Extrapancreatic effects of sulfonylureas--a comparison between glimepiride and conventional sulfonylureas.
The contribution of extrapancreatic effects of sulfonylureas to the blood glucose-decreasing activity was reevaluated in vivo and in vitro with several conventional sulfonylureas and with the new one glimepiride. In vivo, in dogs, after single approximately equipotent blood glucose-decreasing doses, the sulfonylureas were tested for a ranking in the ratios of mean plasma insulin-increasing and blood glucose-decreasing activity. Studies were also performed in hyperglycemic hyperinsulinemic KK-Ay mice under once daily treatment for 8 weeks. In vitro, glimepiride and glibenclamide were tested for the ranking of their extrapancreatic activity with respect to the stimulation of glucose transport and glucose metabolizing processes in normal and insulin-resistant fat cells as well as in the isolated diaphragm. Furthermore, in vitro studies were performed, especially with glimepiride, in order to characterize the molecular mechanism for the extrapancreatic activity. The dog studies revealed a marked ranking in the ratios of plasma insulin-increasing and blood glucose-decreasing activity between the different sulfonylureas (glimepiride < glipizide < gliclazide < glibenclamide). In the hyperglycemic hyperinsulinemic KK-Ay mice, glimepiride reduced blood glucose by 40%, plasma insulin by 50% and HBA1c by 33%, whereas glibenclamide and gliclazide had no effect on these parameters. In vitro, glimepiride and glibenclamide had extrapancreatic effects within the lower microM range, with glimepiride exhibiting 2-3-fold lower ED50 values than glibenclamide. In the absence of insulin, both stimulated glucose transport--up to 60% of the maximum insulin response in the rat diaphragm and up to 35% in 3T3 adipocytes. Glycogenesis was stimulated in the rat diaphragm--up to 55% of the maximum insulin effect; lipogenesis in 3T3 adipocytes--up to 40%. The studies on the molecular mechanism of extrapancreatic activity with rat adipocytes and diaphragm suggest that these direct insulin-mimetic effects rely on the induction of GLUT4 translocation from internal stores to the plasma membrane and on the activation of the key metabolic enzymes, glycogen synthase and glycerol-3-phosphate acyltransferase. These processes occur within the same drug concentration range and with the same ranking between glimepiride and glibenclamide as observed for glucose utilization and transport. The direct effects of sulfonylureas may ultimately be regulated by a glycosyl-phosphatidylinositol-specific phospholipase C, shown to be activated by glimepiride in rat adipocytes. Lipolytic cleavage products thereby generated from glycolipidic structures may in turn stimulate specific protein phosphatases which activate key regulatory proteins/enzymes of glucose and lipid metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
Hoechst AG Frankfurt, Pharmaceutical Research Division, SBU Metabolic Diseases, Germany.
G
G
Müller
Y
Y
Satoh
K
K
Geisen
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology; D004285:Dogs; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; C057619:glimepiride; D000242:Cyclic AMP