Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets
Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets
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DOI：
10.2337/db06-0734
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发表时间：
2007-01-01
期刊：
影响因子：
7.7
通讯作者：
Butler, Peter C.
中科院分区：
文献类型：
--
作者：
Ritzel, Robert A.;Meier, Juris J.;Butler, Peter C.
胰岛中2,000-3,000个β细胞的胰岛素分泌与胰岛素的释放是高度同步的，它们以大约4分钟的间隔协调分泌爆发。胰岛素分泌在2型糖尿病和胰岛移植后逐渐下降。两者的特点都是存在由胰岛淀粉样蛋白多肽（IAPP）衍生的胰岛淀粉样蛋白。在本研究中，我们研究了细胞外人IAPP （h-IAPP）对人胰岛形态和功能的作用。由于已知h-IAPP的低聚物会导致膜破坏，我们质疑将h-IAPP低聚物应用于人类胰岛是否会导致胰岛结构破坏（特别是细胞间粘附）和坐标功能下降（例如，胰岛素分泌熵增加和坐标分泌爆发减少）。这两种假设都得到了证实，从而提出了一种新的假设，即2型糖尿病和胰岛移植后胰岛素分泌受损，特别是通过破坏膜的IAPP低聚物破坏胰岛细胞间的粘附。
Insulin secretion from the 2,000-3,000 beta-cells in an islet is a highly synchronized activity with discharge of insulin in coordinate secretory bursts at approximately 4-min intervals. Insulin secretion progressively declines in type 2 diabetes and following islet transplantation. Both are characterized by the presence of islet amyloid derived from islet amyloid polypeptide (IAPP). In the present studies, we examined the action of extracellular human IAPP (h-IAPP) on morphology and function of human islets. Because oligomers of h-IAPP are known to cause membrane disruption, we questioned if application of h-IAPP oligomers to human islets would lead to disruption of islet architecture (specifically cell-to-cell adherence) and a decrease in coordinate function (e.g., increased entropy of insulin secretion and diminished coordinate secretory bursts). Both hypotheses are affirmed, leading to a novel hypothesis for impaired insulin secretion in type 2 diabetes and following islet transplantation, specifically disrupted cell-to-cell adherence in islets through the actions of membrane-disrupting IAPP oligomers.