Basic & Clinical Pharmacology, 10th Edition

41. Pancreatic Hormones & Antidiabetic Drugs - Martha S. Nolte, MD, & John H. Karam, MD*

THE ENDOCRINE PANCREAS

Introduction

The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland. Within the islets, at least four hormone-producing cells are present (Table 41-1). Their hormone products include insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal inhibitor of secretory cells; and pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified.

The elevated blood glucose associated with diabetes mellitus results from absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories: type 1, insulin-dependent diabetes; type 2, noninsulin-dependent diabetes; type 3, other; and type 4, gestational diabetes mellitus (Expert Committee, 2003).

*Deceased.

Type 1 Diabetes Mellitus

The hallmark of type 1 diabetes is selective B-cell destruction and severe or absolute insulin deficiency. Administration of insulin is essential in patients with type 1 diabetes. Type 1 diabetes is further subdivided into immune and idiopathic causes. The immune form is the most common form of type 1 diabetes. Although most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age. Type 1 diabetes is found in all ethnic groups, but the highest incidence is in people from northern Europe and from Sardinia. Susceptibility appears to involve a multifactorial genetic linkage but only 10-15% of patients have a positive family history.

Type 2 Diabetes Mellitus

Type 2 diabetes 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 the B cells in these patients, it is inadequate to overcome the resistance, and the blood glucose rises. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein (HDL).

Individuals with type 2 diabetes may not require insulin to survive, but 30% or more will benefit from insulin therapy to control the blood glucose. It is likely that 10-20% of individuals in whom type 2 diabetes was initially diagnosed actually have both type 1 and type 2 or a slowly progressing type 1, and ultimately will require full insulin replacement. Although persons with type 2 diabetes ordinarily do not develop ketosis, ketoacidosis may occur as the result of stress such as infection or use of medication that enhances resistance, eg, corticosteroids. Dehydration in untreated and poorly controlled individuals with type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma. In this condition, the blood glucose may rise to 6-20 times the normal range and an altered mental state develops or the person loses consciousness. Urgent medical care and rehydration is required.

Type 3 Diabetes Mellitus

The type 3 designation refers to multiple other specific causes of an elevated blood glucose: nonpancreatic diseases, drug therapy, etc. For a detailed list the reader is referred to Expert Committee, 2003.

Type 4 Diabetes Mellitus

Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. Gestational diabetes is diagnosed in approximately 4% of all pregnancies in the USA. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. Risk assessment for diabetes is suggested starting at the first prenatal visit. High-risk women should be screened immediately. Screening may be deferred in lower-risk women until the 24th to 28th week of gestation.

INSULIN

Chemistry

Insulin is a small protein with a molecular weight in humans of 5808. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges; there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids (shown in dashed circles in Figure 41-1).

Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues; a small quantity of unprocessed or partially hydrolyzed proinsulin is released as well. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the B cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. Originally, the unit was defined on the basis of the hypoglycemic activity of insulin in rabbits. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay purposes contain 28 units per milligram.

Insulin Secretion

Insulin is released from pancreatic B cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose), certain amino acids (eg, leucine, arginine), hormones such as glucagon-like polypeptide-1 and vagal activity are recognized. One mechanism of stimulated insulin release is diagrammed in Figure 41-2. As shown in the figure, hyperglycemia results in increased intracellular ATP levels, which close the ATP-dependent potassium channels. Decreased outward potassium efflux results in depolarization of the B cell and opening of voltage-gated calcium channels. The resulting increased intracellular calcium triggers secretion of the hormone. The insulin secretagogue drug group (sulfonylureas, meglitinides, and D-phenylalanine) exploits parts of this mechanism.

Insulin Degradation

The liver and kidney are the two main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35-40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30-40%. The half-life of circulating insulin is 3-5 minutes.

Circulating Insulin

Basal insulin values of 5-15 uU/mL (30-90 pmol/L) are found in normal humans, with a peak rise to 60-90 uU/mL (360-540 pmol/L) during meals.

The Insulin Receptor

After insulin has entered the circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the membranes of most tissues. The biologic responses promoted by these insulin-receptor complexes have been identified in the primary target tissues, ie, liver, muscle, and adipose tissue. The receptors bind insulin with high specificity and affinity in the picomolar range. The full insulin receptor consists of two covalently linked heterodimers, each containing an a subunit, which is entirely extracellular and constitutes the recognition site, and a b subunit that spans the membrane (Figure 41-3). The b subunit contains a tyrosine kinase. The binding of an insulin molecule to the a subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic b subunits into closer proximity. This facilitates mutual phosphorylation of tyrosine residues on the b subunits and tyrosine kinase activity directed at cytoplasmic proteins.

The first proteins to be phosphorylated by the activated receptor tyrosine kinases are the docking proteins, insulin receptor substrate-1 through -6 (IRS-1 to IRS-6). After tyrosine phosphorylation at several critical sites, the IRS molecules bind to and activate other kinases¾most significantly phosphatidylinositol-3-kinase¾which produce further phosphorylations or to an adaptor protein such as growth factor receptor-binding protein 2, which translates the insulin signal to a guanine nucleotide-releasing factor that ultimately activates the GTP binding protein ras, and the mitogen-activated protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine kinases have binding specificity with downstream molecules based on their surrounding 4-5 amino acid sequences or motifs that recognize specific Src homology 2 (SH2) domains on the other protein. This network of phosphorylations within the cell represents insulin's second message and results in multiple effects, including translocation of glucose transporters (especially GLUT 4, Table 41-2) to the cell membrane with a resultant increase in glucose uptake; increased glycogen synthase activity and increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis; and activation of transcription factors that enhance DNA synthesis and cell growth and division. The IRS-2 signaling pathway is associated with cellular proliferation and mitogenesis.

Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin; growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor b subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation.

Effects of Insulin on Its Targets

Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells (Figure 41-4) and influences cell growth and the metabolic functions of a wide variety of tissues (Table 41-3).

Characteristics of Available Insulin Preparations

Commercial insulin preparations differ in a number of ways, such as differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and duration of their biologic action. In 2006, 17 insulin formulations were available in the USA.

A. PRINCIPAL TYPES AND DURATION OF ACTION OF INSULIN PREPARATIONS
Four principal types of injected insulins are available: (1) rapid-acting, with very fast onset and short duration; (2) short-acting, with rapid onset of action; (3) intermediate-acting; and (4) long-acting, with slow onset of action (Figure 41-5, Table 41-4). An inhaled form of rapid-acting insulin also is marketed. Injected rapid-acting and short-acting insulins are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf-life. Inhaled rapid-acting human insulin is available as a powder for alveolar absorption. Injected intermediate-acting NPH insulins have been modified to provide prolonged action and are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin). Insulin glargine and insulin detemir are the soluble long-acting insulins. The goal of subcutaneous insulin therapy is to replace the normal basal (overnight, fasting, and between meal) as well as bolus or prandial (mealtime) insulin. Current regimens generally use long-acting insulins to provide basal or background coverage, and rapid-acting insulin to meet the mealtime requirements. The latter insulins are given as supplemental doses to correct transient hyperglycemia. Intensive therapy ("tight control") attempts to restore near-normal glucose patterns throughout the day while minimizing the risk of hypoglycemia.

An exact reproduction of the normal glycemic profile is technically not possible because of the limitations inherent in subcutaneous administration of insulin. The most sophisticated insulin regimen delivers rapid-acting insulin through a continuous subcutaneous insulin infusion device; alternative intensive regimens referred to as multiple daily injections (MDI) use long-acting insulins with multiple boluses of rapid-acting insulin. Conventional therapy presently consists of split-dose injections of mixtures of rapid- or short-acting and intermediate-acting insulins.

