been identified. Type 1 diabetes usually has its onset during childhood and results from autoimmune destruction of pancreatic B cells. Type 2 diabetes is a progressive disorder characterized by increasing insulin resistance and diminishing insulin secretory capacity. Type 2 diabetes is frequently associated with obesity and is much more common than type 1 diabetes. Although type 2 diabetes usually has its onset in adulthood, the incidence in children and adolescents is rising dramatically, in parallel with the increase in obesity in children and adolescents.

The clinical history and course of these 2 forms differ considerably, but treatment in both cases requires careful attention to diet, fasting and postprandial blood glucose concentrations, and serum concentrations of hemoglobin A1c, a glycosylated hemoglobin that serves as a marker of glycemia. Type 1 diabetes requires treatment with insulin. The early stages of type 2 diabetes usually can be controlled with noninsulin antidiabetic drugs. However, patients in the later stages of type 2 diabetes often require the addition of insulin to their drug regimen.

Insulin

Physiology

Insulin is synthesized as the prohormone proinsulin, an 86-amino-acid single-chain polypeptide. Cleavage of proinsulin and cross-linking result in the 2-chain 51-peptide insulin molecule and a 31-amino-acid residual C-peptide. Neither proinsulin nor C-peptide appears to have any physiologic actions.

Effects

Insulin has important effects on almost every tissue of the body. When activated by the hormone, the insulin receptor, a transmembrane tyrosine kinase, phosphorylates itself and a variety of intracellular proteins when activated by the hormone. The major target organs for insulin action include:

Liver

Insulin increases the storage of glucose as glycogen in the liver. This involves the insertion of additional GLUT2 glucose transport molecules in cell plasma membranes; increased synthesis of the enzymes pyruvate kinase, phosphofructokinase, and glucokinase; and suppression of several other enzymes. Insulin also decreases protein catabolism.

Skeletal Muscle

Insulin stimulates glycogen synthesis and protein synthesis. Glucose transport into muscle cells is facilitated by insertion of GLUT4 transporters into cell plasma membranes.

Adipose Tissue

Insulin facilitates triglyceride storage by activating plasma lipoprotein lipase, increasing glucose transport into cells via GLUT4 transporters, and reducing intracellular lipolysis.

Insulin Preparations

Human insulin is manufactured by bacterial recombinant DNA technology. The available forms provide 4 rates of onset and durations of effect that range from rapid-acting to long-acting (Figure 41-1). The goals of insulin therapy are to control both basal and postprandial (after a meal) glucose levels while minimizing the risk of hypoglycemia. Insulin formulations with different rates of onset and effect are often combined to achieve these goals.

FIGURE 41-1

Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2-0.3 U/kg; the duration of regular and NPH insulin increases considerably when dosage is increased.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 41-5.)

Rapid-Acting

Three insulin analogs (insulin lispro, insulin aspart, and insulin glulisine) have rapid onsets and early peaks of activity (Figure 41-1) that permit control of postprandial glucose levels. The 3 rapid-acting insulins have small alterations in their primary amino acid sequences that speed their entry into the circulation without affecting their interaction with the insulin receptor. The rapid-acting insulins are injected immediately before a meal and are the preferred insulin for continuous subcutaneous infusion devices. They also can be used for emergency treatment of uncomplicated diabetic ketoacidosis.

Short-Acting

Regular insulin is used intravenously in emergencies or administered subcutaneously in ordinary maintenance regimens, alone or mixed with intermediate- or long-acting preparations. Before the development of rapid-acting insulins, it was the primary form of insulin used for controlling postprandial glucose concentrations, but it requires administration 1 h or more before a meal.

Intermediate-Acting

Neutral protamine Hagedorn insulin (NPH insulin) is a combination of regular insulin and protamine (a highly basic protein also used to reverse the action of unfractionated heparin, Chapter 34) that exhibits a delayed onset and peak of action (Figure 41-1). NPH insulin is often combined with regular and rapid-acting insulins.

Long-Acting

Insulin glargine and insulin detemir are modified forms of human insulin that provide a peakless basal insulin level lasting more than 20 h, which helps control basal glucose levels without producing hypoglycemia.

