Trihormonal Regulation of Metabolic Homeostasis: Redesigning Therapy of Diabetes

描述(由申请人提供)： 由于年轻退伍军人涌入退伍军人系统，1型糖尿病(T1 DM)正成为退伍军人管理局日益严重的问题。自1922年发现胰岛素以来，胰岛素单一疗法一直是治疗T1 DM的唯一方法。我们已经报道，在完全胰岛素缺乏的啮齿动物中诱导高瘦素血症完全逆转了未受控制的糖尿病的临床和实验室表现，并使原本垂死的啮齿动物完全恢复健康。我们发现，瘦素概括了胰岛素的每一种令人满意的作用，并反对其不受欢迎的生脂和生胆固醇作用。胰岛素治疗T1 DM的血糖变异性是由于激素的不同目标组织对胰岛素的需求不同，而外周注射单一浓度的胰岛素和广泛的脂肪酸通量无法满足这一需求。瘦素通过抑制胰高血糖素和脂肪酸，可以克服这两种胰岛素缺陷。现在，我们希望确定这些显著影响的机制，并开始将我们的发现翻译到人类身上。如果它与啮齿动物一样有效，它应该会通过提高血糖稳定性、减少胰岛素注射、采集血糖样本以及减少脂肪生成和胆固醇生成及其大血管疾病来改善糖尿病患者的生活质量。

DESCRIPTION (provided by applicant): Project Summary Type 1 diabetes (T1DM) is becoming an increasing problem for the VA as a result of the influx of younger veterans into the system. Insulin monotherapy has been the only treatment for T1DM since the discovery of insulin in 1922. We have reported that induction of hyperleptinemia in totally insulin deficient rodents completely reverses the clinical and laboratory manifestations of uncontrolled diabetes and restores otherwise moribund rodents to full health. We find that leptin recapitulates every desirable action of insulin and opposes its undesirable lipogenic and cholesterogenic actions. The glycemic variability with insulin treatment of T1DM results from the disparate insulin requirements of the various target tissues of the hormone, which cannot be met by a single concentration of peripherally injected insulin, together with the wide fluxes in fatty acids. Leptin, by suppressing both glucagon and fatty acids, can overcome both of these insulin defects. Now we wish to determine the mechanisms of these remarkable effects and begin translation of our findings to humans. It if works as effectively as in rodents, it should improve the quality of diabetic life through increased glycemic stability, fewer insulin injections, blood glucose sampling, and a reduction in lipogenesis and cholesterogenesis and their macrovascular diseases.