Trihormonal Regulation of Metabolic Homeostasis: Redesigning Therapy of Diabetes

描述（由申请人提供）： 1型糖尿病（T1 DM）正在成为VA的一个日益严重的问题，因为年轻的退伍军人涌入该系统。自1922年发现胰岛素以来，胰岛素单药治疗一直是T1 DM的唯一治疗方法。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不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恢复到完全健康。我们发现，瘦素概括了胰岛素的每一个可取的行动，并反对其不良的脂肪和胆固醇的行动。T1 DM胰岛素治疗的血糖变异性是由于激素的各种靶组织对不同胰岛素的需求不同，这不能通过单一浓度的外周注射胰岛素以及脂肪酸的广泛通量来满足。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转化为人类。如果它能像在啮齿类动物中一样有效，它应该通过增加血糖稳定性、减少胰岛素注射、血糖采样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。 公共卫生相关性： 项目叙述拟议研究与退伍军人健康和/或医疗保健问题的相关性：能够治疗和恢复新一代1型糖尿病退伍军人的完全健康，使他们免受多次胰岛素注射的痛苦和持续低血糖的风险，将是提高他们生活质量的重要一步。此外，瘦素治疗的抗脂肪生成和抗胆固醇生成活性应降低1型患者动脉粥样硬化性疾病的高发病率。如果它在人类身上起作用，就像在啮齿动物身上一样，那么糖尿病的治疗将在87年来首次发生革命性的变化。

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. PUBLIC HEALTH RELEVANCE: Project Narrative Relevance of the proposed research to veterans health and/or healthcare issues: The ability to treat and restore to full health the new generation of type 1 diabetic veterans and spare them the hardships of multiple insulin injections and constant risk of hypoglycemia, would be a major step forward in enhancing the quality of their lives. Furthermore, the antilipogenic and anticholesterogenic activities of leptin treatment should reduce the high incidence of atheromatous disease in type 1 patients. If it works in humans, as it has in rodents, the treatment of diabetes will have been revolutionized for the first time in eighty-seven years.