Insulin Delivery Systems

The standard mode of insulin therapy is subcutaneous injection with conventional disposable needles and syringes. More convenient means of administration are also available.

Portable pen-sized injectors are used to facilitate subcutaneous injection. Some contain replaceable cartridges, whereas others are disposable.

Continuous subcutaneous insulin infusion devices avoid the need for multiple daily injections and provide flexibility in the scheduling of patients' daily activities. Programmable pumps deliver a constant 24-h basal rate, and manual adjustments in the rate of delivery can be made to accommodate changes in insulin requirements (eg, before meals or exercise).

Hazards of Insulin Use

The most common complication is hypoglycemia, resulting from excessive insulin effect. To prevent the brain damage that may result from hypoglycemia, prompt administration of glucose (sugar or candy by mouth, glucose by vein) or of glucagon (by intramuscular injection) is essential. Patients with advanced renal disease, the elderly, and children younger than 7 years are most susceptible to the detrimental effects of hypoglycemia.

The most common form of insulin-induced immunologic complication is the formation of antibodies to insulin or noninsulin protein contaminants, which results in resistance to the action of the drug or allergic reactions. With the current use of highly purified human insulins, immunologic complications are uncommon.

Noninsulin Antidiabetic Drugs

Four well-established groups of oral antidiabetic drugs are used most commonly to treat type 2 diabetes. These include insulin secretagogues, the biguanide metforminthiazolidinediones, and -glucosidase inhibitors (Figure 41-2). Three novel agents—pramlintide, exenatide, and sitagliptin—target endogenous regulators of glucose homeostasis. The durations of action of important members of these groups are listed in Table 41-1.

FIGURE 41-2

Control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. When the extracellular glucose concentration increases, more glucose enters the cell via the GLUT2 glucose transporter and leads, through metabolism, to increased intracellular ATP production with subsequent closure of ATP-dependent K+ channels, membrane depolarization, opening of voltage-gated Ca2+channels, increased intracellular Ca2+, and insulin secretion. Sulfonylurea and other insulin secretagogues enhance insulin release by blocking ATP-dependent K+ channels and thereby triggering the events subsequent to reduced K+ influx.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 41-2.)

TABLE 41-1 Duration of action of representative oral antidiabetic drugs.

Drug Duration of Action (hours) Secretagogues Chlorpropamide Up to 60 Tolbutamide 6-12 Glimepiride 12-24 Glipizide 10-24 Glyburide 10-24 Repaglinide 4-5 Nateglinide 4 Biguanides Metformin 10-12 Thiazolidinediones Pioglitazone 15-24 Rosiglitazone >24 Alpha-glucosidase inhibitors Acarbose 3-4 Miglitol 3-4 Incretin modifiers Sitagliptin 8-14

Insulin Secretagogues

Mechanism and Effects

Insulin secretagogues stimulate the release of endogenous insulin by promoting closure of potassium channels in the pancreatic B-cell membrane (Figure 41-2). Channel closure depolarizes the cell and triggers insulin release. Insulin secretagogues are not effective in patients who lack functional pancreatic B cells.

Most insulin secretagogues are in the chemical class known as sulfonylureas. The second-generation sulfonylureas (glyburide, glipizide, glimepiride) are considerably more potent and used more commonly than the older agents (tolbutamide, chlorpropamide, others). Repaglinide, a meglitinide, and nateglinide, a D-phenylalanine derivative, are also insulin secretagogues. Both have a rapid onset and short duration of action that make them useful for administration just before a meal to control postprandial glucose levels.

Toxicities

The insulin secretagogues, especially those with a high potency (eg, glyburide and glipizide), can precipitate hypoglycemia, although the risk is less than that associated with the insulins. The older sulfonylureas (tolbutamide and chlorpropamide) are extensively bound to serum proteins, and drugs that compete for protein binding may enhance their hypoglycemic effects. Occasionally these drugs cause rash or other allergic reactions. Weight gain is common and is especially undesirable in the large fraction of patients with type 2 diabetes who already are overweight.

Biguanides

Mechanism and Effects

Metformin , the primary member of the biguanide group, reduces postprandial and fasting glucose levels. Biguanides inhibit hepatic and renal gluconeogenesis (Figure 41-3). Other effects include stimulation of glucose uptake and glycolysis in peripheral tissues, slowing of glucose absorption from the gastrointestinal tract, and reduction of plasma glucagon levels. The molecular mechanism of biguanide reduction in hepatic glucose production appears to involve activation of an AMP-stimulated protein kinase.

