Chapter 24. Pancreatic Hormones and Antidiabetic Drugs

The islets of Langerhans in the pancreas contain four main types of endocrine cells (Table 24–1). These cells include glucagon-producing alpha cells (A or α), insulin- and amylin-producing beta cells (B or β), somatostatin-producing delta cells (D or δ), and pancreatic polypeptide-producing cells (F). Of these, the insulin-producing B cells are the most numerous. The most common disease related to pancreatic function is diabetes mellitus (DM), a deficiency of insulin production or effect.

Knowledge of the mechanism of action and physiologic function of insulin is critical in understanding the clinical use of insulin and oral hypoglycemic drugs as the pharmacologic treatments of DM.

Insulin is required in type 1 DM, and several parenteral formulations of insulin are available (Figure 24–1). Type 2 DM can be treated with drug classes that include four types of oral antidiabetic drugs, incretin mimetics, and an amylinomimetic (Figure 24–1), as well as insulin, if required. Glucagon, a hormone that affects the liver, cardiovascular system, and gastrointestinal tract, can be used to treat severe hypoglycemia in patients with DM.

Insulin is synthesized as proinsulin, an 86–amino acid single-chain polypeptide. Proinsulin is processed in the Golgi apparatus of pancreatic B cells and then packaged into granules in the form of crystals consisting of two atoms of zinc and six molecules of insulin. In the Golgi apparatus, cleavage of proinsulin removes a 31–amino acid C peptide and leaves two peptide chains that are then cross-linked by two disulfide bonds. Neither proinsulin nor C peptide appears to have important physiologic actions.

Insulin release from pancreatic B cells occurs at a low basal rate, and at a much higher rate in response to a variety of stimuli, especially glucose. The mechanism by which glucose regulates insulin release is well understood. In B cells, glucose metabolism increases intracellular adenosine triphosphate (ATP) levels. ATP-regulated potassium channels respond to increased ATP concentrations by closing, thus reducing potassium conductance (Figure 24–2). Closure of potassium channels results in membrane depolarization (fewer positive ions leaving the cell), which in turn promotes opening of voltage-gated calcium channels. The resulting increase in intracellular free calcium triggers insulin secretion.

Insulin circulates in the blood and exerts its effects by activating insulin receptors located on almost all cells. The insulin receptor is a transmembrane tyrosine kinase receptor. When activated by insulin binding, the insulin receptor phosphorylates itself and a set of intracellular proteins that comprise intracellular signaling pathways. This series of phosphorylations within the cell results in multiple effects including translocation of glucose transporters (GLUTs) to the plasma membrane, changes in activity of enzymes involved in carbohydrate, protein, and lipid metabolism, and complex effects on cell growth and division.

Physiologic Effects

While insulin has important effects in almost every tissue of the body, the principal targets are liver, muscle, and adipose tissue (Figure 24–3). The cellular functions regulated by insulin in these tissues are outlined in Table 24–2. In the liver, insulin increases glycogen synthesis by increasing the activity of enzymes that convert glucose to glycogen (e.g., glucokinase, glycogen synthase) and by inhibiting enzymes involved in glycogenolysis and gluconeogenesis (e.g., glycogen phosphorylase, glucose-6-phosphate, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase). Insulin also promotes glycolysis and carbohydrate oxidation by increasing the activity of enzymes that convert glucose to pyruvate (e.g., phosphofructokinase and pyruvate kinase) and the enzyme that accomplishes oxidation of pyruvate (pyruvate dehydrogenase). Finally, insulin increases the synthesis and storage of triglycerides and the formation of very low-density lipoprotein (VLDL) and decreases protein catabolism. In muscle, insulin stimulates glucose uptake by recruiting GLUT4 transporters to the plasma membrane. Through effects on enzymes in metabolic pathways, insulin promotes glycogen synthesis, glycolysis, and carbohydrate oxidation. Insulin also promotes protein synthesis and inhibits protein breakdown. Finally, insulin promotes glucose uptake in adipose tissue through GLUT4 transporters. Through effects on enzymes involved in glycolysis and lipid synthesis, glucose is used to fuel synthesis of triglycerides. Simultaneously, insulin inhibits the breakdown of triglycerides to glycerol and free fatty acids. In addition, insulin stimulates synthesis of lipoprotein lipase, which liberates fatty acids from circulating chylomicrons and VLDL so they can enter adipocytes and be converted into triglycerides. Insulin’s net effect in liver, muscle, and adipose tissue is to move glucose from blood into cells, which boosts supplies of glycogen and lipids that can later be used to supply energy during fasting.

