THE INTERPLAY BETWEEN CALCIUM AND CYCLIC AMP IN DIABETES

胰岛素对多种代谢途径的调节机制仍然存在 人们对此知之甚少。胰岛素作为环磷酸腺苷的生理性拮抗剂 在许多组织中；因此，人们假设胰岛素可能起作用。 通过钙作为第二信使。随着钙调蛋白的发现， 钙/钙调蛋白激活调节激素的机制 复杂性已经开始被认识到。有进一步的证据表明 提示钙/钙调蛋白复合体可以激活或失活 某些似乎受胰岛素调节的激酶或磷酸酶。 我们建议解决这一假设，即胰岛素通过 钙/钙调蛋白依赖的磷酸酶钙调神经磷酸酶调节cAMP 单元格中的信号。我们将通过开发一种针对肝脏的抗体来实现这一点 钙调神经磷酸酶及其在大鼠肝细胞中的详细研究 或者用不同的胰岛素、胰升糖素或贝塔处理的肝癌细胞 激动剂。这些研究将扩展到研究猪肝脏中的酶 链脲佐菌素诱导的糖尿病大鼠和db/db小鼠。我们希望这些 研究将进一步加深我们对胰岛素在肝脏中的作用以及 糖尿病病理生理学。

The mechanism of insulin's regulation of various metabolic pathways remains poorly understood. Insulin acts as a physiologic antagonist of cyclic AMP in many tissues; therefore, it has been hypothesized that insulin may act through calcium as a second messenger. With the discovery of calmodulin, the mechanism of hormonal regulation via activation of the Ca++/calmodulin complex has begun to be recognized. There is further evidence which suggests that the Ca++/calmodulin complex can activate or inactivate certain kinases or phosphatases which appear to be regulated by insulin. We propose to address the hypothesis that insulin acts through a Ca++/calmodulin dependent phosphatase, calcineurin, to modulate the cAMP signal in cells. We will do this by developing an antibody to hepatic calcineurin and studying this enzyme in detail in isolated rat hepatocytes or hepatoma cells variously treated with insulin, glucagon or Beta agonists. These studies will be extended to study the enzyme in livers of streptozotocin-induced diabetic rats and db/db mice. We hope that these studies will further our understanding of insulin action in liver and the pathophysiology of diabetes.