ISLET PHOSPHOINOSITIDE HYDROLYSIS AND INSULIN SECRETORY RESPONSES FROM PREDIABETIC FA FA ZDF RATS/

The sequence of events that culminate in the development of diabetes i n the fa/fa Zucker diabetic fatty (ZDF) rat is unclear. In the present series of experiments islets from 5 week old prediabetic fa/fa male r ats were isolated and their phosphoinositide (PI) hydrolysis and insul in secretory responses compared to those obtained from lean nondiabeti c age- and weight-matched control rats. Peak first and second phase in sulin secretory responses to 20mM glucose averaged 77+/-10 (mean+/-SE, n=7) and 491+/-47 pg/islet/min from lean, nondiabetic control islets. The comparable responses from fa/fa prediabetic rat islets were signi ficantly greater, 264+/-51 and 810+/-78 pg/islet/min. In a parallel fa shion H-3-inositol efflux and inositol phosphate responses from predia betic rat islets were also greater than comparable control responses. These findings demonstrate that significant increases in the phospholi pase C-mediated hydrolysis of islet PI pools and insulin release in re sponse to hyperglycemic stimulation can be detected prior to the emerg ence of diabetes in the fa/fa ZDF rat. These early changes in beta cel l responsiveness to glucose may contribute to the hyperinsulinemia and subsequent insulin resistance characteristic of this animal model of non-insulin dependent diabetes mellitus. (C) 1995 Academic Press, Inc.