DM is diagnosed on the basis of more than one fasting blood glucose concentration in excess of 126 mg/dL, a 2-hour oral glucose tolerance test equal to or greater than 200 mg/dL, or a “casual” blood glucose level of greater than 200 mg/dL. Casual is defined as any time during a 24-hour period without regard to the time of the last meal. The serum concentration of hemoglobin (Hb)A1c, a glycosylated hemoglobin, is another important index of the recent glycemic state of a patient. Thus, HbA1c serves as an index of glucose levels over the previous 6 to 12 weeks (although it is heavily weighted toward the most recent 2 weeks), whereas blood or urine glucose concentration reflects glucose control near the time of sample collection. The normal range for HbA1c in nondiabetic individuals is 4 to 6%, and the recommended level for diabetics is 7% or less.

The disease states that are included in the diagnosis of DM fall into three major categories: type 1 (insulin-dependent DM), type 2 (non-insulin-dependent DM), and gestational DM (diabetes of pregnancy). Other forms of DM are uncommon. Regardless of the cause of DM, the treatment of DM requires careful attention to blood glucose and HbA1c concentrations.

Type 1 Diabetes Mellitus

The hallmarks of type 1 DM are selective B-cell destruction in the islets of Langerhans, severe or absolute insulin deficiency, and a high risk of ketoacidosis. This latter dangerous condition results from excessive metabolism of fat when glucose utilization is impaired. Administration of insulin is required in patients with type 1 DM. Type 1 DM is further subdivided into immune and idiopathic causes. The immune form, in which a patient’s immune system mounts a destructive immunologic response to the pancreatic B cells, is the most common form of type 1 DM. Although most patients are younger than 30 years of age at the time of diagnosis of type 1 DM, the onset can occur at any age. Type 1 DM is found in all ethnic groups, but the highest incidence is in people from northern Europe and Sardinia. Susceptibility appears to involve a multifactorial genetic linkage, but only 15 to 20% of patients have a positive family history.

Type 2 Diabetes Mellitus

Type 2 DM is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. A given individual may have more resistance or more B-cell deficiency, and the abnormalities may be mild or severe. Although insulin is produced by B cells in patients with type 2 DM, the amount secreted (which may be quite high) is inadequate to overcome the resistance, and blood glucose levels rise. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels, and a low serum concentration of high-density lipoprotein (HDL), the lipoprotein that has a protective effect against atherosclerosis. Individuals with type 2 DM may not require insulin to survive, but 30% or more will benefit from insulin therapy at some time during their lives to control high blood glucose levels. Ten to twenty percent of individuals in whom type 2 DM was initially diagnosed may actually have both type 1 and type 2 DM, or have a slowly progressing type 1, and ultimately will require full insulin replacement. Dehydration in untreated and poorly controlled individuals with type 2 DM can lead to a life-threatening condition called “non-ketotic hyperosmolar coma.” In this condition, blood glucose may rise to six to twenty times the normal range, and an altered mental state develops that may progress to loss of consciousness. Urgent medical care and rehydration is required. Although people with type 2 DM ordinarily do not develop ketosis, ketoacidosis may occur as the result of a stressor such as infection or the use of a medication that enhances insulin resistance such as a glucocorticoid (Chapter 23).

Gestational Diabetes Mellitus

Gestational DM is defined as any abnormality in glucose levels noted for the first time during pregnancy, and is diagnosed in approximately 4% of pregnancies in the United States. During pregnancy, a hormone produced by the placenta (human placental lactogen) with homology to growth hormone and prolactin exerts an anti-insulin effect. This causes insulin resistance and DM in some women, particularly in the last trimester. Because gestational DM carries risks for maternal and fetal outcomes, pregnant women are routinely screened for gestational diabetes with glucose challenge tests in the second trimester. The standard therapy for gestational diabetes is insulin. However, recent clinical trials suggest that some oral antidiabetic drugs are safe in pregnancy.

