Signal transduction in isolated islets from the ob/ob mouse: enhanced sensitivity of protein kinase C to stimulation.

The insulin secretory responses of islets isolated from ob/ob mice or their lean litter mates to glucose or the phorbol ester tetradecanoyl phorbol acetate were determined. Glucose-induced phospholipase C activation was also monitored. Even though lean mouse islets contained more insulin than ob/ob mouse islets, the first and second phases of 15mM 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 15mM 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 unresponsive to tetradecanoyl phorbol acetate (500nM), a rising and sustained insulin secretory response was evoked from ob/ob mouse islets. The combination of 7.5mM glucose plus tetradecanoyl phorbol acetate resulted in dramatic and sustained insulin secretory responses from ob/ob mouse islets, responses that could be duplicated by stimulation with the combination of 3mM glucose, 500nM tetradecanoyl phorbol acetate and 30mM potassium. Significantly smaller responses to these agonist combinations were observed from lean mouse islets. These findings demonstrate that the sensitivity of ob/ob mouse islet protein kinase C to stimulation is markedly enhanced when compared to islets from lean mice and that the activation of protein kinase C or processes distal to and dependent on the enzyme may account, at least in part, for the amplified insulin secretory responses of these islets.