Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance
Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance
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DOI：
10.2337/db05-1263
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发表时间：
2006-05-01
期刊：
影响因子：
7.7
通讯作者：
Gaisano, HY
中科院分区：
文献类型：
--
作者：
Kwan, EP;Xie, L;Gaisano, HY
Munc13-1是一种二酰甘油(DAG)受体，是突触小泡启动所必需的。我们最近发现Munc13-1在啮齿动物和人胰岛β细胞中表达，并且在2型糖尿病人和大鼠模型的胰岛中表达水平降低，提示Munc13-1缺乏是糖尿病胰岛素分泌异常的原因之一。为了明确地证明Munc13-1在胰岛素分泌中的作用，我们研究了杂合子Munc13-1基因敲除小鼠(+/-)，这些小鼠在腹膜糖耐量试验中表现出高血糖水平，而相应的血清胰岛素水平则较低。Munc13-1(+/-)小鼠表现出正常的胰岛素耐受，表明初级胰岛P细胞分泌缺陷是其高血糖的主要原因。在分离的Munc13-1(+/-)胰岛中，葡萄糖刺激的胰岛素分泌一直减少50%，并且仅被佛波酯增强部分挽救。在表达Munc13-1突变变体的一个等位基因的小鼠中，相应的变化很小，该突变变体不结合DAG(H567K/+)。Munc13-1(+/-)和Munc13-1(H567k/+)胰岛P细胞的电容测量发现颗粒启动过程中存在缺陷，包括可释放池的初始大小和再充盈，这些缺陷因佛波酯增强而变得更加明显。我们得出结论，Munc13-1在葡萄糖刺激的胰岛素分泌中起着重要作用，糖尿病时胰岛Munc13-1缺乏可导致胰岛素分泌减少，从而导致糖稳态异常。
Munc13-1 is a diacylglycerol (DAG) receptor that is essential for synaptic vesicle priming. We recently showed that Munc13-1 is expressed in rodent and human islet beta-cells and that its levels are reduced in islets of type 2 diabetic humans and rat models, suggesting that Munc13-1 deficiency contributes to the abnormal insulin secretion in diabetes. To unequivocally demonstrate the role of Munc13-1 in insulin secretion, we studied heterozygous Munc13-1 knockout mice (+/-), which exhibited elevated glucose levels during intraperitoneal glucose tolerance tests with corresponding lower serum insulin levels. Munc13-1(+/-) mice exhibited normal insulin tolerance, indicating that a primary islet P-cell secretory defect is the major cause of their hyperglycemia. Consistently, glucose-stimulated insulin secretion was reduced 50% in isolated Munc13-1(+/-) islets and was only partially rescued by phorbol ester potentiation. The corresponding alterations were minor in mice expressing one allele of a Munc13-1 mutant variant, which does not bind DAG (H567K/+). Capacitance measurements of Munc13-1(+/-) and Munc13-1(H567k/+) islet P-cells revealed defects in granule priming, including the initial size and refilling of the releasable pools, which become accentuated by phorbol ester potentiation. We conclude that Munc13-1 plays an important role in glucose-stimulated insulin secretion and that Munc13-1 deficiency in the pancreatic islets as occurs in diabetes can reduce insulin secretion sufficient to cause abnormal glucose homeostasis.