Insulin Preparations

Insulins derived from animals (pork or beef) are no longer available in the United States. Pharmaceutical human insulin is manufactured by recombinant DNA technology. Because the native insulin molecule has a half-life of only a few minutes in the circulation, many preparations are formulated to release the hormone slowly into the circulation. The available insulin formulations provide five rates of onset and durations of effect: ultra-rapid onset, rapid onset with short action, intermediate onset and action, slow onset with peak action, and ultra-slow onset with no peak (i.e., plateau only) action (Table 24–3). All insulin preparations contain zinc. The ratio of zinc and other substances to insulin influences the rate of release of active hormone from the site of administration and the duration of action (Figure 24-4).

Ultra-rapid action insulins are represented by insulin lispro, insulin aspart, and insulin glulisine. These preparations are recombinant human insulins that contain transpositions of two amino acids or replacement of one or more native amino acids. These changes alter physical properties of the peptides so that they dissolve more rapidly at the site of administration and enter the circulation approximately twice as fast as regular crystalline insulin. These insulins are suitable for use immediately before meals. Unlike other insulin preparations, increasing the dose only increases the maximum effect, not the duration of effect.

Regular crystalline-zinc insulin is a rapid-onset and short-action formulation. The insulin is used intravenously in emergencies or administered subcutaneously in maintenance regimens, alone or mixed with intermediate- or long-acting preparations. Before the development of the ultra-rapid insulins, regular insulin was the primary rapid-onset agent. However, regular insulin requires administration 1 hour or more before each meal.

A special formulation of regular insulin was approved for inhalation (Exubera) in 2007. This was the first insulin formulation that did not require injection, but interest was too low to support continued production and the drug was discontinued.

The major intermediate-onset and intermediate-action preparation currently available is isophane insulin suspension (NPH insulin). This preparation is given by subcutaneous injection; it is not suitable for intravenous use. Intermediate-onset NPH insulin can be mixed in the syringe or purchased premixed with regular insulin for convenience of administration.

Insulins with very slow onset and prolonged action are represented by ultralente insulin, insulin glargine, and insulin detemir. Ultralente insulin has a very delayed peak at 12 hours after injection and has fallen out of favor. Insulins glargine and detemir achieve a plateau within 3 to 6 hours and maintain a relatively constant blood level for up to 24 hours. These formulations are usually given in the morning only or in the morning and evening to provide maintenance or basal levels for 12 to 24 hours. This basal insulin level may be supplemented (especially in the case of insulins glargine and detemir) with injections of insulin lispro or regular insulin during the day to meet the requirements of carbohydrate intake.

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 pumps avoid the need for multiple daily injections and provide flexibility in the scheduling of patients’ daily activities. These programmable pumps deliver a constant 24-hour basal rate, and manual adjustments in the rate of delivery can be made to accommodate changes in insulin requirements. Dosage changes may be required prior to meals or exercise. While insulin pumps have many advantages over subcutaneous injections, the pump and its disposable accessories (e.g., tubing) are expensive. The inhaled formulation of insulin had pharmacokinetic properties that made it useful for covering mealtime insulin requirements. This insulin formulation was administered within 10 minutes prior to a meal.

Adverse Effects

Diabetic patients who use insulin are subject to two types of complications: hypoglycemia, from excessive insulin effect, and immunologic toxic effects, from the development of antibodies. Hypoglycemia is very dangerous because brain damage may result. Rapid development of hypoglycemia in individuals with intact hypoglycemic awareness causes autonomic hyperactivity, with both sympathetic and parasympathetic manifestations. The sympathetic manifestations include tachycardia, palpitations, sweating, and tremulousness. The parasympathetic manifestations include nausea and hunger. Hypoglycemia may progress to convulsions and coma if untreated. In diabetic patients who experience frequent hypoglycemic episodes, autonomic warning signs can be less frequent or even absent. These patients can develop severe manifestations of hypoglycemia, including confusion, weakness, bizarre behavior, coma, or seizures without warning. Every patient with DM who is receiving hypoglycemic drug therapy should have an identification bracelet, necklace, or card in the wallet or purse, as well as some form of rapidly absorbed glucose. In patients with hypoglycemia, prompt administration of glucose or simple sugars is essential. The glucose may be given either as sugar or candy by mouth or as intravenous glucose. Alternatively, an intramuscular injection of glucagon can be used to raise serum glucose concentrations. Patients with advanced renal disease, the elderly, and children younger than 7 years are most susceptible to hypoglycemia and its detrimental effects.