1. Rapid-acting insulin¾ Three injected rapid-acting insulin analogs: insulin lispro, insulin aspart, and insulin glulisine, and one inhaled form of rapid-acting insulin, human insulin recombinant inhaled, are commercially available. The rapid-acting insulins permit more physiologic prandial insulin replacement because their rapid onset and early peak action more closely mimic normal endogenous prandial insulin secretion than does regular insulin, and they have the additional benefit of allowing insulin to be taken immediately before the meal without sacrificing glucose control. Their duration of action is rarely more than 3-5 hours (with the exception of inhaled insulin, which may last 6-7 hours), which decreases the risk of late postmeal hypoglycemia. The injected rapid-acting insulins have the lowest variability of absorption (approximately 5%) of all available commercial insulins (compared to 25% for regular insulin and 25-50% for intermediate- and long-acting formulations). They are the preferred insulins for use in continuous subcutaneous insulin infusion devices.

Insulin lispro, the first monomeric insulin analog to be marketed, is produced by recombinant technology wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29, and lysine at position B29 has been moved to B28 (Figure 41-1). Reversing these two amino acids does not interfere in any way with insulin lispro's binding to the insulin receptor, its circulating half-life, or its immunogenicity, which are similar to those of human regular insulin. However, the advantage of this analog is its very low propensity¾in contrast to human insulin¾to self-associate in antiparallel fashion and form dimers. To enhance the shelf-life of insulin in vials, insulin lispro is stabilized into hexamers by a cresol preservative. When injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5-15 minutes and peak activity as early as 1 hour. The time to peak action is relatively constant, regardless of the dose.

Insulin aspart is created by the substitution of the B28 proline with a negatively charged aspartic acid (Figure 41-1). This modification reduces the normal ProB28 and GlyB23 monomer-monomer interaction, thereby inhibiting insulin self-aggregation. Its absorption and activity profile is similar to that of insulin lispro, and it is more reproducible than regular insulin, but has similar binding properties, activity, and mitogenicity characteristics to regular insulin and equivalent immunogenicity.

Insulin glulisine is formulated by substituting an asparagine for lysine at B3 and glutamic acid for lysine at B29. Its absorption, action, and immunologic characteristics are similar to the other injected rapid-acting insulins. After high-dose insulin glulisine-insulin receptor interaction, there may be downstream differences in IRS-2 pathway activation relative to human insulin. The clinical significance of such differences is unclear.

Inhaled human insulin is a powder form of rDNA human insulin that is administered through an inhaler device and is marketed for pre-prandial and blood sugar correction use in adults with type 1 and 2 diabetes. Because of concerns about lung safety, it is not approved for use in children, teenagers, or adults with asthma, bronchitis, emphysema, smokers, or those within 6 months of quitting smoking. Although this route of administration is well tolerated, studies have shown that less than 30% of users were able to achieve target blood glucoses after 6 months of therapy with inhaled human insulin.

2. Short-acting insulin¾ Regular insulin is a short-acting soluble crystalline zinc insulin made by recombinant DNA techniques to produce a molecule identical to human insulin. Its effect appears within 30 minutes and peaks between 2 and 3 hours after subcutaneous injection and generally lasts 5-8 hours. In high concentrations, eg, in the vial, regular insulin molecules self-aggregate in antiparallel fashion to form dimers that stabilize around zinc ions to create insulin hexamers. The hexameric nature of regular insulin causes a delayed onset and prolongs the time to peak action. After subcutaneous injection, the insulin hexamers are too large and bulky to be transported across the vascular endothelium into the bloodstream. As the insulin depot is diluted by interstitial fluid and the concentration begins to fall, the hexamers break down into dimers and finally monomers. This results in three rates of absorption of the injected insulin, with the final monomeric phase having the fastest uptake out of the injection site. The delayed absorption results in a mismatching of insulin availability with need.

Specifically, when regular insulin is administered at mealtime, the blood glucose rises faster than the insulin with resultant early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Regular insulin should be injected 30-45 or more minutes before the meal to minimize the mismatching. As with all older insulin formulations, the duration of action as well as the time of onset and the intensity of peak action increase with the size of the dose. Clinically, this is a critical issue because the pharmacokinetics and pharmacodynamics of small doses of regular and NPH insulins differ greatly from those of large doses. Short-acting soluble insulin is the only type that should be administered intravenously because the dilution causes the hexameric insulin to immediately dissociate into monomers. It is particularly useful for intravenous therapy in the management of diabetic ketoacidosis and when the insulin requirement is changing rapidly, such as after surgery or during acute infections.

3. Intermediate-acting and long-acting insulins¾

a. NPH (neutral protamine Hagedorn, or isophane) insulin¾ NPH insulin is an intermediate-acting insulin wherein absorption and the onset of action are delayed by combining appropriate amounts of insulin and protamine so that neither is present in an uncomplexed form ("isophane"). Protamine is a mixture of six major and some minor compounds of similar structure isolated from the sperm of rainbow trout. They appear to be basic, arginine-rich peptides with an average molecular weight of approximately 4400. To form an isophane complex (one in which neither component retains any free binding sites), approximately a 1:10 ratio by weight of protamine to insulin is required, representing approximately six molecules of insulin per molecule of protamine. After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. NPH insulin has an onset of approximately 2-5 hours and duration of 4-12 hours (Figure 41-5); it is usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement in patients with type 1 diabetes. The dose regulates the action profile; specifically, small doses have lower, earlier peaks and a short duration of action with the converse true for large doses.

b. Insulin glargine¾ Insulin glargine is a soluble, "peakless" (ie, having a broad plasma concentration plateau), ultra-long-acting insulin analog. This product was designed to provide reproducible, convenient, background insulin replacement. The attachment of two arginine molecules to the B chain carboxyl terminal and substitution of a glycine for asparagine at the A21 position created an analog that is soluble in an acidic solution but precipitates in the more neutral body pH after subcutaneous injection. Individual insulin molecules slowly dissolve away from the crystalline depot and provide a low, continuous level of circulating insulin. Insulin glargine has a slow onset of action (1-1.5 hours) and achieves a maximum effect after 4-6 hours. This maximum activity is maintained for 11-24 hours or longer. Glargine is usually given once daily, although some very insulin-sensitive individuals benefit from split (twice a day) dosing. To maintain solubility, the formulation is unusually acidic (pH 4.0) and insulin glargine should not be mixed with other insulins. Separate syringes must be used to minimize the risk of contamination and subsequent loss of efficacy. The absorption pattern of insulin glargine appears to be independent of the anatomic site of injection, and this drug is associated with less immunogenicity than human insulin in animal studies. Glargine's interaction with the insulin receptor is similar to that of native insulin and shows no increase in mitogenic activity in vitro. It has sixfold to sevenfold greater binding than native insulin to the insulin-like growth factor-1 (IGF-1) receptor, but the clinical significance of this is unclear.

c. Insulin detemir¾ This insulin is the most recently developed long-acting insulin analog. The terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the terminal B29 lysine. These modifications prolong the availability of the injected analog by increasing both self-aggregation in subcutaneous tissue and reversible albumin binding. Insulin detemir has the most reproducible effect of the intermediate- and long-acting insulins, and its use is associated with less hypoglycemia than NPH insulin. Insulin detemir has a dose-dependent onset of action of 1-2 hours and duration of action of more than 24 hours. It is given twice daily to obtain a smooth background insulin level.

4. Mixtures of insulins¾ Because intermediate-acting NPH insulins require several hours to reach adequate therapeutic levels, their use in type 1 diabetic patients requires supplements of rapid- or short-acting insulin before meals. For convenience, these are often mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH insulin without affecting their rapid absorption. However, premixed preparations have thus far been unstable. To remedy this, intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed. These intermediate insulins have been designated as "NPL" (neutral protamine lispro) and "NPA" (neutral protamine aspart) and have the same duration of action as NPH insulin. They have the advantage of permitting formulation as premixed combinations of NPL and insulin lispro, and as NPA and insulin aspart, and they have been shown to be safe and effective in clinical trials. The FDA has approved 50%/50% and 75%/25% NPL/insulin lispro and 70%/30% NPA/insulin aspart premixed formulations. Additional ratios are available abroad. Insulin glargine and detemir must be given as separate injections. They are not miscible acutely or in a premixed preparation with any other insulin formulation.

