Preclinical studies of glimepiride.
The treatment of NIDDM is advancing on a number of fronts, ranging from the understanding of the mechanisms of action of existing agents to the development of new drugs. Glimepiride, the most recently U.S. approved sulfonylurea, is evaluated for its pancreatic and extrapancreatic activities in addition to safety, when compared with glibenclamide in preclinical studies. Glimepiride uniquely binds to the 65 kDa protein K(ATP) channel in pancreatic islet beta-cell membranes and directly stimulates insulin secretion. Glimepiride has a lower binding affinity and causes less insulin release than glibenclamide in normal dogs and humans. However, in various animal models, glimepiride produces a more rapid and pronounced blood glucose-decreasing activity than glibenclamide. In vivo studies indicate that glimepiride also significantly reduces HbA1c, blood glucose and fasting insulin levels via extrapancreatic activities. These insulin mimetic effects are supported by demonstration of stimulated lipogenesis in 3T3 adipocytes and glycogenesis in rat diaphragm, by more efficient translocation of GLTU4 in fat and skeletal muscle tissues, and by activation of key metabolic enzymes. The insulin sensitivity effects of glimepiride have been demonstrated in vivo by increased glucose disposal rates in euglycemic clamp studies and in vitro by increased sensitivity and responsiveness of insulin-induced glucose uptake. Moreover, glimepiride might stimulate insulin-mediated glucose utilization in hepatocytes. With exercise-induced hypoglycemia, a suppression of endogenous insulin secretion was observed for glimepiride only. Data accumulated from in vitro and animal studies suggest that glimepiride has the least cardiotoxic potential. Its relative activities in multiple cardiovascular studies do not correlate with its potency to lower blood glucose levels. Similar cardiovascular effects have been seen in human studies. In contrast to the lack of an acute action, chronic application of glimepiride to cultured cardiomyocytes was found to produce an approximate doubling of the basal glucose uptake rates by an insulin-independent pathway most probably involving increased protein expression of both GLUT1 and GLUT4. Like glibenclamide, glimepiride possibly has antiatherogenic activity by inhibiting platelet aggregation via suppression of arachidonic acid metabolism. Our recent studies on rats and humans indicated that glimepiride has immunomodulatory activity and this action appears to be related to lowering autoimmune responses rather than metabolic action. These studies have been extended to include glimepiride involvement with prevention of diabetes in BB rats using an islet transplantation model. Finally, sulfonylureas, including glimepiride, may be useful for treating and preventing NIDDM.
Nguyen
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Diabetes Research Program, University of California, Irvine, California 92697, USA.
Pan
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Charles
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MA