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 insulin’s action or allergic reactions. With the current use of highly purified human insulins, immunologic complications are very uncommon. Insulin may also cause weight gain, which is particularly undesirable in patients with type 2 DM, who are frequently overweight.

Amylinomimetic

Amylin, a 37–amino acid protein that activates G protein–coupled receptors, is co-secreted with insulin from the B cells. Pramlintide is a synthetic analog of amylin. Administration of pramlintide has multiple effects on glucose regulation. The drug reduces postprandial glucose elevation by prolonging gastric emptying and reducing glucagon secretion following a meal. Through centrally mediated appetite suppression, it reduces caloric intake and causes weight loss, an important benefit for overweight patients. Administration is by subcutaneous injection, with a time to peak plasma concentration of 20 minutes and a half-life of 48 minutes (Table 24–4). Pramlintide is used in both types 1 and 2 DM.

Adverse Effects

Headaches, nausea, vomiting, and loss of appetite occur. Severe hypoglycemia also occurs and is more common in patients with type 1 DM compared to patients with type 2 DM. Arthralgia has been reported in some patients, and allergic reactions are possible.

Incretin Mimetic

Exenatide, a newer drug for treating type 2 diabetes, is a long-acting peptide with a high degree of homology to a hormone called glucagon-like peptide-1 (GLP-1). A finding that long puzzled endocrinologists was the ability of oral glucose to induce more insulin release than an equivalent amount of intravenous glucose. This finding suggested the existence of a gastrointestinal tract–derived substance that stimulates insulin release. Further research led to discovery of two hormones, called incretins, that are released from endocrine cells in the bowel epithelium in response to food. One of these is GLP-1. GLP-1 and exenatide have multiple effects. In addition to augmentation of glucose-stimulated insulin release from pancreatic B cells, they retard gastric emptying, inhibit glucagon secretion, and produce a sense of satiety. Exenatide must be injected subcutaneously twice daily, has a time to peak plasma concentration of approximately 2 hours, and has an elimination half-life of 2.5 hours; the duration is given in Table 24–4. Exenatide has modest therapeutic utility, and is always used in combination with metformin or a secretagogue.

Adverse Effects

Nausea, especially early in the course of treatment, is a problem and can be accompanied by vomiting and diarrhea. Hypoglycemia has occurred when exenatide is combined with an insulin secretagogue but has not been seen when exenatide is combined with metformin.

Oral Antidiabetic Drugs

Five groups of drugs are used for the oral treatment of type 2 DM: insulin secretagogues, biguanides, thiazolidinediones, gliptins, and α-glucosidase inhibitors. Important members of these groups are listed in Table 24–4.

Insulin Secretagogues

The primary action of the insulin secretagogues is to stimulate the release of endogenous insulin. Most of the insulin secretagogues are in the chemical class known as sulfonylureas. The sulfonylureas close the ATP-regulated potassium channels in the pancreatic B cell membranes; channel closure depolarizes the cells, which triggers insulin release (Figure 24–2). Insulin secretagogues are not effective in patients who lack functional B cells. These drugs may also reduce glucagon release and increase the number of functional insulin receptors in peripheral tissues. The second-generation sulfonylureas such as glyburide, glipizide, or glimepiride are considerably more potent and much more commonly used than the older agents such as tolbutamide or chlorpropamide.

Repaglinide and nateglinide are newer insulinsecretagogues. Repaglinide is from a chemical class called meglitinides, whereas nateglinide is a D-phenylalanine derivative. Both of these drugs also promote insulin release by closing ATP-regulated potassium channels in pancreatic B cell membranes. The most notable difference between the newer drugs and sulfonylureas is the rapid onset and short duration of action of the newer agents (Table 24–4). They can be taken just before meals to control postprandial glucose concentrations.

