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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.

为了阐明糖尿病时葡萄糖诱导胰岛β细胞胰岛素分泌受损的细胞内机制，本研究采用实验诱导的非胰岛素依赖型糖尿病（NIDDM）大鼠胰岛β细胞和体外高糖暴露的胰岛β细胞，研究了胰岛β细胞内钙信号系统和离子通道功能的改变。与对照组相比，这些细胞中葡萄糖诱导的胰岛素释放显著减少。此外，细胞内钙（[Ca^2+]i）响应在葡萄糖负荷后类似地降低。这些事实清楚地表明，β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。为进一步阐明[Ca^<2+>]i反应降低的发病机制，应用膜片钳技术研究了NIDDM大鼠ATP敏感性K^+通道（K_ channel）的特性<ATP>。葡萄糖对β细胞钾通道活性的抑制作用<ATP>在NIDDM大鼠明显减弱，但对ATP的敏感性在NIDDM大鼠与对照组之间无明显差异。因此，K_通道的葡萄糖不敏感性<ATP>可能是由于NIDDM β细胞葡萄糖代谢受损导致ATP产生不足所致。由于K_通道活性抑制减弱而引起的β细胞质膜去极化不足<ATP>，可能导致NIDDM β细胞[Ca^2+]i升高降低，从而导致葡萄糖诱导的胰岛素分泌受损。