Gembal M, Detimary P, Gilon P, Gao Z Y, Henquin J C
Unité de Diabétologie et Nutrition, Faculty of Medicine, University of Louvain, Brussels, Belgium.
J Clin Invest. 1993 Mar;91(3):871-80. doi: 10.1172/JCI116308.
Glucose stimulation of insulin release involves closure of ATP-sensitive K+ channels (K(+)-ATP channels), depolarization, and Ca2+ influx in B cells. However, by using diazoxide to open K(+)-ATP channels, and 30 mM K to depolarize the membrane, we could demonstrate that another mechanism exists, by which glucose can control insulin release independently from changes in K(+)-ATP channel activity and in membrane potential (Gembal et al. 1992. J. Clin. Invest. 89:1288-1295). A similar approach was followed here to investigate, with mouse islets, the nature of this newly identified mechanism. The membrane potential-independent increase in insulin release produced by glucose required metabolism of the sugar and was mimicked by other metabolized secretagogues. It also required elevated levels of cytoplasmic Cai2+, but was not due to further changes in Cai2+. It could not be ascribed to acceleration of phosphoinositide metabolism, or to activation of protein kinases A or C. Thus, glucose did not increase inositol phosphate levels and hardly affected cAMP levels. Moreover, increasing inositol phosphates by vasopressin or cAMP by forskolin, and activating protein kinase C by phorbol esters did not mimic the action of glucose on release, and down-regulation of protein kinase C did not prevent these effects. On the other hand, it correlated with an increase in the ATP/ADP ratio in islet cells. We suggest that the membrane potential-independent control of insulin release exerted by glucose involves changes in the energy state of B cells.
葡萄糖刺激胰岛素释放涉及ATP敏感性钾通道（K(+)-ATP通道）的关闭、去极化以及B细胞中Ca2+的内流。然而，通过使用二氮嗪来开放K(+)-ATP通道，并使用30 mM K使膜去极化，我们能够证明存在另一种机制，通过该机制葡萄糖可以独立于K(+)-ATP通道活性和膜电位的变化来控制胰岛素释放（Gembal等人，1992年。《临床研究杂志》89:1288 - 1295）。这里采用了类似的方法，用小鼠胰岛来研究这种新发现机制的本质。葡萄糖产生的与膜电位无关的胰岛素释放增加需要糖的代谢，并且可被其他代谢性促分泌剂模拟。它还需要细胞质中Ca2+水平升高，但并非由于Ca2+的进一步变化。它不能归因于磷酸肌醇代谢的加速，也不能归因于蛋白激酶A或C的激活。因此，葡萄糖不会增加肌醇磷酸水平，并且几乎不影响cAMP水平。此外，通过加压素增加肌醇磷酸或通过福斯高林增加cAMP，以及通过佛波酯激活蛋白激酶C并不能模拟葡萄糖对释放的作用，并且蛋白激酶C的下调也不能阻止这些效应。另一方面，它与胰岛细胞中ATP/ADP比值的增加相关。我们认为，葡萄糖对胰岛素释放的与膜电位无关的控制涉及B细胞能量状态的变化。
