Leptin constrains acetylcholine-induced insulin secretion from pancreatic islets of ob/ob mice
Leptin constrains acetylcholine-induced insulin secretion from pancreatic islets of ob/ob mice
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DOI：
10.1172/jci119629
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发表时间：
1997-09-01
影响因子：
15.9
通讯作者：
Romsos, DR
中科院分区：
文献类型：
--
作者：
Chen, NG;Swick, AG;Romsos, DR
胰腺的胰岛素分泌过多是一些遗传性肥胖动物（包括ob/ob小鼠）和一些肥胖倾向的人类中最早可检测到的代谢改变之一。由于ob/ob小鼠肥胖的主要原因是由于ob基因突变而缺乏瘦素，我们测试了瘦素靶向胰岛中的调节途径以防止胰岛素分泌过多的假设，胰岛素分泌受血糖变化以及来自胃肠道的肽和激活胰岛腺苷酸环化酶的神经递质（例如，胰高血糖素样肽-1）和磷脂酶C（PLC）（例如，乙酰胆碱）信号传导途径进一步增强葡萄糖诱导的胰岛素分泌。因此检查了瘦素对这些调节途径中的每一种的作用。瘦素不影响葡萄糖或胰高血糖素样肽-1诱导的肥胖/肥胖或瘦小鼠胰岛分泌胰岛素，这与早期发现一致，即这些调节途径不会导致肥胖/肥胖小鼠胰岛早发性胰岛素分泌过多。然而，瘦素确实限制了ob/ob小鼠胰岛的PLC介导的胰岛素分泌特征的增强，而不影响瘦小鼠胰岛的释放。PLC介导的胰岛素分泌的特异性增强是ob/ob小鼠胰岛胰岛素分泌的最早报道的发育改变，因此是瘦素作用的逻辑靶点。瘦素对PLC介导的胰岛素分泌的这种作用是剂量依赖性的，快速起效的（即，3分钟内）和可逆的瘦素在抑制由蛋白激酶C（PKC）激活（PLC信号途径的下游介体）引起的ob/ob小鼠胰岛的胰岛素释放增强方面同样有效。因此，瘦素在控制身体组成中的一个功能是靶向胰岛内PLC-PKC信号传导系统的PKC调节组分以防止胰岛素分泌过多。
Hypersecretion of insulin from the pancreas is among the earliest detectable metabolic alterations in some genetically obese animals including the ob/ob mouse and in some obesity-prone humans, Since the primary cause of obesity in the ob/ob mouse is a lack of leptin due to a mutation in the ob gene, we tested the hypothesis that leptin targets a regulatory pathway in pancreatic islets to prevent hypersecretion of insulin, Insulin secretion is regulated by changes in blood glucose, as well as by peptides from the gastrointestinal tract and neurotransmitters that activate the pancreatic islet adenylyl cyclase (e.g., glucagon-like peptide-1) and phospholipase C (PLC) (e,g., acetylcholine) signaling pathways to further potentiate glucose-induced insulin secretion, Effects of leptin on each of these regulatory pathways were thus examined. Leptin did not influence glucose or glucagon-like peptide-1-induced insulin secretion from islets of either ob/ob or lean mice, consistent with earlier findings that these regulatory pathways do not contribute to the early-onset hypersecretion of insulin from islets of ob/ob mice. However, leptin did constrain the enhanced PLC-mediated insulin secretion characteristic of islets from ob/ob mice, without influencing release from islets of lean mice, A specific enhancement in PLC-mediated insulin secretion is the earliest reported developmental alteration in insulin secretion from islets of ob/ob mice, and thus a logical target for leptin action. This action of leptin on PLC-mediated insulin secretion was dose-dependent, rapid-onset (i,e., within 3 min), and reversible, Leptin,was equally effective in constraining the enhanced insulin release from islets of ob/ob mice caused by protein kinase C (PKC) activation, a downstream mediator of the PLC signal pathway. One function of leptin in control of body composition is thus to target a PKC-regulated component of the PLC-PKC signaling system within islets to prevent hypersecretion of insulin.