Physiological and molecular biological studies on altered function of the intracellular signal transduction system in pancreatic beta cells of diabetes mellitus.

糖尿病胰腺β细胞细胞内信号转导系统功能改变的生理和分子生物学研究。

基本信息

批准号：
03671145
负责人：
ISHIDA Hitoshi
金额：
$ 1.34万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

In order to elucidate the intracellular mechanisms of impaired insulin secretion induced by glucose from pancreatic beta cells in diabetes mellitus, the altered functions of intracellular calcium signaling system and ion channels were investigated using beta cells obtained from rats of experimentally-induced non-insulin-dependent diabetes mellitus (NIDDM), or those exposed to high glucose in vitro. The glucose-induced insulin release is significantly reduced in these cells compared to the controls. In addition, the intracellular calcium ([Ca^<2+>]i) response is similarly decreased after the glucose loading. These facts clearly indicate that the abnormalities in intracellular calcium signaling system in beta cells is closely related to the impaired insulin secretion induced by glucose in NIDDM. To further elucidate the pathogenesis of reduced [Ca^<2+>]i response, the properties of ATP sensitive K^+ channel (K_<ATP> channel) was studied in NIDDM rats using the patch-clamp technique. The inhibitory effect of glucose on beta cell K_<ATP> channel activities is significantly impaired in NIDDM rats compared to the controls, but the ATP sensitivity is identical between them. The glucose insensitivity of K_<ATP> channels is, therefore, probably due to an insufficient ATP production caused by impaired glucose metabolism in beta cells of NIDDM. The insufficient depolarization of beta cell plasma membrane due to the reduced inhibition of K_<ATP> channel activities seems to cause the decreased [Ca^<2+>]i elevation in NIDDM beta cells, leading to the impaired isulin secretion induced by glucose.

为了阐明糖尿病中胰腺β细胞引起的葡萄糖诱导的胰岛素分泌的细胞内机制，使用实验诱导的非胰岛素依赖性疾病依赖型蛋白依赖的β-体外葡萄糖。与对照组相比，这些细胞中葡萄糖诱导的胰岛素释放显着降低。另外，葡萄糖负荷后，细胞内钙（[Ca^<2+>] I）类似地降低了反应。这些事实清楚地表明，β细胞中细胞内钙信号系统的异常与NIDDM中葡萄糖诱导的胰岛素分泌受损密切相关。为了进一步阐明降低[Ca^<2+>] i响应的发病机理，使用贴片钳技术在NIDDM大鼠中研究了ATP敏感K^+通道（K_ <ATP>通道）的性质。与对照组相比，NIDDM大鼠中葡萄糖对β细胞K_ <ATP>通道活性的抑制作用显着受损，但是它们之间的ATP敏感性相同。因此，K_ <ATP>通道的葡萄糖不敏感性可能是由于NIDDMβ细胞中葡萄糖代谢受损引起的ATP产生不足所致。由于K_ <ATP>通道活性抑制减少，β细胞质膜的去极化不足似乎导致NIDDMβ细胞的[Ca^<2+>] I升高降低，从而导致葡萄糖诱导的固醇分泌受损。