B. INSULIN PRODUCTION

. Human insulins¾ Mass production of human insulin and insulin analogs by recombinant DNA techniques is carried out by inserting the human or a modified proinsulin gene into Escherichia coli or yeast and treating the extracted proinsulin to form the insulin or insulin analog molecules.

C. CONCENTRATION
All insulins in the USA and Canada are currently available in a concentration of 100 U/mL (U100). A limited supply of U500 regular human insulin is available for use in rare cases of severe insulin resistance in which larger doses of insulin are required.

Insulin Delivery Systems

The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes. During the last three decades, much effort has gone into exploration of other means of administration, and inhaled insulin is now available.

A. PORTABLE PEN INJECTORS
To facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pen-sized injectors have been developed. These contain cartridges of insulin and replaceable needles. Disposable insulin pens are also available for selected formulations. These are regular insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, and several mixtures of NPH with regular, lispro, or aspart insulin (Table 41-4). They have been well accepted by patients because they eliminate the need to carry syringes and bottles of insulin to the workplace and while traveling.

B. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION DEVICES (CSII, INSULIN PUMPS)
Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery. The devices have a user-programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results. Normally, the 24-hour background basal rates are relatively constant from day to day, although temporarily altered rates can be superimposed to adjust for a short-term change in requirement. For example, the basal delivery rate might need to be decreased for several hours because of the increased insulin sensitivity associated with strenuous activity. In contrast, the bolus amounts frequently vary and are used to correct high blood glucose levels and to cover mealtime insulin requirements based on the carbohydrate content of the food and concurrent activity. The pump¾which contains an insulin reservoir, the program chip, the keypad, and the display screen¾is about the size of a pager. It is usually placed on a belt or in a pocket, and the insulin is infused through thin plastic tubing that is connected to the subcutaneously inserted infusion set. The abdomen is the favored site for the infusion set, although flanks and thighs are also used. The insulin reservoir, tubing, and infusion set need to be changed using sterile techniques every 2 or 3 days. CSII delivery is regarded as the most physiologic method of insulin replacement.

The use of these continuous infusion devices is encouraged for individuals who are unable to obtain target control while on multiple injection regimens and in circumstances in which excellent glycemic control is desired, such as during pregnancy. Their optimal use requires responsible involvement and commitment by the patient. Velosulin (a regular insulin) and insulin aspart, lispro, and glulisine are all specifically approved for pump use. Insulins aspart, lispro, and glulisine are preferred pump insulins because their favorable pharmacokinetic attributes allow glycemic control without increasing the risk of hypoglycemia.

C. INHALED INSULIN
The FDA has approved an inhaled insulin preparation of finely powdered and aerosolized human insulin. Insulin is readily absorbed into the bloodstream through alveolar walls, but the challenge has been to create particles that are small enough to pass through the bronchial tree without being trapped and still enter the alveoli in sufficient amounts to have a clinical effect. Insulin delivered by the inhaled route has pharmacokinetic and pharmacodynamic characteristics of both rapid- and short-acting insulin. It has a rapid onset and peak insulin levels (by 30 minutes) similar to insulin lispro, aspart, and glulisine, and peak effect (2-2.5 hours) and duration of action (6-8 hours) similar to regular insulin. Inhaled insulin can be used to cover mealtime insulin requirements or to correct high glucose levels, but not to provide background or basal insulin coverage. Less than 10% of the inhaled insulin dose (which ranges from 1 mg to 6 mg) is absorbed. One milligram of inhaled insulin is equivalent to 2-3 units of regular human insulin injected subcutaneously. Safety concerns include possible pulmonary fibrosis or hypertension, reduced lung volume or oxygen diffusing capacity, and excessive insulin antibody formation.

Treatment with Insulin

The current classification of diabetes mellitus identifies a group of patients who have virtually no insulin secretion and whose survival depends on administration of exogenous insulin. This insulin-dependent group (type 1) represents 5-10% of the diabetic population in the USA. Most type 2 diabetics do not require exogenous insulin for survival, but many need exogenous supplementation of their endogenous secretion to achieve optimum health.

Benefit of Glycemic Control in Diabetes Mellitus

The consensus of the American Diabetes Association is that intensive glycemic control associated with comprehensive self-management training should become standard therapy in type 1 patients (see Box: Benefits of Tight Glycemic Control in Diabetes). Exceptions include patients with advanced renal disease and the elderly, since the risks of hypoglycemia outweigh the benefit of tight glycemic control in these groups. In children under the age of 7 years, the extreme susceptibility of the developing brain to damage from hypoglycemia contraindicates attempts at intensive glycemic control. A similar conclusion regarding the benefits of tight control in type 2 diabetes was reached as the result of a large study in the United Kingdom.


BENEFITS OF TIGHT GLYCEMIC CONTROL IN DIABETES

A long-term randomized prospective study involving 1441 type 1 patients in 29 medical centers reported in 1993 that "near normalization" of blood glucose resulted in a delay in onset and a major slowing of progression of microvascular and neuropathic complications of diabetes during follow-up periods of up to 10 years (Diabetes Control And Complications Trial [DCCT] Research Group, 1993). In the intensively treated group, a mean glycated hemoglobin HbA_1c of 7.2% (normal <6%) and a mean blood glucose of 155 mg/dL were achieved, whereas in the conventionally treated group, HbA_1c averaged 8.9% with an average blood glucose of 225 mg/dL. Over the study period, which averaged 7 years, approximately a 60% reduction in risk of diabetic retinopathy, nephropathy, and neuropathy was noted in the tight control group compared with the standard control group.

The DCCT study, in addition, has introduced the concept of glycemic memory, which comprises the long-term benefits of any significant period of glycemic control. During a 6-year follow-up period, both the intensively and the conventionally treated groups had similar levels of glycemic control, and both had progression of carotid intimal-medial thickness. However, the intensively treated cohort had significantly less progression of intimal thickness.

The United Kingdom Prospective Diabetes Study (UKPDS) was a very large randomized prospective study carried out to study the effects of intensive glycemic control with several types of therapies and the effects of blood pressure control in type 2 diabetic patients. A total of 3867 newly diagnosed type 2 diabetic patients were studied over 10 years. A significant fraction of these were overweight and hypertensive. Patients were given dietary treatment alone or intensive therapy with insulin, chlorpropamide, glyburide, or glipizide. Metformin was an option for patients with inadequate response to other therapies. Tight control of blood pressure was added as a variable, with an angiotensin-converting enzyme inhibitor, b-blocker or, in some cases, a calcium channel blocker available for this purpose.

Tight control of diabetes, with reduction of HbA_1c from 9.1% to 7%, was shown to reduce the risk of microvascular complications overall compared with that achieved with conventional therapy (mostly diet alone, which decreased HbA_1c to 7.9%). Cardiovascular complications were not noted for any particular therapy; metformin treatment alone reduced the risk of macrovascular disease (myocardial infarction, stroke).

Tight control of hypertension also had a surprisingly significant effect on microvascular disease (as well as more conventional hypertension-related sequelae) in these diabetic patients. These studies show that tight glycemic control benefits both type 1 and type 2 patients.

The STOP-NIDDM trial followed up 1429 patients with impaired glucose tolerance who were randomized to treatment with acarbose or placebo over 3 years. This trial demonstrated that normalization of glycemic control in subjects with impaired glucose tolerance significantly diminished cardiovascular risk. The acarbose-treated group had a significant reduction in the development of major cardiovascular events and hypertension. A prospective placebo-controlled subgroup analysis has shown a marked decrease in the progression of intimal-medial thickness.



