Long-term effects of glibenclamide and nateglinide upon pancreatic islet function in normal and diabetic rats

Both control and hereditarily diabetic (Goto-Kakizaki) rats were administer ed twice daily for 7 days with an oral solution of carboxymethylcellulose c ontaining, when required, glibenclamide (1.0 mu g g(-1) body wt.) or nategl inide (50.0 mu g g(-1) body wt.). The increase in plasma D-glucose concentr ation and decrease in insulinogenic index caused by the bleeding and handli ng of the rats prior to sacrifice was more pronounced in the hyperglycaemic and hyperinsulinemic diabetic rats than in the control animals. Eighteen h ours after the last oral loading, a sizeable fall in plasma D-glucose conce ntration and increase in plasma insulin concentration was only observed in the glibenclamide-treated control rats, indicating a more prolonged biologi cal effect of the hypoglycaemic sulphonylurea, as compared to the meglitini de analog. This coincided with the fact that the insulin content of the isl ets, their secretory response to a high concentration of D-glucose and thei r basal biosynthetic activity were more severely affected in glibenclamide than nateglinide-treated animals, especially in the control rats. It is pro posed, therefore, that the meglitinide analog, considered as a new insulino tropic tool for the treatment of non-insulin-dependent diabetic subjects, m ay offer the far-from-negligible advantage of minimising the risk of a sust ained decrease in both islet insulin content and glycaemia. (C) 1999 Academ ic Press.