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 from these young ob/ob and lean mice increased insulin secretion similarly in response to glucose (10 or 20 mM), whereas responsiveness to glucose plus acetylcholine (10 microM) was greater in islets from ob/ob mice than lean mice. This phenotype-specific effect of acetylcholine was mimicked by phorbol 12-myristate 13-acetate (PMA, 100 nM), a protein kinase C (PKC) agonist, whereas prior downregulation of PKC abolished this phenotype-specific effect of acetylcholine. A high concentration of PMA (1 microM) equally and substantially increased insulin secretion from islets of ob/ob and lean mice, suggesting an enhanced regulatory sensitivity rather than altered responsiveness of the PKC system in islets of ob/ob mice. Addition of BAY K 8644, a Ca2+ channel agonist, to the perifusate enhanced acetylcholine-induced insulin secretion from islets 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 Ca2+ channels, and that it persists even when islets are cultured for up to 12 days.
Chen
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NG
Department of Food Science and Human Nutrition, Michigan State University, East Lansing 48824-1224, USA.
Romsos
D R
DR
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000494:pharmacology*; D012016:Reference Values; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D007328:Insulin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011493:Protein Kinase C; D000109:Acetylcholine; D013755:Tetradecanoylphorbol Acetate