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 (KATP channel) is located immediately at the upstream signal of voltage dependent Ca2+ channels on the signaling pathway of insulin secretion. KATP 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 KATP 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 KATP 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 KATP channels interacting directly with a sulfonylurea receptor.
Watanabe
Masatomo
M
Department of Hygiene, Dokkyo University School of Medicine, Mibu-machi, Tochigi, Japan.
Watanabe
Keita
K
Matsui
Hisao
H
D000284:Administration, Oral; D000496:Alloxan; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D009947:Organotin Compounds; D011817:Rabbits; D014044:Tolbutamide / Q000008:administration & dosage / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009947:Organotin Compounds; D014280:Triglycerides; D000496:Alloxan; D014044:Tolbutamide; C012594:triphenyltin chloride