FIGURE 41-3

Major actions of the principal oral antidiabetic drugs used to treat type 2 diabetes.

In patients with insulin resistance, metformin reduces endogenous insulin production presumably through enhanced insulin sensitivity. Because of this insulin-sparing effect and because it does not increase weight—unlike insulin, secretagogues, or the thiazolidinediones—metformin is increasingly the drug of first choice in overweight patients with type 2 diabetes. Recent clinical trials suggest that metformin reduces the risk of diabetes in high-risk patients. Metformin is also used to restore fertility in anovulatory women with polycystic ovary disease (PCOD) and evidence of insulin resistance.

Toxicities

Unlike the sulfonylureas, the biguanides do not cause hypoglycemia. Their most common toxicity is gastrointestinal distress (nausea, diarrhea), and they can cause lactic acidosis, especially in patients with renal or liver disease, alcoholism, or conditions that predispose to tissue anoxia and lactic acid production (eg, chronic cardiopulmonary dysfunction).

Thiazolidinediones

Mechanism and Effects

The thiazolidinediones, rosiglitazone and pioglitazone, increase target tissue sensitivity to insulin by activating the peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR- receptor). This nuclear receptor regulates the transcription of genes encoding proteins involved in carbohydrate and lipid metabolism. A primary effect of the thiazolidinediones is increasing glucose uptake in muscle and adipose tissue (Figure 41-3). They also inhibit hepatic gluconeogenesis and have effects on lipid metabolism and the distribution of body fat. Thiazolidinediones reduce both fasting and postprandial hyperglycemia. They are used as monotherapy or in combination with insulin or other oral antidiabetic drugs. Like metformin, the thiazolidinediones have been shown to reduce the risk of diabetes in high-risk patients.

Toxicities

When these drugs are used alone, hypoglycemia is extremely rare. Thiazolidinediones can cause fluid retention, which presents as mild anemia and edema and may increase the risk of heart failure. Recent data have linked rosiglitazone to increased risk of myocardial infarction. The original thiazolidinedione (troglitazone) was removed from the market in several countries because of hepatotoxicity. Rosiglitazone and pioglitazone have not been linked to serious liver dysfunction but still require routine monitoring of liver function. Female patients taking thiazolidinediones appear to have an increased risk of bone fractures. Pioglitazone and troglitazone induce cytochrome P450 activity (especially the 3A4 isozyme) and can reduce the serum concentrations of drugs that are metabolized by these enzymes (eg, oral contraceptives, cyclosporine).

-Glucosidase Inhibitors

Mechanism and Effects

Acarbose and miglitol are carbohydrate analogs that act within the intestine to inhibit -glucosidase, an enzyme necessary for the conversion of complex starches, oligosaccharides, and disaccharides to the monosaccharides that can be transported out of the intestinal lumen and into the bloodstream. As a result of slowed absorption, postprandial hyperglycemia is reduced. These drugs lack an effect on fasting blood sugar. Both drugs can be used as monotherapy or in combination with other antidiabetic drugs. They are taken just before a meal. Like metformin and the thiazolidinediones, the -glucosidase inhibitors have been shown to prevent type 2 diabetes in prediabetic persons.

Toxicities

The primary adverse effects of the -glucosidase inhibitors include flatulence, diarrhea, and abdominal pain resulting from increased fermentation of unabsorbed carbohydrate by bacteria in the colon. Patients taking an -glucosidase inhibitor who experience hypoglycemia should be treated with oral glucose (dextrose) and not sucrose, because the absorption of sucrose will be delayed.

Pramlintide

Pramlintide is an injectable synthetic analog of amylin, a 37-amino acid hormone produced by pancreatic B cells. Amylin contributes to glycemic control by activating high-affinity receptors that are a complex of the calcitonin receptor and a receptor-activity modifying receptor (RANK). Pramlintide suppresses glucagon release, slows gastric emptying, and works in the CNS to reduce appetite. After subcutaneous injection, it is rapidly absorbed and has a short duration of action. It is used in combination with insulin to control postprandial glucose levels. The major adverse effects associated with pramlintide are hypoglycemia and gastrointestinal disturbances.