Adverse Effects

Hypoglycemia is the most common adverse effect of the secretagogues. Occasionally, rash and allergy are reported. The older sulfonylureas, which include tolbutamide and chlorpropamide, are extensively bound to serum proteins, and drugs that compete for protein binding may enhance their hypoglycemic effects. Chlorpropamide has a long duration of action, and liver and kidney disease may greatly increase blood levels of the drug. Like insulin, insulin secretagogues cause weight gain, which is undesirable in the large number of patients with type 2 DM who are overweight.

Biguanides

The biguanides act by a poorly understood mechanism to reduce postprandial and fasting glucose levels in patients with type 2 DM. Their effects do not depend on functional B islet cells. Proposed mechanisms for their action include reduced hepatic gluconeogenesis, stimulation of glycolysis in peripheral tissues, reduction of glucose absorption from the gastrointestinal tract, and reduction of plasma glucagon levels. Several biguanides are in use overseas. Metformin is the only member of this group available in the United States. Unlike the sulfonylureas, the biguanides do not cause hypoglycemia. Unlike all other oral antidiabetic drugs and insulin, metformin does not cause weight gain. The duration of action of metformin is intermediate when compared to most other oral antidiabetic drugs (Table 24–4).

Adverse Effects

The most common toxicity associated with metformin is nausea and diarrhea, and the most serious toxicity is lactic acidosis. The increased risk of lactic acidosis presumably arises because of impaired conversion of lactic acid to glucose, an important reaction normally performed in the liver. Patients with renal or liver disease, alcoholism, or conditions that predispose them to tissue anoxia and excess lactic acid production, such as chronic cardiopulmonary dysfunction, are at greatest risk. Metformin also inhibits vitamin B12 absorption.

Thiazolidinediones

Thiazolidinediones increase target tissue sensitivity to insulin. Troglitazone was the first thiazolidinedione introduced, but it was removed from the market in several countries because of hepatotoxicity. Rosiglitazone and pioglitazone appear to carry less risk of serious liver dysfunction. The mechanism of action of the thiazolidinediones is not fully understood, but they stimulate the peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR-γ receptor). This nuclear receptor regulates the transcription of genes encoding proteins involved in carbohydrate and lipid metabolism.

The thiazolidinediones increase glucose uptake in muscle and adipose tissue, 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. Durations of action of thiazolidinediones are presented in Table 24–4.

Adverse Effects

When these drugs are used alone, hypoglycemia is extremely rare. Liver function should be monitored. Thiazolidinediones can cause volume expansion, which presents as edema and mild anemia, especially when combined with exogenous insulin. Heart failure and other cardiovascular complications may occur. Some evidence suggests an increased risk of fractures. Because pioglitazone and troglitazone appear to induce cytochrome P450 enzymes, these drugs can reduce serum concentrations of drugs such as oral contraceptives or cyclosporine that are also metabolized by these enzymes.

Gliptins

The gliptins are orally active inhibitors of dipeptidyl peptidase-4, the enzyme that metabolizes endogenous incretins and similar GLP-1–like molecules. Their effects on glucose metabolism thus resemble those of exenatide, which mimics GLP-1. Elimination is via the kidney, so dosage must be reduced in patients with renal impairment. Sitagliptin is the first of this class to be approved. The adverse effects of the drug include headache, nasopharyngitis, and upper respiratory tract infections.

α-Glucosidase Inhibitors

Acarbose and miglitol are carbohydrate analogs that act within the intestine to inhibit α-glucosidase, an enzyme necessary for the conversion of complex starches, oligosaccharides, and disaccharides to monosaccharides that can be transported out of the intestinal lumen and into the bloodstream. As a result of impaired absorption, postprandial hyperglycemia is reduced. These drugs have no effect on fasting blood sugar. Both drugs can be used as monotherapy, or in combination with other anti-diabetic drugs. This drug class has one of the shorter durations of action of the oral antidiabetic drugs (Table 24–4).

