Hypoglycemic and hypotriglyceridemic effects of tolbutamide in triphenyltin chloride-induced diabetic rabbits

Triphenyltin (TPT) induces transient hyperglycemia and hypertriglyceridemia in rabbits and hamsters through inhibition of the insulin release stimulated by glucose. The disturbed site in TPT-diabetes is a result of signal transduction occurring before the voltage-dependent Ca2+ channel. The ATP-sensitive K+ channel (K-ATP channel) is located immediate at the upstream signal of voltage dependent Ca2+ channels on the signaling pathway of insulin secretion. K-ATP channel produces depolarization by a signal of ATP through glucose metabolism and by stimulation from sulfonylurea drugs (tolbutamide, glibenclamide). To clarify if the insulin secretion that a K-ATP channel mediates is inhibited in vivo, we studied the effects of tolbutamide (a sulfonylurea) on changes in plasma glucose, triglyceride and insulin in TPT-diabetic rabbits prepared by po administration of 100 mg TPT-chloride/kg bw. In TPT-diabetic rabbits, plasma glucose decreased to a minimum at about 50% and plasma triglyceride levels also decreased. Insulin release was detected after injecting = 10 mg tolbutamide/kg, and insulin was secreted much higher than in normal rabbits. These findings suggest that the insulin released by tolbutamide stimulus decreased the plasma glucose and triglyceride levels in the TPT-diabetic rabbits. Moreover, a possible mechanism to be considered is as follows: tolbutamide combines with sulfonylurea receptor; membrane depolarization is induced by a K-ATP channel with the signal of a sulfonylurea receptor; insulin is released. The inhibition of insulin secretion by TPT may be caused by a glucose metabolic disorder in beta cells before the occurrence of membrane depolarization due to closed K-ATP channels interacting directs with a sulfonylurea receptor.