Complications of Insulin Therapy

A. HYPOGLYCEMIA

1. Mechanisms and diagnosis¾ Hypoglycemic reactions are the most common complication of insulin therapy. They may result from a delay in taking a meal, inadequate carbohydrate consumed, unusual physical exertion, or a dose of insulin that is too large for immediate needs.

Rapid development of hypoglycemia in individuals with intact hypoglycemic awareness causes signs of autonomic hyperactivity, both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger) and may progress to convulsions and coma if untreated.

In individuals exposed to frequent hypoglycemic episodes during tight glycemic control, autonomic warning signals of hypoglycemia are less common or even absent. This dangerous acquired condition is termed "hypoglycemic unawareness." When patients lack the early warning signs of low blood glucose, they may not take corrective measures in time. In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may develop¾confusion, weakness, bizarre behavior, coma, seizures¾at which point they may not be able to procure or safely swallow glucose-containing foods. Hypoglycemic awareness may be restored by preventing frequent hypoglycemic episodes. An identification bracelet, necklace, or card in the wallet or purse, as well as some form of rapidly absorbed glucose, should be carried by every diabetic who is receiving hypoglycemic drug therapy.

2. Treatment of hypoglycemia¾ All the manifestations of hypoglycemia are relieved by glucose administration. To expedite absorption, simple sugar or glucose should be given, preferably in a liquid form. To treat mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given. If more severe hypoglycemia has produced unconsciousness or stupor, the treatment of choice is to give 20-50 mL of 50% glucose solution by intravenous infusion over a period of 2-3 minutes. If intravenous therapy is not available, 1 mg of glucagon injected either subcutaneously or intramuscularly usually restores consciousness within 15 minutes to permit ingestion of sugar. If the patient is stuporous and glucagon is not available, small amounts of honey or syrup can be inserted into the buccal pouch. In general, however, oral feeding is contraindicated in unconscious patients. Emergency medical services should be called for all episodes of severely impaired consciousness.

B. IMMUNOPATHOLOGY OF INSULIN THERAPY
At least five molecular classes of insulin antibodies may be produced in diabetics during the course of insulin therapy: IgA, IgD, IgE, IgG, and IgM. There are two major types of immune disorders in these patients:

1. Insulin allergy¾ Insulin allergy, an immediate type hypersensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis results. Because sensitivity is often to noninsulin protein contaminants, the human and analog insulins have markedly reduced the incidence of insulin allergy, especially local reactions.

2. Immune insulin resistance¾ A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated with other systemic autoimmune processes such as lupus erythematosus.

C. LIPODYSTROPHY AT INJECTION SITES
Injection of older animal insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection. This type of immune complication is almost never seen since the development of human and analog insulin preparations of neutral pH. Injection of these newer preparations directly into the atrophic area often results in restoration of normal contours. Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site. However, this may be corrected by avoidance of that specific injection site or with liposuction.

ORAL ANTIDIABETIC AGENTS

INTRODUCTION

Four categories of oral antidiabetic agents are now available in the USA: insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives), biguanides, thiazolidinediones, and a-glucosidase inhibitors. The sulfonylureas and biguanides have been available the longest and are the traditional initial treatment choice for type 2 diabetes. Novel classes of rapidly acting insulin secretagogues, the meglitinides and D-phenylalanine derivatives, are alternatives to the short-acting sulfonylurea, tolbutamide. The thiazolidinediones, under development since the early 1980s, are very effective agents that reduce insulin resistance. Alpha-glucosidase inhibitors have a relatively weak antidiabetic effect and significant adverse effects, and they are used primarily as adjunctive therapy in individuals who cannot achieve their glycemic goals with other medications.

INSULIN SECRETAGOGUES: SULFONYLUREAS

Mechanism of Action

The major action of sulfonylureas is to increase insulin release from the pancreas (Table 41-5). Two additional mechanisms of action have been proposed¾a reduction of serum glucagon levels and closure of potassium channels in extrapancreatic tissues.

A. INSULIN RELEASE FROM PANCREATIC B CELLS
Sulfonylureas bind to a 140-kDa high-affinity sulfonylurea receptor (Figure 41-2) that is associated with a B-cell inward rectifier ATP-sensitive potassium channel. Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin.

B. REDUCTION OF SERUM GLUCAGON CONCENTRATIONS
Long-term administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels, which may contribute to the hypoglycemic effect of the drugs. The mechanism for this suppressive effect of sulfonylureas on glucagon levels is unclear but appears to involve indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit A-cell secretion.

C. POTASSIUM CHANNEL CLOSURE IN EXTRAPANCREATIC TISSUES
Insulin secretagogues bind to sulfonylurea receptors in potassium channels in extrapancreatic tissues, but the binding affinity varies among the drug classes and is much less avid than for the B-cell receptors. The clinical significance of extrapancreatic binding is not known.

Efficacy & Safety of the Sulfonylureas

In 1970, the University Group Diabetes Program (UGDP) in the USA reported that the number of deaths due to cardiovascular disease in diabetic patients treated with tolbutamide was excessive compared with either insulin-treated patients or those receiving placebos. Owing to design flaws, this study and its conclusions were not generally accepted. A study in the United Kingdom, the UKPDS, did not find an untoward cardiovascular effect of sulfonylurea usage in their large, long-term study.

The sulfonylureas continue to be widely prescribed, and six are available in the USA (Table 41-6). They are conventionally divided into first-generation and second-generation agents, which differ primarily in their potency and adverse effects. The first-generation sulfonylureas are increasingly difficult to procure, and as the second-generation agents become generic and less expensive, the older compounds probably will be discontinued.

1. First-Generation Sulfonylureas

Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short, with an elimination half-life of 4-5 hours, and it is best administered in divided doses. Because of its short half-life, it is the safest sulfonylurea for elderly diabetics. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain drugs (eg, dicumarol, phenylbutazone, some sulfonamides) that inhibit the metabolism of tolbutamide.

Chlorpropamide has a half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity; approximately 20-30% is excreted unchanged in the urine. Chlorpropamide also interacts with the drugs mentioned above that depend on hepatic oxidative catabolism, and it is contraindicated in patients with hepatic or renal insufficiency. Dosages higher than 500 mg daily increase the risk of jaundice. The average maintenance dosage is 250 mg daily, given as a single dose in the morning. Prolonged hypoglycemic reactions are more common in elderly patients, and the drug is contraindicated in this group. Other side effects include a hyperemic flush after alcohol ingestion in genetically predisposed patients and dilutional hyponatremia. Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs in less than 1% of patients.

Tolazamide is comparable to chlorpropamide in potency but has a shorter duration of action. Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours. Its half-life is about 7 hours. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d are required, the dose should be divided and given twice daily.

2. Second-Generation Sulfonylureas

Introduction

The second-generation sulfonylureas are more frequently prescribed in the USA than the first-generation agents because they have fewer adverse effects and drug interactions. These potent sulfonylurea compounds¾glyburide, glipizide, and glimepiride¾should be used with caution in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.

Glyburide is metabolized in the liver into products with very low hypoglycemic activity. The usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage is 5-10 mg/d given as a single morning dose; maintenance dosages higher than 20 mg/d are not recommended. A formulation of "micronized" glyburide (Glynase PresTab) is available in a variety of tablet sizes. However, there is some question as to its bioequivalence with nonmicronized formulations, and the FDA recommends careful monitoring to retitrate dosage when switching from standard glyburide doses or from other sulfonylurea drugs.

Glyburide has few adverse effects other than its potential for causing hypoglycemia. Flushing has rarely been reported after ethanol ingestion, and the compound slightly enhances free water clearance. Glyburide is contraindicated in the presence of hepatic impairment and in patients with renal insufficiency.

