ENHANCED SENSITIVITY OF PANCREATIC-ISLETS FROM PREOBESE 2-WEEK-OLD OBOB MICE TO NEUROHORMONAL STIMULATION OF INSULIN-SECRETION/

Insulin secretion from perifused islets of preobese, 2-week-old, genet ically obese (ob/ob) mice and their lean littermates was examined to i dentify early-onset abnormalities in regulation of insulin secretion b y ob/ob mice. The ob/ob mice were slightly hyperinsulinemic (+20%) and hypoglycemic (-12%) at 2 weeks of age. Pancreatic islet size, DNA con tent, and insulin content were similar in ob/ob and lean mice. The res ponsiveness of islets to glucose, as determined by 20 mM glucose-induc ed insulin secretion, and the sensitivity of islets to glucose, as det ermined by the glucose threshold for insulin secretion, were unaffecte d by phenotype, but two insulin secretagogues that potentiate glucose- induced insulin secretion via activation of the phospholipase-C signal transduction pathway (i.e. acetylcholine, and cholecystokinin) were m ore effective in stimulating insulin secretion from islets of ob/ob mi ce than from islets of lean mice. Both responsiveness and sensitivity to acetylcholine and cholecystokinin potentiation of glucose-induced i nsulin secretion were enhanced in islets from ob/ob mice. Further, glu cose-dependent insulinotropic polypeptide, which stimulates glucose-in duced insulin secretion via activation of adenylate cyclase, interacte d with acetylcholine to further augment differences in insulin secreti on between islets from ob/ob and lean mice. The signal transduction pa thway common to acetylcholine and cholecystokinin, and cross-talk betw een this pathway and the glucose-dependent insulinotropic polypeptide signal transduction pathway are loci far early-onset defects in contro l of insulin secretion from islets of ob/ob mice.