PRESERVED INITIATORY AND POTENTIATORY EFFECT OF ALPHA-KETOISOCAPROATEON INSULIN RELEASE IN ISLETS OF GLUCOSE INTOLERANT RATS

Insulin responses to glucose and non-glucose secretagogues were studie d in short-term cultured pancreatic islets and perfused pancreata of t he glucose intolerant F-1 hybrid rats of spontaneously diabetic Goto-K akizaki and control Wister rats. After culture at 5.5 mmol/l glucose, hybrid islet responses to 11.1, 16.7 and 27.0 mmol/l glucose were betw een 60 and 40 % of control islet responses. A combination of 1 mmol/l isobutylmethylxanthine and 16.7 mmol/l glucose induced a pronounced in sulin release, which was of similar magnitude in hybrid and control ra t islets. This response was not further augmented by addition of glibe nclamide and arginine. The slope of potentiation of arginine (10 mmol/ l)-stimulated insulin secretion by glucose (5.5-16.7 mmol/l) was great ly impaired in hybrid islets. In contrast to glucose, alpha-ketoisocap roate (KIC), which is metabolized in Krebs cycle, dose-dependently sti mulated insulin secretion to similar levels in hybrid and control isle ts, cultured at 5.5 mmol/l glucose. Also in hybrid islets depolarized by potassium chloride (30 mmol/l) and with adenosine triphosphate-sens itive K+-channels kept open by diazoxide, insulin responses to glucose were greatly impaired but intact to KIC. Furthermore, KIC potentiated normally the insulin response to arginine in hybrid islets. In the is olated perfused pancreas, KIC induced similar insulin responses in hyb rid rats and control rats. The potentiating effect by 5.5 mmol/l gluco se on the KIC-stimulatcd insulin responses was, however, greatly reduc ed in isolated islets and absent in the perfused pancreata of hybrid r ats. Taken together, these findings suggest an intact capacity for ins ulin release, although the initiating and potentiating effect by gluco se on insulin release are defective in the Goto-Kakizaki-hybrid rats. An abnormal beta-cell glucose metabolism proximal to the Krebs cycle i s likely to account for the impairment of insulin release.