Porth's Essentials of Pathophysiology, 4e

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Diabetes Mellitus and the Metabolic Syndrome

C h a p t e r 3 3

K channel +

Sulfonylureas

Ca ++ channel depolarizing opens

+

FIGURE 33-9. One model of control of release of insulin by the pancreatic beta cells and the action of the sulfonylurea agents. In the resting beta cell with low adenosine triphosphate (ATP) levels, potassium diffuses through the ATP- gated channels, maintaining the resting membrane potential. As blood glucose rises and is transported into the beta cell by the glucose transporter, ATP rises, causing the potassium channels to close and depolarization to occur. Depolarization results in opening of the voltage-gated calcium channels, which leads to insulin secretion. (Modified from Karam JH.Type II diabetes and syndrome X. Endocrinol Metab Clin North Am. 1992;21(2):329–350.)

K

Glucose transporter

ATP

Ca ++

Metabolism

Glucose

Insulin granules

Insulin

sucrose (table sugar), whose breakdown may be blocked by the action of the α -glucosidase inhibitors. Thiazolidinediones. The thiazolidinediones (TZDs) or glitazones (e.g., pioglitazone, rosiglitazone) are the only class of drugs that directly target insulin resis- tance. They do this by increasing insulin sensitivity in the insulin-responsive tissues—liver, skeletal muscle, and fat—allowing the tissues to respond to endoge- nous insulin more efficiently without increased output from already dysfunctional beta cells. 3,32 Because of the previous problem with liver toxicity in this class of drugs, liver enzymes should be monitored before start- ing therapy according to guidelines. Both agents can cause fluid accumulation and are therefore contraindi- cated in patients with stage III and IV heart failure 33 (see Chapter 20, Table 20-1). Other potential adverse effects include an increased risk of bone fractures 34 and of bladder cancer. Incretin-BasedAgents. Incretins are hormones released into the circulation by the gastrointestinal tract after a meal, especially one high in carbohydrates, that amplify the glucose-induced release of insulin (see Chapter 28). 3,6 The main incretins secreted are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). 3,35,36 Both GLP-1 and GIP are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 enzyme inhibitors work by inhibiting the DPP-4 enzyme and increasing GLP-1 and GIP levels, which then increase insulin release. Glucagon-like peptide 1 also helps to suppress glucagon release. Exenatide, a synthetic analog of GLP-1 that is resis- tant to DPP-4 degradation, is approved as an injectable adjunctive therapy for people with type 2 diabetes. The drug has been shown to have multiple actions such as potentiation of glucose-mediated insulin release, slowed gastric emptying, and a central loss of appetite. Although

exenatide was the first GLP-1 agonist to be developed and approved, other agents and formulations have also been approved. 36 Many other novel classes of antidiabetes agents are also approved for type 2 diabetes including the SGLT2 inhibitor, canagliflozin. This agent, which works by inhibiting glucose reabsorption from the kidney, results in about 70 g (approximately 300 Kcal) glucose loss per day. The adverse effects are understandable, including polyuria due to osmotic diuresis and increased urinary tract infections and genitourinary Candida infections. Insulin Type 1 diabetes mellitus always requires treatment with insulin, and many people with type 2 diabetes eventually require insulin therapy. Insulin is destroyed in the gas- trointestinal tract and must be administered by injection or inhalation. An inhaled form of insulin (Exubera) was on the market for a short time in the United States but was withdrawn for commercial reasons. Other inhaled insulin formulations are in clinical development. Human insulin has become widely available, pro- viding an alternative to forms of insulin obtained from bovine and porcine sources. Its manufacture uses recom- binant deoxyribonucleic acid (DNA) technology. More recently, analogs to human insulin have become avail- able that offer even better and more reproducible release characteristics. 37 Four insulin types are classified by length and peaking of action: short acting, rapid acting, intermediate act- ing, and long acting. 32,37 Short-acting insulin (regular) is a soluble crystalline insulin whose effects begin within 30 minutes after subcutaneous injection and generally last for 5 to 8 hours. The rapid-acting insulins (lispro, aspart, glulisine) are produced by recombinant technol- ogy and have a more rapid onset, peak, and duration of action than short-acting regular insulin. The rapid-acting