Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance
Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance
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DOI：
10.2337/db06-0878
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发表时间：
2006-12-01
期刊：
影响因子：
7.7
通讯作者：
Yada, Toshihiko
中科院分区：
文献类型：
--
作者：
Dezaki, Katsuya;Sone, Hideyuki;Yada, Toshihiko
胃激素ghrelin及其受体生长激素促分泌素受体（GHSR）在胰腺中表达。在这里，我们报告说，生长素释放从胰岛调节葡萄糖诱导的胰岛素释放。胰腺静脉中生长素释放肽和胰岛素的血浆浓度高于动脉。GHSR拮抗剂和内源性ghrelin的免疫中和作用均能增强葡萄糖诱导的胰腺胰岛素释放，而外源性ghrelin则能抑制胰岛素释放，GHSR拮抗剂能增加胃切除大鼠和正常大鼠的血浆胰岛素水平。Ghrelin基因敲除小鼠表现出增强的葡萄糖诱导的胰岛素释放从孤立的胰岛，而胰岛密度，大小，胰岛素含量和胰岛素mRNA水平不变;在Ghrelin基因敲除小鼠的葡萄糖耐量试验（GTT）显示增加胰岛素和降低葡萄糖反应。高脂饮食治疗在野生型小鼠的GTT中产生葡萄糖耐受不良。在ghrelin基因敲除小鼠中，高脂饮食诱导的葡萄糖耐受不良在很大程度上得到了预防，而胰岛素对GTT的反应明显增强。这些发现表明，来自胰岛的ghrelin是葡萄糖诱导的胰岛素释放的生理调节剂。生长激素释放肽功能的拮抗作用可以增强胰岛素释放，以满足高脂饮食诱导的肥胖症中对胰岛素的需求增加，从而使血糖控制正常化，这可能提供潜在的治疗应用以对抗2型糖尿病的进展。
The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered; Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet-induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes.