Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and glibenclamide, is correlated with modulations of the cAMP regulatory cascade

Abstract

Abstract--The long-term hypoglycemic activity of sulphonylurea drugs has been attributed, in part at least, to the stimulation of glucose utilization in extra-pancreatic tissues. The novel sulphonylurea, glimepiride, gives rise to a longer lasting reduction in the blood sugar level in dogs and rabbits compared to glibenclamide (Geisen K, Drug Res 38: 1120-1130). This cannot be explained adequately by elevated plasma insulin levels. This study investigated whether this prolonged hypoglycemic phase was based on the drug's abilities to stimulate glucose utilization and affect the underlying regulatory mechanisms in insulin-sensitive cells in vitro. It was found that in the absence of added insulin, glimepiride and glibenclamide (1-50/iM) stimulated lipogenesis (3T3 adipocytes) and glycogenesis (isolated rat diaphragm) -4.5-and 2.5-fold, respectively, and reduced the isoproterenol-stimulated lipolysis (rat adipocytes) up to 40-60%. The increased glucose utilization was correlated with a 3-4-fold higher 2-deoxyglucose transport rate and amount of GLUT4 at the plasma membrane, as well as with increased activities of key metabolic enzymes (glycerol-3-phosphate acyltransferase, glycogen synthase) within the same concentration range. Furthermore, the low K,, cAMP-specific phosphodiesterase was activated 1.8-fold, whereas the cytosolic cAMP level and protein kinase A activity ratios were significantly lowered after incubation of isoproterenol-stimulated rat adipocytes with the sulphonylureas. In many of the aspects studied the novel sulphonylurea, glimepiride, exhibited slightly lower EDs0-values than glibenclamide. This study demonstrates correlations existing between druginduced stimulation of glucose transport/metabolism and cAMP degradation/protein kinase A inhibition as well as between the relative efficiencies of,glimepiride and glibenclamide in inducing these extrapancreatic processes. Therefore, it is suggested that the stimulation of glucose utilization by sulphonylureas is mediated by a decrease of cAMP-dependent phosphorylation of GLUT4 and glucose metabolizing enzymes. The therapeutic relevance of extra-pancreatic effects of sulphonylureas, in general, and of the differences between glimepiride and glibenclamide as observed in vitro in this work, in particular, remain to be elucidated.

Effect of Sitagliptin and Glimepiride on Glucose Homeostasis and cAMP Levels in Peripheral Tissues of HFD/STZ Diabetic Rats

“…It was documented that, gluconeogenesis and hepatic glucose production were inhibited by sitagliptin in HFD-induced obese rats due to decreased glycerol availability as a result of reduced glycerol release from adipose tissues [22]. Furthermore, studies suggested an insulin sensitizing action of glimepiride possibly by stimulation of GLUT4 transport protein activation and/or translocation in fat and muscle [23].…”

Leptin Impairs Metabolic Actions of Insulin in Isolated Rat Adipocytes

“…]glucose (300 mCi/mmol, DuPont NEN) into glycogen (28,29). 0.5 ml of adipocytes in KRH were diluted with 0.5 ml of KRH and incubated in the absence or presence of insulin in a shaking water bath under an atmosphere of 5% CO 2 for 20 min at 37°C.…”

Metabolomic analysis of healthy human urine following administration of glimepiride using a liquid chromatography-tandem mass spectrometry

“…More importantly, other studies revealed that glimepiride not only stimulates cAMP-PDE but also decreases protein kinase A (PKA) activity, possibly due to reduced intracellular cAMP concentration. [25,26] These results indicate that glimepiride decreases cytosolic cAMP levels via the regulation of cAMP-PDE and PKA. Furthermore, insulin has been reported to reduce cytosolic cAMP level by activating cAMP-PDE [27][28][29] and inhibiting adenylcyclase synthesis.…”