Adverse Effects

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

Type 1 Diabetes Mellitus

Therapy of type 1 DM involves dietary instruction and separate or mixed parenteral administration of shorter and longer acting insulins to maintain stable blood glucose levels during the day and night. The patient must also give careful attention to factors that change insulin requirements. These factors include exercise, infection, other forms of stress, and deviations from the regular diet. Large clinical studies indicate that tight control of blood glucose levels (i.e., “glycemic control”) by frequent blood glucose 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 Mellitus

Type 2 DM is usually a progressive disease, and treatment for an individual patient generally escalates over time. Initial treatment begins with weight reduction and dietary control because most type 2 diabetics are overweight. Initial drug therapy is usually monotherapy, often with a second-generation sulfonylurea such as glyburide, glipizide, glimepiride, or, increasingly for patients with type 2 DM and obesity, metformin. Although the initial response to monotherapy is usually good, erosion of glycemic control within 5 to 10 years is common. When monotherapy fails to provide adequate glycemic control, oral antidiabetic drugs are used in combination with each other or with insulin. Because type 2 DM involves both insulin resistance and eventual inadequate insulin production, pharmacotherapy often combines an agent that augments insulin’s action with one that augments insulin blood levels. The former includes metformin, a thiazolidinedione, or an α-glucosidase inhibitor, and the latter includes insulin secretagogues, exenatide, or insulin. Sulfonylureas, metformin, thiazolidinediones, and some insulin formulations are long-acting drugs that help control both fasting and postprandial blood glucose levels. In contrast, repaglinide, α-glucosidase inhibitors, exenatide, regular insulin, and the ultra-short insulins are short-acting drugs that primarily target postprandial glucose levels. As is the case for type 1 DM, clinical trials have shown that tight glycemic control in patients with type 2 DM reduces the risk of vascular complications.

Glucagon

Glucagon is a hormone secreted by the A cells of the endocrine pancreas. Glucagon acts through G protein–coupled receptors to stimulate adenylyl cyclase and increase intracellular cyclic adenosine monophosphate (cAMP). Activation of glucagon receptors induces positive chronotropic and inotropic effects in the heart, increases hepatic glycogenolysis and gluconeogenesis, and relaxes smooth muscle, particularly smooth muscle in the gastrointestinal tract.

Clinical Uses

Glucagon can be used to treat severe hypoglycemia in patients with DM or insulin-secreting tumors, but its hyperglycemic action requires intact hepatic glycogen stores. The drug is given intramuscularly or intravenously. Glucagon is also valuable for radiographic studies of the bowel or abdomen when temporary reduction of motility is necessary for optimal visualization. In the management of severe adrenergic β-blocker overdose, glucagon may be the most effective method for stimulating the depressed heart because it increases cardiac cAMP without accessing β receptors.

Because diabetes is so common (especially type 2), physical therapists often treat patients with this disease. The therapist may work with an overweight patient to develop an exercise program to promote weight loss, conduct exercise stress treadmill testing as a precursor to the exercise program, or treat the patient because of a complication of long-standing DM. These complications include stroke, cardiovascular disease, nephropathy, retinopathy, repeated infections, and various neuropathies and chronic nonhealing wounds associated with vascular insufficiency or reduced sensation in weight-bearing areas.

Initiation of an exercise regimen along with changes in lifestyle, diet, and pharmacotherapy are four cornerstones of the treatment of both type 1 and 2 DM. Lifestyle changes for patients with type 2 DM include weight reduction and smoking cessation. Dietary goals include eating balanced meals at regular intervals with a reduction in simple carbohydrates following the guidelines set forth by the American Diabetes Association. Some patients with type 2 DM can delay pharmacotherapy with appropriate exercise, diet, and lifestyle changes. Patients with type 1 DM may also improve their glycemic control with a regular exercise program. Regular exercise by patients with both types of DM helps maintain cardiovascular and respiratory function and prevent osteoporosis.

Exercise stress testing should precede the design of an exercise program, especially if cardiovascular pathophysiology is present or a risk. Exercise programs for DM patients should include both aerobic and resistive exercise training because both have been shown to benefit this patient population. In healthy young nondiabetic patients, heart rate is the primary guide to aerobic exercise intensity; maximum target heart rate is often set at 60 to 90% of the age-predicted maximum heart rate. However, in patients medicated with β blockers or those with long-standing DM, the Borg Relative Perceived Exertion (RPE) should be used. In the latter case, autonomic neuropathy can affect heart rate, and RPE may be a better indicator of exercise intensity. In diabetic patients, the target heart rate should be adjusted to 55 to 79% of maximum (9 to 11 RPE). Lower target heart rates of 50 to 60% of maximum (7 to 9 RPE) during exercise should be considered if the initial fitness level is low.