Exenatide

Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones, which are released from endocrine cells in the epithelium of the bowel in response to food. The incretins augment glucose-stimulated insulin release from pancreatic B cells, retard gastric emptying, inhibit glucagon secretion, and produce a feeling of satiety. The GLP-1 receptor is a G-protein-coupled receptor (GPCR) that increases cAMP and also increases the free intracellular concentration of calcium.

Exenatide, a long-acting injectable peptide analog of GLP-1, is used in combination with metformin or a sulfonylurea for treatment of type 2 diabetes. The major adverse effects are gastrointestinal disturbances, particularly nausea during initial therapy, and hypoglycemia when exenatide is combined with a sulfonylurea. The drug has also caused serious and sometimes fatal acute pancreatitis.

Sitagliptin

Sitagliptin is an oral inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades GLP-1 and other incretins. It is approved for use in type 2 diabetes as monotherapy or in combination with metformin or a thiazolidinedione. Like exenatide, sitagliptin promotes insulin release, inhibits glucagon secretion, delays gastric emptying, and has an anorexic effect. The most common adverse effects associated with sitagliptin are headache, nasopharyngitis, and upper respiratory tract infection.

Treatment of Diabetes Mellitus

Type 1 Diabetes

Therapy for type 1 diabetes involves dietary instruction, parenteral insulin (a mixture of shorter and longer acting forms to maintain control of basal and postprandial glucose levels) and possibly pramlintide for improved control of postprandial glucose levels, plus careful attention by the patient to factors that change insulin requirements: exercise, infections, other forms of stress, and deviations from the regular diet. Large clinical studies indicate that tight control of blood sugar, by frequent blood sugar testing and insulin injections, reduces the incidence of vascular complications, including renal and retinal damage. The risk of hypoglycemic reactions is increased in tight control regimens but not enough to obviate the benefits of better control.

Type 2 Diabetes

Because type 2 diabetes is usually a progressive disease, therapy for an individual patient generally escalates over time. It begins with weight reduction and dietary control. Initial drug therapy usually is oral monotherapy with metformin. Although initial responses to monotherapy usually are good, secondary failure within 5 yrs is common. Increasingly, noninsulin antidiabetic agents are being used in combination with each other or with insulin to achieve better glycemic control and minimize toxicity. Because type 2 diabetes involves both insulin resistance and inadequate insulin production, it makes sense to combine an agent that augments insulin's action (metformin, a thiazolidinedione, or an -glucosidase inhibitor) with one that augments the insulin supplies (insulin secretagogue or insulin). Long-acting drugs (sulfonylureas, metformin, thiazolidinediones, exenatide, sitagliptin, some insulin formulations) help control both fasting and postprandial blood glucose levels, whereas short-acting drugs (-glucosidase inhibitors, repaglinide, pramlintide, rapid-acting insulins) primarily target postprandial levels. As is the case for type 1 diabetes, clinical trials have shown that tight control of blood glucose in patients with type 2 diabetes reduces the risk of vascular complications.

Skill Keeper: Diabetes and Hypertension

(See Chapter 11)

Diabetes is linked to hypertension in several important ways. Obesity predisposes patients to hypertension as well as to type 2 diabetes, so many patients suffer from both diseases. Both diseases damage the kidney and predispose patients to coronary artery disease. A large clinical trial of patients with type 2 diabetes suggests that poorly controlled hypertension exacerbates the microvascular disease caused by long-standing diabetes. Because of these links, it is important to consider the treatment of hypertension in diabetic patients.

1. Identify the major drug groups used for chronic treatment of essential hypertension.

2. Which of these drug groups have special implications for the treatment of patients with diabetes?

Hyperglycemic Drugs: Glucagon

Glucagon

Chemistry, Mechanism, and Effects

Glucagon is a protein hormone secreted by the A cells of the endocrine pancreas. Acting through G-protein-coupled receptors in heart, smooth muscle, and liver, glucagon increases heart rate and force of contraction, increases hepatic glycogenolysis and gluconeogenesis, and relaxes smooth muscle. The smooth muscle effect is particularly marked in the gut.

