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

为了阐明葡萄糖诱导糖尿病患者胰腺β细胞胰岛素分泌受损的细胞内机制，我们利用体外实验诱导的非胰岛素依赖型糖尿病（NIDDM）大鼠和高糖暴露大鼠的β细胞，研究了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明显减少。此外，细胞内钙（[Ca^<2+>]i）反应在葡萄糖负荷后也同样下降。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。为了进一步阐明[Ca^<2+>]i反应降低的发病机制，我们利用膜片钳技术研究了NIDDM大鼠ATP敏感的K^+通道（K_<ATP>通道）的特性。与对照组相比，葡萄糖对NIDDM大鼠β细胞K_<ATP>通道活性的抑制作用明显减弱，但两者对ATP的敏感性相同。因此，K_<ATP>通道的葡萄糖不敏感可能是由于NIDDM β细胞葡萄糖代谢受损导致ATP产生不足。由于K_<ATP>通道活性抑制减弱导致β细胞膜去极化不足，可能导致NIDDM β细胞[Ca^<2+>]i升高降低，导致葡萄糖诱导的胰岛素分泌受损。

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.