Glipizide has the shortest half-life (2-4 hours) of the more potent agents. For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before breakfast, because absorption is delayed when the drug is taken with food. The recommended starting dosage is 5 mg/d, with up to 15 mg/d given as a single dose. When higher daily dosages are required, they should be divided and given before meals. The maximum total daily dosage recommended by the manufacturer is 40 mg/d, although some studies indicate that the maximum therapeutic effect is achieved by 15-20 mg of the drug. An extended-release preparation (Glucotrol XL) provides 24-hour action after a once-daily morning dose (maximum of 20 mg/d). However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over the latter (which can be obtained as a generic drug).

Because of its shorter half-life, the regular formulation of glipizide is much less likely than glyburide to produce serious hypoglycemia. At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients with significant hepatic or renal impairment, who would be at high risk for hypoglycemia.

Glimepiride is approved for once-daily use as monotherapy or in combination with insulin. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound. A single daily dose of 1 mg has been shown to be effective, and the recommended maximal daily dose is 8 mg. It has a long duration of effect with a half-life of 5 hours, allowing once-daily dosing and thereby improving compliance. It is completely metabolized by the liver to inactive products.

Secondary Failure & Tachyphylaxis to Sulfonylureas

Secondary failure, ie, failure to maintain a good response to sulfonylurea therapy over the long term, remains a disconcerting problem in the management of type 2 diabetes. A progressive decrease in B-cell mass, reduction in physical activity, decline in lean body mass, or increase in ectopic fat deposition in chronic type 2 diabetes also may contribute to secondary failure.

INSULIN SECRETAGOGUES: MEGLITINIDES

The meglitinides are a relatively new class of insulin secretagogues. Repaglinide, the first member of the group, was approved for clinical use in 1998 (Table 41-7). These drugs modulate B-cell insulin release by regulating potassium efflux through the potassium channels previously discussed. There is overlap with the sulfonylureas in their molecular sites of action because the meglitinides have two binding sites in common with the sulfonylureas and one unique binding site.

Repaglinide has a very fast onset of action, with a peak concentration and peak effect within approximately 1 hour after ingestion, but the duration of action is 5-8 hours. It is hepatically cleared by CYP3A4 with a plasma half-life of 1 hour. Because of its rapid onset, repaglinide is indicated for use in controlling postprandial glucose excursions. The drug should be taken just before each meal in doses of 0.25-4 mg (maximum, 16 mg/d); hypoglycemia is a risk if the meal is delayed or skipped or contains inadequate carbohydrate. This drug should be used cautiously in individuals with renal and hepatic impairment. Repaglinide is approved as monotherapy or in combination with biguanides. There is no sulfur in its structure, so repaglinide may be used in type 2 diabetic individuals with sulfur or sulfonylurea allergy.

INSULIN SECRETAGOGUE: D-PHENYLALANINE DERIVATIVE

Nateglinide, a D-phenylalanine derivative, is the latest insulin secretagogue to become clinically available. Nateglinide stimulates very rapid and transient release of insulin from B cells through closure of the ATP-sensitive K⁺ channel. It also partially restores initial insulin release in response to an intravenous glucose tolerance test. This may be a significant advantage of the drug because type 2 diabetes is associated with loss of this initial insulin response. The restoration of more normal insulin secretion may suppress glucagon release early in the meal and result in less endogenous or hepatic glucose production. Nateglinide may have a special role in the treatment of individuals with isolated postprandial hyperglycemia, but it has minimal effect on overnight or fasting glucose levels. Nateglinide is efficacious when given alone or in combination with nonsecretagogue oral agents (such as metformin). In contrast to other insulin secretagogues, dose titration is not required.

Nateglinide is ingested just before meals. It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is hepatically metabolized by CYP2C9 and CYP3A4 with a half-life of 1.5 hours. The overall duration of action is less than 4 hours.

Nateglinide amplifies the insulin secretory response to a glucose load but has a markedly diminished effect in the presence of normoglycemia. The incidence of hypoglycemia may be the lowest of all the secretagogues, and it has the advantage of being safe in individuals with very reduced renal function.

BIGUANIDES

Introduction

The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the USA because of its association with lactic acidosis and because there was no documentation of any long-term benefit from its use.



Mechanisms of Action

A full explanation of the biguanides' mechanism of action remains elusive. Their blood glucose-lowering action does not depend on functioning pancreatic B cells. Patients with type 2 diabetes have considerably less fasting hyperglycemia as well as lower postprandial hyperglycemia after biguanides; however, hypoglycemia during biguanide therapy is essentially unknown. These agents are therefore more appropriately termed "euglycemic" agents. Currently proposed mechanisms of action include (1) reduced hepatic and renal gluconeogenesis; (2) slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes; (3) direct stimulation of glycolysis in tissues, with increased glucose removal from blood; and (4) reduction of plasma glucagon levels.

Metabolism & Excretion

Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin's blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, biguanides accumulate and thereby increase the risk of lactic acidosis, which appears to be a dose-related complication.

Clinical Use

Biguanides have been most often prescribed for patients whose hyperglycemia is due to ineffective insulin action, ie, insulin resistance syndrome. Because metformin is an insulin-sparing agent and does not increase weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such individuals. The UKPDS reported that metformin therapy decreases the risk of macrovascular as well as microvascular disease; this is in contrast to the other therapies, which only modified microvascular morbidity. Biguanides are also indicated for use in combination with insulin secretagogues or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate. Metformin is useful in the prevention of type 2 diabetes; the landmark Diabetes Prevention Program concluded that metformin is efficacious in preventing the new onset of type 2 diabetes in middle-aged, obese persons with impaired glucose tolerance and fasting hyperglycemia. It is interesting that metformin did not prevent diabetes in older, leaner prediabetics.

The dosage of metformin is from 500 mg to a maximum of 2.55 g daily, with the lowest effective dose being recommended. A common schedule would be to begin with a single 500-mg tablet given with breakfast for several days. If this is tolerated without gastrointestinal discomfort and if hyperglycemia persists, a second 500-mg tablet may be added with the evening meal. If further dose increases are required after 1 week, an additional 500-mg tablet can be added to be taken with the midday meal, or the larger (850-mg) tablet can be prescribed twice daily or even three times daily (the maximum recommended dosage) if needed. Dosage should always be divided because ingestion of more than 1000 mg at any one time usually provokes significant gastrointestinal side effects.

Toxicities

The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, diarrhea) and occur in up to 20% of patients. They are dose-related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3-5% of patients because of persistent diarrhea. Absorption of vitamin B₁₂ appears to be reduced during long-term metformin therapy, and annual screening of serum vitamin B₁₂ levels and red blood cell parameters has been encouraged by the manufacturer to determine the need for vitamin B₁₂ injections. In the absence of hypoxia or renal or hepatic insufficiency, lactic acidosis is less common with metformin therapy than with phenformin therapy.

Biguanides are contraindicated in patients with renal disease, alcoholism, hepatic disease, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary dysfunction), because of an increased risk of lactic acidosis induced by biguanide drugs in the presence of these diseases.

THIAZOLIDINEDIONES

Thiazolidinediones (Tzds) act to decrease insulin resistance. Their primary action is the regulation of genes involved in glucose and lipid metabolism and adipocyte differentiation. Tzds are ligands of peroxisome proliferator-activated receptor-gamma (PPAR-g), part of the steroid and thyroid superfamily of nuclear receptors. These PPAR receptors are found in muscle, fat, and liver. PPAR-g receptors are complex and modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation. The available Tzds do not have identical clinical effects, and new drug development will focus on defining PPAR effects and designing ligands that have selective action¾much like the selective estrogen receptor modulators (see Chapter 40).

In addition to targeting adipocytes, myocytes, and hepatocytes, Tzds also have significant effects on vascular endothelium, the immune system, the ovaries, and tumor cells. Some of these responses may be independent of the PPAR-g pathway.

In persons with diabetes, a major site of Tzd action is adipose tissue, where the drug promotes glucose uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins involved in energy regulation. Tzds also regulate adipocyte apoptosis and differentiation. Numerous other effects have been documented in animal studies but applicability to human tissues has yet to be determined.

