PERSISTENTLY ENHANCED SENSITIVITY OF PANCREATIC-ISLETS FROM OB OB MICE TO PKC-STIMULATED INSULIN-SECRETION/

Islets from 2-wk-old ob/ob and lean littermate mice were cultured for 4-12 days and then perifused or statically incubated to identify early -onset differences in their regulation of insulin secretion. Islets fr om these young ob/ob and lean mice increased insulin secretion similar ly in response to glucose (10 or 20 mM), whereas responsiveness to glu cose plus acetylcholine (10 mu M) was greater in islets from ob/ob mic e than lean mice. This phenotype-specific effect of acetylcholine was mimicked by phorbol 12-myristate 13-acetate (PMA, 100 nM), a protein k inase C (PKC) agonist, whereas prior downregulation of PKC abolished t his phenotype-specific effect of acetylcholine. A high concentration o f PMA (1 mu M) equally and substantially increased insulin secretion f rom islets of ob/ob and lean mice, suggesting an enhanced regulatory s ensitivity rather than altered responsiveness of the PKC system in isl ets of ob/ob mice. Addition of BAY K 8644, a Ca2+ channel agonist, to the perifusate enhanced acetylcholine-induced insulin secretion from i slets of lean mice to attain the high rates observed in islets from ob /ob mice exposed to acetylcholine alone. We propose that acetylcholine -induced PKC regulation of insulin secretion is altered in islets from ob/ob mice, that this alteration may directly or indirectly involve C a2+ channels, and that it persists even when islets are cultured for u p to 12 days.