Molecular physiological and biological studies on the mechanismof impaired glucose-induced insulin secretion in diabetes mellitus

在订购用2型糖尿病melitus中对葡萄糖诱导胰岛素保密的影响的分子机制时，我们考察了SNARE蛋白的改变表达（syntaxin 1A和SNAP-25），谁知道在胰岛素秘密颗粒的外氧化过程中扮演一个重要的角色，即传感器分子用于内聚Cay D12+ D1的提升和代谢信号从葡萄糖衍生出来的重要角色，Diabetic GK （Goto-Kakizaki）老鼠。免疫细胞分析揭示了GK大鼠切片中合成素1A和SNAP-25的蛋白质水平被降级到控制大鼠切片中60%的水平。恢复这些蛋白质在GK老鼠中的正常水平是通过重组腺病毒介导的基因转移系统实现的。葡萄糖刺激胰岛素从Adex 1CA合成酶1A和Adex 1CA SNAP-25感染的GK大鼠胰岛增加到正常大鼠胰岛。SNARE蛋白的破坏性表达至少是在受损害的胰岛素保密的一部分中被排除在外。对于代理人的筛选，可以增加Ca-D12 +-D1的外ocytotic Mechanism的敏感性， Pimobendan和JTT-608被审查。他们中的两个都被加了葡萄糖诱导的胰岛素的秘密-依赖性。Using electrically permeabilized rat pancreatic islets， they augmented the sensitivity for intracellular CaイイD12+イエD1 elevation to trigger the exocytosis。它被揭示了pimobendan可以通过部分激活Ca-D12 +--D1/calmodulin dependent protein kinase II，并且JTT-608可以通过抑制磷酸酶活性来增加内源性cAMP水平来实现。事实上，这些药物将成为2型糖尿病中的新颖治疗意味着对2型糖尿病的永久胰岛素保密的治疗。

In order to elucidate the molecular mechanism of impairment of glucose-induced insulin secretion in type 2 diabetes mellitus, we examined the altered expression of SNARE proteins (syntaxin 1A and SNAP-25), which are known to play an important role on exocytolic process of insulin secretary granules as sensor molecules for the intracellular CaィイD12+ィエD1 elevation and metabolic signals derived from glucose, in diabetic GK (Goto-Kakizaki) rats. Immunoblot analysis revealed that protein levels of syntaxin 1A and SNAP-25 in GK rat islets decreased to 〜60% of the levels in control rat islets. Restoration of these proteins to normal levels in GK rats was achieved via the recombinant adenovirus-mediated gene transduction system. Glucose-stimulated insulin release from Adex 1CA syntaxin 1A and Adex 1CA SNAP-25-infected GK rat islets increased up to those from normal rat islets. The decreased expression of SNARE proteins is at least in part the defect responsible for impaired insulin secretion. For the screening of the agents, which can augment the CaィイD12+ィエD1 sensitivity of exocytotic mechanism of insulin secretory granules, pimobendan and JTT-608 were examined. Both of them increased the glucose-induced insulin secretion dose-dependently. Using electrically permeabilized rat pancreatic islets, they augmented the sensitivity for intracellular CaィイD12+ィエD1 elevation to trigger the exocytosis. It is revealed that pimobendan can exhibit its effect by in part activating CaィイD12+ィエD1/calmodulin dependent protein kinase II, and that JTT-608 can do it by inhibiting phosphodiesterase activity to increase intracellular cAMP levels. Accordingly, these agents would become novel therapeutic means for the treatment of impaired insulin secretion in type 2 diabetes mellitus.