Exercise is not always beneficial to the patient with DM and may be detrimental, depending upon current glycemic control. Exercise is contraindicated when ketosis is present because exercise may exacerbate ketoacidosis. Because exercise increases peripheral uptake of glucose, insulin or oral hypoglycemic drug dosages need to be adjusted to prevent hypoglycemic episodes. Hypoglycemia is always a risk in patients being treated with insulin or secretagogue oral antidiabetic drugs. Physical therapists need to be aware of the fact that repeated bouts of hypoglycemia, resulting from exercise or other causes of poor glycemic control, may result in blunted autonomic nervous system warning symptoms.

Adverse Drug Reactions

Insulin, exenatide, and pramlintide

• • Hypoglycemia, mainly with insulin
• • Nausea and vomiting
• • Weight gain, mainly with insulin and pramlintide

Oral Hypoglycemics

• • Hypoglycemia with the insulin secretagogues
• • Weight gain with the insulin secretagogues
• • Lactic acidosis with biguanides
• • Myocardial infarction, edema, heart failure, and anemia with thiazolidinediones
• • Flatulence, diarrhea, and abdominal pain with the α-glucosidase inhibitors

Effects Interfering with Rehabilitation

• • Post–exercise-induced hypoglycemia may be exacerbated by insulin, pramlintide, and insulin secretagogues.

Possible Therapy Solutions

• • Monitor blood glucose levels in all DM patients prior to exercise.
• • Check blood pressure and heart rate in patients prior to exercise.
• • Discuss with patient the importance of regular meals in conjunction with exercise to control glycemic levels.

Potentiation of Functional Outcomes Secondary to Drug Therapy

• • Long-term glycemic control with a conditioning program will assist in weight and glycemic control and improve cardiovascular status.

Brief History: The patient is a 50-year-old male with a body mass index of 30 and a 15-year history of type 2 DM and hypertension. The patient is a lawyer with a sedentary lifestyle who previously declined his health-care provider’s recommendations to participate in aerobic conditioning programs. The patient controls his diet poorly. He quit smoking 2 years ago.

On examination, the resting heart rate is 68 beats per minute and blood pressure is 130/85 mm Hg. His past history of HbA1c ranges from 7.5 to 8.7%, with the high value being the most recent. His recent finger-stick blood glucose levels have ranged from 95 to 280 mg/dL. Recently, he experienced left shoulder pain that was diagnosed as atherosclerotic exertional angina pectoris. Following this diagnosis, he expressed an interest in developing a regular conditioning program along with dietary changes to improve glycemic control. The patient underwent cardiac stress testing and cardiac catheterization. Electrocardiographic changes were noted during the stress test, and catheterization revealed single vessel disease with 40% occlusion. The cardiologist recommended that the patient continue his medications and begin an exercise program. The patient was sent to an outpatient rehabilitation clinic for program development.

Current Medical Status and Drug Therapy: Previously, the patient was using insulin glargine to provide daily background control in combination with insulin lispro to achieve optimal postprandial glycemic control. The oral hypoglycemic was rosiglitazone. Within the past 3 weeks, the patient converted to a single-compartment insulin pump. Insulin lispro is used in the pump at a lower background rate with boluses at mealtime. Since the medication change, finger-stick daily blood glucose levels have been 58 to 120 mg/dL prior to meals and at bedtime. The pharmacotherapy for hypertension includes labetalol, enalapril, and hydrochlorothiazide. Labetalol also provides prophylaxis for angina pectoris, while enalapril provides prophylaxis for DM nephropathy.