Two thiazolidinediones are currently available: pioglitazone and rosiglitazone (Table 41-8). Their distinct side chains create differences in therapeutic action, metabolism, metabolite profile, and adverse effects. A third compound, troglitazone, was withdrawn from the market because of hepatic toxicity thought to be related to its side chain. Pioglitazone has PPAR-a as well as PPAR-g activity. It is absorbed within 2 hours of ingestion; although food may delay uptake, total bioavailability is not affected. Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites. The bioavailability of numerous other drugs also degraded by these enzymes may be affected by pioglitazone therapy, including estrogen-containing oral contraceptives; additional methods of contraception are advised. Pioglitazone may be taken once daily; the usual starting dose is 15-30 mg. The triglyceride lowering effect is more significant than that observed with rosiglitazone, presumably because of its PPAR-a binding characteristics. Pioglitaxone therapy reduces mortality and macrovascular events (myocardial infarction and stroke). Pioglitazone is approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the treatment of type 2 diabetes.

Rosiglitazone is rapidly absorbed and highly protein-bound. It is metabolized in the liver to minimally active metabolites, predominantly by CYP2C8 and to a lesser extent by CYP2C9. It is administered once or twice daily; 4-8 mg is the usual total dose. Rosiglitazone shares the common Tzd adverse effects but does not seem to have any significant drug interactions. The drug is approved for use in type 2 diabetes as monotherapy or in combination with a biguanide, sulfonylurea, in combination with a biguanide and sulfonylurea, and insulin.

Tzds are considered "euglycemics" and are efficacious in about 70% of new users. The overall response is similar to sulfonylurea and biguanide monotherapy. Individuals experiencing secondary failure to other oral agents should benefit from the addition (rather than substitution) of a Tzd. Because their mechanism of action involves gene regulation, the Tzds have a slow onset and offset of activity over weeks or even months. Combination therapy with sulfonylureas and insulin can lead to hypoglycemia and may require dosage adjustment. Long-term therapy is associated with a drop in triglyceride levels and a slight rise in HDL and low-density lipoprotein (LDL) cholesterol values. An adverse effect common to both Tzds is fluid retention, which presents as a mild anemia and peripheral edema, especially when used in combination with insulin or insulin secretagogues. Some reports have suggested an increased risk of heart failure. Rarely, new or worsening macular edema has been reported in association with rosiglitazone treatment. Many users have a dose-related weight gain (average 1-3 kg), which may be fluid-related. These agents should not be used during pregnancy or in the presence of significant liver disease (ALT more than 2.5 ´ upper limit of normal), or if there is a concurrent diagnosis of heart failure. Anovulatory women may resume ovulation and should be counseled on the increased risk of pregnancy. Because of the hepatotoxicity observed with troglitazone, a discontinued Tzd, the FDA continues to require monitoring of liver function tests before initiation of Tzd therapy and periodically afterward. To date, hepatotoxicity has not been associated with rosiglitazone or pioglitazone.

Thiazolidinediones have an emerging benefit in the prevention of type 2 diabetes. The Diabetes Prevention Trial reported a 75% reduction in the diabetes incidence rate when troglitazone was administered to patients with prediabetes. Another study reported that troglitazone therapy significantly decreased the recurrence of diabetes mellitus in high-risk Hispanic women with a history of gestational diabetes. Other trials using clinically available Tzds are in progress.

ALPHA-GLUCOSIDASE INHIBITORS

Only monosaccharides, such as glucose and fructose, can be transported out of the intestinal lumen and into the bloodstream. Complex starches, oligosaccharides, and disaccharides must be broken down into individual monosaccharides before being absorbed in the duodenum and upper jejunum. This digestion is facilitated by enteric enzymes, including pancreatic a-amylase, and a-glucosidases that are attached to the brush border of the intestinal cells. Acarbose and miglitol are competitive inhibitors of the intestinal a-glucosidases and reduce the postprandial digestion and absorption of starch and disaccharides (Table 41-9). Miglitol differs structurally from acarbose and is six times more potent in inhibiting sucrase. Although the binding affinity of the two compounds differs, acarbose and miglitol both target the a-glucosidases: sucrase, maltase, glycoamylase, and dextranase. Miglitol alone has effects on isomaltase and on b-glucosidases, which split b-linked sugars such as lactose. Acarbose alone has a small effect on a-amylase. The consequence of enzyme inhibition is to minimize upper intestinal digestion and defer digestion (and thus absorption) of the ingested starch and disaccharides to the distal small intestine, thereby lowering postmeal glycemic excursions as much as 45-60 mg/dL and creating an insulin-sparing effect. Monotherapy with these drugs is associated with a modest drop (0.5-1%) in glycohemoglobin levels and a 20-25 mg/dL fall in fasting glucose levels. They are FDA-approved for persons with type 2 diabetes as monotherapy and in combination with sulfonylureas, in which the glycemic effect is additive. Both acarbose and miglitol are taken in doses of 25-100 mg just before ingesting the first portion of each meal; therapy should be initiated with the lowest dose and slowly titrated upward.

Prominent adverse effects include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas. These side effects tend to diminish with ongoing use because chronic exposure to carbohydrate induces the expression of a-glucosidase in the jejunum and ileum, increasing distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon. Although not a problem with monotherapy or combination therapy with a biguanide, hypoglycemia may occur with concurrent sulfonylurea treatment. Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked. These drugs are contraindicated in patients with inflammatory bowel disease or any intestinal condition that could be worsened by gas and distention. Because both miglitol and acarbose are excreted by the kidneys, these medications should not be prescribed in individuals with renal impairment. Acarbose has been associated with reversible hepatic enzyme elevation and should be used with caution in the presence of hepatic disease.

The STOP-NIDDM trial demonstrated that a-glucosidase therapy in prediabetic individuals successfully prevented a significant number of new cases of type 2 diabetes and helped restore B-cell function, in addition to reducing cardiovascular disease and hypertension. Intervention with acarbose also reduced cardiovascular events in individuals with diabetes. Diabetes and cardiovascular disease prevention may become a further indication for this class of medications.

PRAMLINTIDE

Pramlintide, a synthetic analog of amylin, is an injectable antihyperglycemic that modulates postprandial glucose levels and is approved for preprandial use in individuals with type 1 and type 2 diabetes. It is administered in addition to insulin in those individuals who are unable to achieve their target postprandial blood sugars. Pramlintide suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system-mediated anorectic effects. It is rapidly absorbed after subcutaneous administration; levels peak within 20 minutes, and the duration of action is not more than 150 minutes. Pramlintide is renally metabolized and excreted, but even at low creatinine clearance there is no significant change in bioavailability. It has not been evaluated in dialysis patients. The most reliable absorption is from the abdomen and thigh; arm administration is less reliable. Pramlintide should be injected immediately before eating; doses range from 15 mcg to 120 mcg subcutaneously. Therapy with this agent should be initiated with the lowest dose and titrated upward. Because of the risk of hypoglycemia, concurrent rapid- or short-acting mealtime insulin doses should be decreased by 50% or more. Pramlintide should always be injected by itself with a separate syringe; it cannot be mixed with insulin. The major side effects of pramlintide are hypoglycemia and gastrointestinal symptoms including nausea, vomiting, and anorexia.

EXENATIDE

As a synthetic analog of glucagon-like-polypeptide 1 (GLP-1), exenatide is the first incretin therapy to become available for the treatment of diabetes. Exenatide is approved as an injectable, adjunctive therapy in individuals with type 2 diabetes treated with metformin or sulfonylureas who still have suboptimal glycemic control. In clinical studies, exenatide therapy is shown to have multiple actions such as potentiation of glucose-mediated insulin secretion, suppression of postprandial glucagon release through as-yet unknown mechanisms, slowed gastric emptying and a central loss of appetite. The increased insulin secretion is speculated to be due in part to an increase in B-cell mass. It is not known whether the increased B-cell mass results from a decreased B-cell turnover, increased B-cell formation, or both.