Clinical Uses

Glucagon is used to treat severe hypoglycemia in diabetics, but its hyperglycemic action requires intact hepatic glycogen stores. The drug is given intramuscularly or intravenously. In the management of severe -blocker overdose, glucagon may be the most effective method for stimulating the depressed heart because it increases cardiac cAMP without requiring access to  receptors (Chapter 59).

Skill Keeper Answers: Diabetes and Hypertension

(Chapter 11)

1. The major antihypertensive drug groups are (a) -adrenoceptor blockers; (b) 1-selective adrenoceptor blockers (eg, prazosin); (c) centrally acting sympathoplegics (eg, clonidine or methyldopa); (d) calcium channel blockers (eg, diltiazem, nifedipine, verapamil); (e) angiotensin-converting enzyme (ACE) inhibitors (eg, captopril); (f) angiotensin receptor antagonists (eg, losartan); and (g) thiazide diuretics.

2. ACE inhibitors slow the progression of diabetic nephropathy and help stabilize renal function. Angiotensin receptor antagonists may have similar protective effects in patients with diabetes. Beta-adrenoceptor blockers can, in theory, mask the symptoms of hypoglycemia in diabetic patients; however, many patients with diabetes and cardiovascular disease are successfully treated with these drugs. A large clinical trial showed that control of hypertension decreases diabetes-associated microvascular disease. This trial included many patients being maintained on -adrenoceptor blockers. Thiazide diuretics impair the release of insulin and tissue utilization of glucose, so they should be used with caution for patients with diabetes.

Checklist

When you complete this chapter, you should be able to:

 Describe the effects of insulin on hepatocytes, muscle, and adipose tissue.

 List the types of insulin preparations and their durations of action.

 Describe the major hazards of insulin therapy.

List the prototypes and describe the mechanisms of action, key pharmacokinetic features, and toxicities of the major classes of agents used to treat type 2 diabetes.

 Give 3 examples of rational drug combinations for treatment of type 2 diabetes mellitus.

 Describe the clinical uses of glucagon.

Drug Summary Table: Antidiabetic Agents

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Insulins Regular insulin Activate insulin receptor Type 1 and type 2 diabetes Parenteral administration, short-acting Hypoglycemia, weight gain Rapid-acting: Lispro, aspart, glulisine Intermediate-acting: NPH Long-acting: Detemir, glargine Biguanides Metformin Decreased endogenous glucose production Type 2 diabetes Oral administration Gastrointestinal (GI) disturbances, lactic acidosis (rare) Insulin secretagogues Glipizide Increases insulin secretion from pancreatic beta cells by closing ATP-sensitive K+channels

Type 2 diabetes Oral administration Hypoglycemia, weight gain Glyburide, glimepiride: Like glipizide, sulfonylurea drugs with intermediate duration of action Repaglinide, nateglinide: Fast-acting insulin secretagogues Chlorpropamide, tolbutamide: Older sulfonylurea drugs, lower potency, greater toxicity; rarely used Alpha-glucosidase inhibitors Acarbose Inhibit intestinal -glucosidases Type 2 diabetes Oral administration GI disturbances Miglitol: Similar to acarbose Thiazolidinediones Rosiglitazone Regulates gene expression by binding to PPAR- Type 2 diabetes Oral administration Fluid retention, edema, anemia, weight gain, bone fractures in women, may worsen heart disease Pioglitazone: Similar to rosiglitazone Incretin-based drugs Exenatide Analog of glucagon-like peptide-1 (GLP-1) activates GLP-1 receptors Type 2 diabetes Parenteral administration GI disturbances, headache, pancreatitis Sitagliptin Inhibitor of the dipeptidyl peptidase-4 (DPP-4) that degrades GLP-1 and other incretins Type 2 diabetes Oral administration Rhinitis, upper respiratory infections, rare allergic reactions Amylin analogPramlintide Analog of amylin activates amylin receptors Type 1 and type 2 diabetes Parenteral administration GI disturbances, hypoglycemia, headache Glucagon Glucagon Activates glucagon receptors Severe hypoglycemia, -blocker overdose Parenteral administration GI disturbances, hypotension

PPAR-, peroxisome proliferator-activated receptor-gamma.



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