Rehabilitation Setting: Due to documented pathology obtained from the electrocardiogram and cardiac catheterization, poor initial fitness level of the patient, and presence of a β-receptorantagonist (labetalol), the target exertion level for the exercise program was set at 7 RPE. The program included 10 minutes of warm-up with resistive weight training, 20 minutes of treadmill walking at the target RPE, followed by stretching during a 10-minute cool-down period. This program was to be conducted every day. The patient was complaining about his busy day when he arrived for his first supervised session following work this afternoon. The insulin pump was left on with the background infusion at the preestablished value. The patient completed both the warm-up phase and aerobic training without incident. However, during the cool-down period, he appeared confused and could not follow instructions, and noted that he was hungry and wondered whether he should have had a larger lunch. His skin was cool and clammy; however, his heart rate was 78 bpm and blood pressure was 138/89 mm Hg. No assessment of blood glucose was available, but the patient was provided a regular (nondiet) soda. The emergency paramedics were contacted. By the time they arrived, the patient was coherent, standing, and talking. Measurement of finger-stick blood glucose taken by the paramedics was 68 mg/dL. The patient was transferred to the local hospital for further evaluation.

Problem/Clinical Options: The patient had a previous history of poor glycemic control. Periods of both hyperglycemia and hypoglycemia were documented in the medical history. Three weeks previously, the change to the insulin pump tightened glycemic control, decreasing hyperglycemic episodes, but also causing recorded hypoglycemic episodes. Exercise increased the effects of insulin and the pump was left on at the background infusion rate, setting the stage for a hypoglycemic episode. No documentation of glucose concentration was available, but hypoglycemia likely occurred as a result of the combination of a small meal at lunch, stress from a busy day, exercise, and insulin. In addition, the β-receptor antagonist would have blunted sympathetic manifestations of hypoglycemia. A nondiet soda (which contains a fair amount of glucose) was given to the patient counter potential hypoglycemia.

Oral Hypoglycemic Preparations

Sulfonylureas

Acetohexamide (Dymelor) (Rarely Used)

Oral: 250-, 500-mg tablets

Chlorpropamide (Generic, Diabinese)

Oral: 100-, 250-mg tablets

Glimepiride (Amaryl)

Oral: 1-, 2-, 4-mg tablets

Glipizide (Generic, Glucotrol, Glucotrol XL)

Oral: 5-, 10-mg tablets; 5-, 10-mg extended-release tablets

Glyburide (Generic, Diabeta, Micronase, Glynase PresTab)

Oral: 1.25-, 2.5-, 5-mg tablets; 1.5-, 3-, 4.5-, 6-mg Glynase PresTab, micronized tablets

Tolazamide (Generic, Tolinase)

Oral: 100-, 250-, 500-mg tablets

Tolbutamide (Generic, Orinase)

Oral: 500-mg tablets

Meglitinide and Related Drugs

Repaglinide (Prandin)

Oral: 0.5-, 1-, 2-mg tablets

Nateglinide (Starlix)

Oral: 60-, 120-mg tablets

Biguanide and Biguanide Combinations

Metformin (Glucophage, Glucophage XR)

Oral: 500-, 850-, 1000-mg tablets; extended-release (XR): 500-mg tablets

Metformin Combinations

Glipizide Plus Metformin (Metaglip)

Oral: 2.5/250-, 2.5/500-, 5/500-mg tablets

Glyburide Plus Metformin (Glucovance)

Oral: 1.25/250-, 2.5/500-, 5/500-mg tablets

Rosiglitazone Plus Metformin (Avandamet)

Oral: 1/500-, 2/500-, 4/500-mg tablets

Thiazolidinedione Derivatives

Pioglitazone (Actos)

Oral: 15-, 30-, 45-mg tablets

Rosiglitazone (Avandia)

Oral: 2-, 4-, 8-mg tablets

α-Glucosidase Inhibitors

Acarbose (Precose)

Oral: 50-, 100-mg tablets

Miglitol (Glyset)

Oral: 25-, 50-, 100-mg tablets

Incretin Enhancer

Sitaglipin (Januvia)

Oral: 25-, 50-, 100-mg tablets

Amylinomimetic

Pramlinitide (Symlin)

Parenteral: subcutaneous administration 0.6 mg/mL

Incretin Mimetic

Exenatide (Byetta)

Parenteral: 5, 10 mcg/dose in prefilled pens for subcutaneous administration

Glucagon

Glucagon (Generic)

Parenteral: 1-mg lyophilized powder to reconstitute for injection

1See Table 24–3 for examples of Insulin preparations.