Exenatide is absorbed equally from arm, abdomen, or thigh injection sites, reaching a peak concentration in approximately 2 hours with a duration of up to 10 hours. It undergoes glomerular filtration, and dosage adjustment is required only when the creatinine clearance is less than 30 mL/min. Exenatide is injected subcutaneously within 60 minutes before a meal; therapy is initiated at 5 mcg twice daily, with a maximum dosage of 10 mcg twice daily. When exenatide is added to preexisting sulfonylurea therapy, the oral hypoglycemic dosage may need to be decreased to prevent hypoglycemia. The major side effects are nausea (about 44% of users) and vomiting and diarrhea. The nausea decreases with ongoing exenatide usage.

SITAGLIPTIN

Introduction

Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin and other GLP-1-like molecules. This drug appears likely to be approved for use in type 2 diabetes. In phase 2 and 3 clinical trials, sitagliptin was reported to have a bioavailability of approximately 80% and a half-life of 8-14 hours. Control of hyperglycemia and reductions in HbA_1c were documented at doses of 100 mg orally once daily. Dosage should be reduced in patients with renal impairment. Hypoglycemic episodes were rare and the drug facilitated weight loss. Sitagliptin therapy can be combined with metformin, Tzds, or sulfonylureas. The drug will be marketed as Januvia.

Combination Therapy with Oral Antidiabetic Agents & Injectable Medication

A. COMBINATION THERAPY IN TYPE 2 DIABETES MELLITUS

1. Combination therapy with exenatide¾ Exenatide is approved for use in individuals who fail to achieve desired glycemic control on biguanides, sulfonylureas, or both. Although the combination of exenatide and Tzds, D-phenylalanine derivatives, meglitinides, a-glucosidase inhibitors, and insulin has not been studied, these regimens are clinically prescribed. Hypoglycemia is a risk when exenatide is used with an insulin secretagogue or insulin. The doses of the latter drugs have to be reduced at the initiation of exenatide therapy and subsequently titrated.

2. Combination therapy with pramlintide¾ Pramlintide is approved for concurrent mealtime administration in individuals with type 2 diabetes treated with insulin, metformin, or a sulfonylurea who are unable to achieve their postmeal glucose targets. Combination therapy results in a significant reduction in early postprandial glucose excursions; mealtime insulin or sulfonylurea doses usually have to be reduced to prevent hypoglycemia.

3. Combination therapy with insulin¾ Bedtime insulin has been suggested as an adjunct to oral antidiabetic therapy in patients with type 2 diabetes patients who have not responded to maximal oral therapy. Clinical practice has evolved to include sulfonylureas, meglitinides, D-phenylalanine derivatives, biguanides, thiazolidinediones, or a-glucosidase inhibitors given in conjunction with insulin.

Individuals unable to achieve glycemic control with bedtime insulin as described above generally require full insulin replacement and multiple daily injections of insulin. Insulin secretagogues are redundant when an individual is receiving multiple daily insulin injections, but persons with severe insulin resistance may benefit from the addition of one of the biguanides, thiazolidinediones, or a-glucosidase inhibitors. In some cases, multiple oral agents have been required together with insulin. When oral agents are added to the regimen of a person already taking insulin, the blood glucose should be closely monitored and the insulin dosage decreased as needed to avoid hypoglycemia.

B. COMBINATION THERAPY IN TYPE 1 DIABETES MELLITUS

1. Combination therapy with pramlintide¾ Pramlintide is approved for concurrent mealtime administration in individuals with type 1 diabetes who have poor glucose control after eating despite optimal insulin therapy. The addition of pramlintide leads to a significant reduction in early postprandial glucose excursions; mealtime insulin doses usually have to be reduced to prevent hypoglycemia.

2. Combination therapy with oral medications¾ There is no indication for combining insulin with insulin secretagogues (sulfonylureas, meglitinides, or D-phenylalanine derivatives) in individuals with type 1 diabetes. Type 1 diabetics with diets very high in starch may benefit from the addition of a-glucosidase inhibitors, but this is not typically practiced in the USA. Although not approved for use in type 1 diabetes, Tzds have been prescribed for type 1 individuals with significant insulin resistance and a combined type 1, type 2 phenotype, or latent autoimmune diabetes mellitus of adulthood (LADA). The insulin dose has to be reduced with the addition of Tzd therapy to prevent hypoglycemia.

GLUCAGON

Chemistry & Metabolism

Glucagon is synthesized in the A cells of the pancreatic islets of Langerhans (see Table 41-1). Glucagon is a peptide¾identical in all mammals¾consisting of a single chain of 29 amino acids, with a molecular weight of 3485. Selective proteolytic cleavage converts a large precursor molecule of approximately 18,000 MW to glucagon. One of the precursor intermediates consists of a 69-amino-acid peptide called glicentin, which contains the glucagon sequence interposed between peptide extensions.

Glucagon is extensively degraded in the liver and kidney as well as in plasma and at its tissue receptor sites. Because of its rapid inactivation by plasma, chilling of the collecting tubes and addition of inhibitors of proteolytic enzymes are necessary when samples of blood are collected for immunoassay of circulating glucagon. Its half-life in plasma is between 3 and 6 minutes, which is similar to that of insulin.

"Gut Glucagon"

Glicentin immunoreactivity has been found in cells of the small intestine as well as in pancreatic A cells and in effluents of perfused pancreas. The intestinal cells secrete enteroglucagon, a family of glucagon-like peptides, of which glicentin is a member, along with glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). Unlike the pancreatic A cell, these intestinal cells lack the enzymes to convert glucagon precursors to true glucagon by removing the carboxyl terminal extension from the molecule.

The function of the enteroglucagons has not been clarified, although smaller peptides can bind hepatic glucagon receptors where they exert partial activity. A derivative of the 37-amino-acid form of GLP-1 that lacks the first six amino acids (GLP-1[7-37]) is a potent stimulant of insulin release. It represents the predominant form of GLP in the human intestine and has been termed "insulinotropin." It has been considered as a potential therapeutic agent in type 2 diabetes. However, it requires continuous subcutaneous infusion to produce a sustained lowering of both fasting and postprandial hyperglycemia in type 2 diabetic patients; therefore, its clinical usefulness is limited. Exenatide (see above) is an analog of GLP-1.

Pharmacologic Effects of Glucagon

A. METABOLIC EFFECTS
The first six amino acids at the amino terminal of the glucagon molecule bind to specific receptors on liver cells. This leads to a G_s protein-coupled increase in adenylyl cyclase activity and the production of cAMP, which facilitates catabolism of stored glycogen and increases gluconeogenesis and ketogenesis. The immediate pharmacologic result of glucagon infusion is to raise blood glucose at the expense of stored hepatic glycogen. There is no effect on skeletal muscle glycogen, presumably because of the lack of glucagon receptors on skeletal muscle. Pharmacologic amounts of glucagon cause release of insulin from normal pancreatic B cells, catecholamines from pheochromocytoma, and calcitonin from medullary carcinoma cells.

B. CARDIAC EFFECTS
Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism described above. Thus, it produces an effect very similar to that of b-adrenoceptor agonists without requiring functioning b receptors.

C. EFFECTS ON SMOOTH MUSCLE
Large doses of glucagon produce profound relaxation of the intestine. In contrast to the above effects of the peptide, this action on the intestine may be due to mechanisms other than adenylyl cyclase activation.

Clinical Uses

A. SEVERE HYPOGLYCEMIA
The major use of glucagon is for emergency treatment of severe hypoglycemic reactions in patients with type 1 diabetes when unconsciousness precludes oral feedings and intravenous glucose is not possible. Recombinant glucagon is currently available in 1-mg vials for parenteral use (Glucagon Emergency Kit). Nasal sprays have been developed for this purpose but have not yet received FDA approval.

