Insulin secretagogues: Old and new

Insulin secretagogues are drugs that increase endogenous insulin secretion. There are three classes of insulin secretagogues: sulfonylureas, meglitinides, and D-phenylalanine derivatives. All stimulate insulin release by closing the K(ATP) channel of the β-cell plasma membrane. Differences in their pharmacologic action are determined by their pharmacokinetic characteristics and the affinity and kinetics of their binding to their receptors on the K(ATP) channel. Insulin secretagogues vary, from those that act very rapidly and have a short duration of action to those that act slowly and have a prolonged duration of action. They increase both basal and glucose-stimulated insulin secretion. The glucose dependence of their insulin secretory action appears to differ somewhat among the various drugs. Insulin secretagogues can achieve decreases in fasting plasma glucose of 50-80 mg/dl and in HbA(1c) of 1.0-2.5% in most newly diagnosed type 2 diabetic patients. Since β-cell function in type 2 diabetic patients decreases with time, insulin secretagogues are very effective in reducing hyperglycemia during the first few years of clinically diagnosed diabetes and are relatively ineffective in many people who have had clinically diagnosed type 2 diabetes for > 10 years. Their major side effects are hypoglycemia and weight gain. The extent to which these side effects occur depends on the characteristics of the action of the specific insulin secretagogue. Cardiovascular tissues also contain K(ATP) channels. Some insulin secretagogues have significant interactions with those cardiovascular K(ATP) channels and others do not. There are data to indicate that the cardiovascular response to ischemia and hypoxia can be altered by some but not all insulin secretagogues.