SIGNAL-TRANSDUCTION IN ISOLATED ISLETS FROM THE OB OB MOUSE - ENHANCED SENSITIVITY OF PROTEIN-KINASE-C TO STIMULATION/

The insulin secretory responses of islet isolated from ob/ob mice or t heir lean litter mates to glucose or the phorbol ester tetradecanoyl p horbol acetate were determined. Glucose-induced phospholipase C activa tion was also monitored. Even though lean mouse islets contained more insulin than ob/ob mouse islets, the first and second phases of 15 mM glucose-induced secretion were significantly greater from ob/ob mouse islets. The kinetics of this amplified response were similar to those seen from lean islets as was the ability of 15 mM glucose to activate phospholipase C. A striking dichotomy in responsiveness to the protein kinase C activator tetradecanoyl phorbol acetate was observed between lean and ob/ob mouse islets: while islets from lean animals were unre sponsive to tetradecanoyl phorbol acetate (500 nM), a rising and susta ined insulin secretory response was evoked from ob/ob mouse islets. Th e combination of 7.5 mM glucose plus tetradecanoyl phorbol acetate res ulted in dramatic and sustained insulin secretory responses from ob/ob mouse islets, responses that could be duplicated by stimulation with the combination of 3 mM glucose, 500 nM tetradecanoyl phorbol acetate and 30 mM potassium. Significantly smaller responses to these agonist combinations were observed from lean mouse islets. These findings demo nstrate that the sensitivity of ob/ob mouse islet protein kinase C to stimulation is markedly enhanced when compared to islets from lean mic e and that the activation of protein kinase C or processes distal to a nd dependent on the enzyme may account, at least in part, for the ampl ified insulin secretory responses of these islets. (C) 1996 Academic P ress, Inc.