Chen N G, Romsos D R
Department of Food Science and Human Nutrition, Michigan State University, East Lansing 48824-1224.
Endocrinology. 1995 Feb;136(2):505-11. doi: 10.1210/endo.136.2.7835283.
Insulin secretion from perifused islets of preobese, 2-week-old, genetically obese (ob/ob) mice and their lean littermates was examined to identify early-onset abnormalities in regulation of insulin secretion by ob/ob mice. The ob/ob mice were slightly hyperinsulinemic (+20%) and hypoglycemic (-12%) at 2 weeks of age. Pancreatic islet size, DNA content, and insulin content were similar in ob/ob and lean mice. The responsiveness of islets to glucose, as determined by 20 mM glucose-induced insulin secretion, and the sensitivity of islets to glucose, as determined by the glucose threshold for insulin secretion, were unaffected 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 more effective in stimulating insulin secretion from islets of ob/ob mice than from islets of lean mice. Both responsiveness and sensitivity to acetylcholine and cholecystokinin potentiation of glucose-induced insulin secretion were enhanced in islets from ob/ob mice. Further, glucose-dependent insulinotropic polypeptide, which stimulates glucose-induced insulin secretion via activation of adenylate cyclase, interacted with acetylcholine to further augment differences in insulin secretion between islets from ob/ob and lean mice. The signal transduction pathway common to acetylcholine and cholecystokinin, and cross-talk between this pathway and the glucose-dependent insulinotropic polypeptide signal transduction pathway are loci for early-onset defects in control of insulin secretion from islets of ob/ob mice.
研究了2周龄的肥胖前期、遗传性肥胖（ob/ob）小鼠及其瘦型同窝小鼠的胰岛在灌流状态下的胰岛素分泌情况，以确定ob/ob小鼠胰岛素分泌调节方面的早期异常。ob/ob小鼠在2周龄时轻度高胰岛素血症（+20%）且低血糖（-12%）。ob/ob小鼠和瘦型小鼠的胰岛大小、DNA含量及胰岛素含量相似。通过20 mM葡萄糖诱导的胰岛素分泌所测定的胰岛对葡萄糖的反应性，以及通过胰岛素分泌的葡萄糖阈值所测定的胰岛对葡萄糖的敏感性，均不受表型影响，但两种通过激活磷脂酶-C信号转导途径来增强葡萄糖诱导的胰岛素分泌的促胰岛素分泌剂（即乙酰胆碱和胆囊收缩素），在刺激ob/ob小鼠胰岛的胰岛素分泌方面比在刺激瘦型小鼠胰岛时更有效。ob/ob小鼠胰岛对乙酰胆碱和胆囊收缩素增强葡萄糖诱导的胰岛素分泌的反应性和敏感性均增强。此外，通过激活腺苷酸环化酶来刺激葡萄糖诱导的胰岛素分泌的葡萄糖依赖性促胰岛素多肽，与乙酰胆碱相互作用，进一步加大了ob/ob小鼠和瘦型小鼠胰岛之间胰岛素分泌的差异。乙酰胆碱和胆囊收缩素共有的信号转导途径，以及该途径与葡萄糖依赖性促胰岛素多肽信号转导途径之间的相互作用，是ob/ob小鼠胰岛胰岛素分泌控制方面早期缺陷的位点。
