THE INTERPLAY BETWEEN CALCIUM AND CYCLIC AMP IN DIABETES

胰岛素调节各种代谢途径的机制仍然存在 不太了解。 胰岛素是环磷酸腺苷的生理拮抗剂 在许多组织中;因此，假设胰岛素可能起作用， 通过钙作为第二信使。 随着钙调素的发现， 通过激活Ca++/钙调蛋白的激素调节机制 复杂性已经开始被认识。 有进一步的证据表明， 表明Ca++/钙调素复合物可以激活或抑制 某些似乎受胰岛素调节的激酶或磷酸酶。 我们建议解决胰岛素通过一个 Ca++/钙调蛋白依赖性磷酸酶，钙调神经磷酸酶，调节cAMP 细胞中的信号。 我们将通过开发一种抗肝细胞癌的抗体来做到这一点。 钙调神经磷酸酶和研究这种酶的详细分离大鼠肝细胞 或用胰岛素、胰高血糖素或β-胰岛素治疗的肝癌细胞 激动剂 这些研究将扩展到研究肝脏中的酶， 链脲霉素诱导的糖尿病大鼠和db/db小鼠。 我们希望这些 研究将进一步了解胰岛素在肝脏中的作用， 糖尿病的病理生理学

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.