STIMULATION OF GLUCOSE-UTILIZATION IN 3T3 ADIPOCYTES AND RAT DIAPHRAGM IN-VITRO BY THE SULFONYLUREAS, GLIMEPIRIDE AND GLIBENCLAMIDE, IS CORRELATED WITH MODULATIONS OF THE CAMP REGULATORY CASCADE

The long-term hypoglycemic activity of sulphonylurea drugs has been at tributed, in part at least, to the stimulation of glucose utilization in extra-pancreatic tissues. The novel sulphonylurea, glimepiride, giv es rise to a longer lasting reduction in the blood sugar level in dogs and rabbits compared to glibenclamide (Geisen K, Drug Res 38: 1120-11 30, 1988). This cannot be explained adequately by elevated plasma insu lin levels. This study investigated whether this prolonged hypoglycemi c phase was based on the drug's abilities to stimulate glucose utiliza tion and affect the underlying regulatory mechanisms in insulin-sensit ive cells in vitro. It was found that in the absence of added insulin, glimepiride and glibenclamide (1-50 mu M) stimulated lipogenesis (3T3 adipocytes) and glycogenesis (isolated rat diaphragm) similar to 4.5- and 2.5-fold, respectively, and reduced the isoproterenol-stimulated lipolysis (rat adipocytes) up to 40-60%. The increased glucose utiliza tion was correlated with a 3-4-fold higher 2-deoxyglucose transport ra te and amount of GLUT4 at the plasma membrane, as well as with increas ed activities of key metabolic enzymes (glycerol-3-phosphate acyltrans ferase, glycogen synthase) within the same concentration range. Furthe rmore, the low K-m cAMP-specific phosphodiesterase was activated 1.8-f old, whereas the cytosolic cAMP level and protein kinase A activity ra tios were significantly lowered after incubation of isoproterenol-stim ulated rat adipocytes with the sulphonylureas. In many of the aspects studied the novel sulphonylurea, glimepiride, exhibited slightly lower ED(50)-values than glibenclamide. This study demonstrates correlation s existing between drug-induced stimulation of glucose transport/metab olism and cAMP degradation/protein kinase A inhibition as well as betw een the relative efficiencies of glimepiride and glibenclamide in indu cing these extrapancreatic processes. Therefore, it is suggested that the stimulation of glucose utilization by sulphonylureas is mediated b y a decrease of cAMP-dependent phosphorylation of GLUT4 and glucose me tabolizing enzymes. The therapeutic relevance of extra-pancreatic effe cts of sulphonylureas, in general, and of the differences between glim epiride and glibenclamide as observed in vitro in this work, in partic ular, remain to be elucidated.