B. ENDOCRINE DIAGNOSIS
Several tests use glucagon to diagnose endocrine disorders. In patients with type 1 diabetes mellitus, a standard test of pancreatic B-cell secretory reserve uses 1 mg of glucagon administered as an intravenous bolus. Because insulin-treated patients develop circulating anti-insulin antibodies that interfere with radioimmunoassays of insulin, measurements of C-peptide are used to indicate B-cell secretion.

C. BETA-BLOCKER POISONING
Glucagon is sometimes useful for reversing the cardiac effects of an overdose of b-blocking agents because of its ability to increase cAMP production in the heart. However, it is not clinically useful in the treatment of cardiac failure.

D. RADIOLOGY OF THE BOWEL
Glucagon has been used extensively in radiology as an aid to x-ray visualization of the bowel because of its ability to relax the intestine.

Adverse Reactions

Transient nausea and occasional vomiting can result from glucagon administration. These are generally mild, and glucagon is relatively free of severe adverse reactions.

ISLET AMYLOID POLYPEPTIDE (IAPP, AMYLIN)

Amylin is a 37-amino-acid peptide originally derived from islet amyloid deposits in pancreas material from patients with long-standing type 2 diabetes or insulinomas. It is produced by pancreatic B cells, packaged within B-cell granules in a concentration 1-2% that of insulin and co-secreted with insulin in a pulsatile manner and in response to physiologic secretory stimuli. Approximately 1 molecule of amylin is released for every 10 molecules of insulin. It circulates in a glycated (active) and nonglycated (inactive) form with physiologic concentrations ranging from 4-25 pmol/L and is primarily renally excreted. Amylin appears to be a member of the superfamily of neuroregulatory peptides, with 46% homology with the calcitonin gene-related peptide CGRP (see Chapter 17). The physiologic effect of amylin may be to modulate insulin release by acting as a negative feed back on insulin secretion. At pharmacologic doses, amylin reduces glucagon secretion, slows gastric emptying by a vagally medicated mechanism, and centrally decreases appetite. An analog of amylin, pramlintide (see above), differs from amylin by the substitution of proline at positions 25, 28, and 29. These modifications make pramlintide soluble and non-self-aggregating.



PREPARATIONS AVAILABLE*

SULFONYLUREAS

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 & RELATED DRUGS

Repaglinide (Prandin)
Oral: 0.5, 1, 2 mg tablets
Nateglinide (Starlix)
Oral: 60, 120 mg tablets

BIGUANIDE

Metformin (generic, Glucophage, Glucophage XR)
Oral: 500, 850, 1000 mg tablets; extended-release (XR): 500 mg tablets; 500 mg/5 mL solution

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; 2/1000, 4/1000 mg tablets

THIAZOLIDINEDIONE DERIVATIVES

Pioglitazone (Actos)
Oral: 15, 30, 45 mg tablets
Rosiglitazone (Avandia)
Oral: 2, 4, 8 mg tablets

THIAZOLIDINEDIONE COMBINATIONS

Rosiglitazone plus glimeperide (Avandaryl)
Oral: 4/1, 4/2, 4/4 mg rosiglitazone/mg glimeperide tablets

ALPHA-GLUCOSIDASE INHIBITORS

Acarbose (Precose)
Oral: 25, 50, 100 mg tablets
Miglitol (Glyset)
Oral: 25, 50, 100 mg tablets

AMYLIN ANALOGS

Pramlintide (Symlin)
Parenteral: vial: 0.6 mg/mL (2.5 units [15 mcg] to 20 units [120 mcg])

GLUCAGON-LIKE POLYPEPTIDE-1 ANALOGS

Exenatide (Byetta)
Parenteral: 5, 10 mcg/dose pen injectors

GLUCAGON

Glucagon (generic)
Parenteral: 1 mg lyophilized powder to reconstitute for injection

*See Table 41-4 for insulin preparations.



REFERENCES

Bloomgarden ZT: Gut-derived incretin hormones and new therapeutic approaches. Diabetes Care 2004;27:2554.

Buchanan TA: Protection from type 2 diabetes persists in the TRIPOD cohort eight months after stopping troglitazone. Diabetes 2001;50(Suppl 2):A81.

Chapman I et al: Effect of pramlintide on satiety and food intake in obese subjects and subjects with type 2 diabetes. Diabetologia 2005;48:838.

Chiasson JL et al: Acarbose for prevention of type 2 diabetes mellitus: The STOP-NIDDM randomized trial. Lancet 2002;359:2072.

Chaisson JL et al: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. JAMA 2003;290:486.

Diabetes Control and Complications Trial Research Group: Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med 1991;90:450.

Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977.

Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Intensive Diabetes Therapy and Carotid Intima-Media Thickness in Type 1 Diabetes Mellitus. N Engl J Med 2003;348:2294.

Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393.

Diabetes Prevention Program Research Group: Prevention of type 2 diabetes with troglitazone in the diabetes prevention program. Diabetes 2005;54:1150.

Dormandy JA et al: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial in macroVascular Events): A randomized controlled trial. Lancet 2005,366:1280.

Dunn CJ et al: Nateglinide. Drugs 2000;60:607.

Dunning BE et al: Alpha cell function in health and disease: Influence of glucagon-like peptide-1. Diabetologia 2005;48:1700.

Dupre J: Extendin-4 Normalized Postcibial Glycemic Excursions in Type 1 Diabetes. J Clin Endocrinol Metab 2004;89:3469.

Dupre J: Glycemic effects of incretins in Type 1 diabetes mellitus: A concise review, with emphasis on studies in humans. Regul Pept 2005;128:149.

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003,26(Suppl 1):S5.

Goldberg RB et al: A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547.

Hanefeld M et al: Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: Meta-analysis of seven long term studies. Eur Heart J 2004;25:10.

Heinemann L et al: Time action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 2000;23:644.

Heptulla RA et al: The role of amylin and glucagon in the dampening of glycemic excursions in children with type 1 diabetes. Diabetes 2005;54:1100.

Kolterman O et al: Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health-Syst Pharm 2005;62:173.

Lepore M et al: Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000;49:2142.

Levien TL: Nateglinide therapy for type 2 diabetes mellitus. Ann Pharmacother 2001;35:1426.

Mudaliar S et al: New oral therapies for type 2 diabetes mellitus: The glitazones or insulin sensitizers. Annu Rev Med 2001;52:239.

Nauck MA et al: Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul Pept 2005;128:135.

Ottensmeyer FP et al: Mechanism of transmembrane signalling: Insulin binding and the insulin receptor. Biochemistry 2000;39:12103.

Owens DR: Repaglinide: A new short-acting insulinotropic agent for the treatment of type 2 diabetes. Eur J Clin Invest 1999;29(Suppl 2):30.

Plank J et al: A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care 2005;28:1107.

Quattrin T et al: Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes. Diabetes Care 2004;27:2622.

Ratner RE et al: Amylin replacement with pramlintide as an adjunct to insulin therapy improves long term glycemic and weight control in type 1 diabetes mellitus: A 1-year randomized controlled trial. Diabetic Med 2004;21:1204.

Rave K et al: Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care 2005;28:1077.

Schmitz O et al: Amylin agonists: A novel approach in the treatment of diabetes. Diabetes 2004;53(Suppl 3):S233.

Shepherd PR, Kahn BB: Glucose transporters and insulin action¾implications for insulin resistance and diabetes mellitus. N Engl J Med 1999;341:248.

Skyler JS et al: Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects. Diabetes Care 2005; 28:1630.

Toft-Nielsen MB, Madsbad S, Holst JJ: Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 1999;22:1137.

United Kingdom Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes: UKPDS 34. Lancet 1998;352:854.

United Kingdom Prospective Diabetes Study (UKPDS) Group: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies: UKPDS 49. JAMA 1999;281:2005.

United Kingdom Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes: UKPDS 33. Lancet 1998;352:837.

United Kingdom Prospective Diabetes Study (UKPDS) Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703.