INCREASED GLUCOSE PHOSPHORYLATING ACTIVITY CORRELATES WITH INSULIN SECRETORY CAPACITY OF MALE JCR-LA-CORPULENT RAT ISLETS

In this study the glucose responsiveness of isolated, overnight-cultured islets of obese LA/N-corpulent (cp/cp) rats was compared with glucose phosphorylating activity to determine whether changes in the function of glucokinase could be identified. Islets from both male and female cp/cp rats showed a left-shifted concentration response to glucose, with EC(50) values of 1.5 and 4.6 mM, respectively, compared with 9.2 mM for lean control islets. Islets from cp/cp rats were partially resistant to inhibition by mannoheptulose, a glucokinase inhibitor. Minimum inhibitory concentrations were 10 mM in cp/cp vs. 3 mM in lean rat islets. Glucose phosphorylating potential was markedly increased in islets of male cp/cp, but not female cp/cp, compared with lean rats. The maximal velocity (V-max) of hexokinase was increased fi-fold, while the K-m of glucokinase was significantly decreased, in male cp/cp compared with the lean control islets (3.6 vs. 35.2 mM). The K-m for glucokinase was also decreased in female cp/cp rat islets (17.2 mM). The data from male cp/cp rat islets are consistent with the idea that increased glucose phosphorylation capacity can contribute to insulin hypersecretion and an extreme leftward shift in the concentration - response curve. However, other factors must also be considered because female cp/cp rats have moderately increased insulin secretory capacity without marked changes in total glucose phosphorylating capacity.