New Drugs for the Treatment of Diabetes Mellitus

Abstract

AbstractThis chapter reviews agents other than insulin that are being considered or recently introduced for the treatment of hyperglycemia. These include agents that lower blood glucose by delaying the intestinal digestion and absorption of carbohydrates, increase insulin concentrations, or potentiate insulin action. Other agents under investigation act independently of insulin to enhance glucose utilization, reduce glucose production, decrease obesity, or increase glucose elimination. Intestinal carbohydrate digestion is delayed by fiber supplements and by agents that competitively inhibit α‐glucosidase enzymes (e.g., miglitol and voglibose), thereby decreasing postprandial glucose excursions. Several insulin secretagogues have been designed to rapidly and transiently close ATP‐sensitive potassium channels in the pancreatic B‐cells (e.g., novel meglitinides and imidazolines). Analogues of the intestinal incretin glucagon‐like peptide 1 (GLP‐1) (7‐36 amide), which are more stable and longer acting than the native peptide, act predominantly via the cAMP pathway within the B‐cells to potentiate nutrient‐induced insulin secretion, and enhance insulin biosynthesis. Additionally these agents delay gastric emptying, promote satiety, and, most interestingly, appear to increase formation of new B‐cells. Inhibitors of the circulating enzyme dipeptidyl peptidase 4 augment the effects of GLP‐1 by slowing the degradation of GLP‐1. Non‐peptide compounds have been identified that can activate insulin receptor signaling and prevent normal deactivation of insulin receptor signaling (e.g., inhibitors of certain protein tyrosine phosphatases). Several new thiazolidinedione and non‐thiazolidinedione peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists are in development, along with dual PPAR‐γ and ‐α agonists to address both hyperglycemia and dyslipidemia. Various anti‐obesity agents have been shown to benefit glycemic control, including new β3‐adrenoceptor agonists to stimulate thermogenesis. The amylin analogue pramlintide, which acts centrally to reduce appetite, suppress glucagon secretion, and slow gastric emptying offers an adjunct to insulin therapy, without causing weight gain. Further agents are being considered to antagonize glucagon receptors, reduce the metabolic effects of glucocorticoids, and directly stimulate glucose uptake and metabolism by muscle. Approaches to reduce hepatic glucose output include compounds that inhibit glycogen phosphorylase, glucose‐6‐phosphatase, or other enzymes of gluconeogenesis. Increased glucose elimination is being considered by inhibiting renal glucose reabsorption.