Metabolic Actions of Brain Leptin Receptors Signaling in Type 1 Diabetes

描述(申请人提供)：根据青少年糖尿病研究基金会，1型糖尿病(T1D)在美国困扰着100-300万人，原因尚不清楚，其发病率一直以每年约3%的惊人速度增长。因此，T1D患者的数量预计将在未来几年大幅增加。T1D的发生是胰腺细胞丢失导致致命的代谢失衡的结果。目前的T1D救命干预措施包括每日胰岛素注射。这些疗法可降低高血糖、糖化血红蛋白、恶病质，并预防或延缓某些与T1D相关的疾病。然而，即使在目前的胰岛素递送系统中，T1D继发并发症包括虚弱、持久和具有经济挑战性的条件，例如心脏病、失明、肾功能衰竭、神经病和高血压。可能是由于胰岛素的生脂作用，长期的胰岛素治疗被怀疑是T1D患者异位脂肪过度沉积(即：在非脂肪组织中)和冠状动脉疾病极高发病率(55岁后90%)的基础。此外，部分由于胰岛素的强大、快速起效和降血糖作用，强化胰岛素治疗显著增加了低血糖的风险，这一事件使S致残，甚至可能是致命的。因此，迫切需要新的、更好的抗T1D疗法。开发新的甚至可能是无胰岛素的治疗方法的一个主要障碍是，没有胰岛素的生活是不相容的。然而，在Roger Unger博士和他的同事最近报道瘦素单一疗法(不使用胰岛素)可以逆转T1D啮齿动物模型中胰岛素缺乏引起的致命后果和许多代谢缺陷后，这一范式可能需要修改。因此，脂肪细胞分泌的激素瘦素的缓慢作用、降血糖作用可能是当前T1D疗法的一种有吸引力的替代和/或辅助疗法。在这里，将直接检验这一假设，即大脑中的LEPR，特别是下丘脑神经元中的LEPR介导了瘦素的抗T1D作用。为了直接验证我们的假设，我们将评估中枢神经系统限制性瘦素在两种不同的胰岛素缺乏小鼠模型中的代谢结果。那么，我们会 利用其他独特的基因工程小鼠品系来确定参与这些活动的神经元的生化特性。我们坚信，本文提出的研究结果将有助于更好地理解瘦素拯救T1D致命性和改善T1D代谢的机制(S)。一旦确定，这种分子成分(S)就可以被利用来开发新的有效的抗T1D策略，而不会有低血糖和心血管疾病的风险。 公共卫生相关性：根据青少年糖尿病研究基金会的数据，在美国，1型糖尿病(T1D)困扰着100-300万人，其发病率以每年约3%的惊人速度增长，原因尚不清楚。对于T1D患者来说，每天服用胰岛素是挽救生命的，但可能是由于胰岛素的生脂作用和强大的、快速起作用的降血糖效果，强化胰岛素治疗显著增加了T1D患者患冠状动脉疾病(55岁后90%)和低血糖的风险。在这里，我们将进行旨在确定瘦素治疗改善T1D的神经回路和分子机制的实验；我们相信，本申请中提出的实验结果将为开发更好的治疗T1D的方法铺平道路，而不会有低血糖和心血管疾病的风险。

DESCRIPTION (provided by applicant): According to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million of people in the United States of America and, for reasons yet to be understood, its incidence has been increasing at an alarming annual rate of ~3%. Thus, the number of T1D patients is expected to increase significantly in the next years. T1D occurs as a consequence of pancreatic ¿-cell loss leading to a lethal metabolic imbalance. Current T1D life-saving interventions include daily insulin administrations. These therapies reduce hyperglycemia, glycosylated hemoglobin, cachexia and prevent or delay some of T1D-associated morbidities. However, even with the current and much improved insulin delivery systems, T1D secondary complications include debilitating, long-lasting and economically challenging conditions as for example heart disease, blindness, kidney failure, neuropathy, and hypertension. Probably owing to insulin's lipogenic actions, long-term insulin treatment is suspected to underlie the excessive ectopic lipid deposition (i.e.: in non-adipose tissues) and the extremely high incidence of coronary artery disease (> 90% after age 55) seen in T1D subjects. Furthermore, in part due to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk of hypoglycemia, an event that s disabling and can even be fatal. New and better anti-T1D therapies are therefore urgently needed. A major barrier to the development of new and potentially even insulin-free treatments has been the paradigm that life without insulin is not compatible. This paradigm may need to be revised however after Dr. Roger Unger and colleagues recently reported that leptin monotherapy (without the use of insulin) can reverse the lethal consequences and many of the metabolic defects caused by insulin deficiency in rodent models of T1D. The slow-acting, glycemia-lowering effects of the adipocyte- secreted hormone leptin may therefore represent an attractive alternative and/or adjuvant to current T1D therapies. Here, will directly test the hypothesis that LEPRs in brain and specifically in hypothalamic neurons mediate leptin's anti-T1D action. To directly test our hypothesis, we will assess the metabolic outcomes of CNS-restricted leptin administration in two different mouse models of insulin deficiency. Then, we will make use of other unique genetically-engineered mouse lines to determine the biochemical identity of the neurons mediating these actions. We strongly believe that results from the studies proposed herein will lead to a better understanding of the mechanism(s) by which leptin rescues lethality and improves metabolism in T1D. Once identified, this molecular component(s) can then be exploited to develop new and effective anti-T1D strategies without the risks of hypoglycemia and cardiovascular disease. PUBLIC HEALTH RELEVANCE: According to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million of people in the United States of America and, for reasons yet to be understood, its incidence has been increasing at an alarming annual rate of ~3%. Daily insulin administrations are life-saving for people with T1D but probably owing to insulin's lipogenic actions and potent, fast-acting, glycemia- lowering effects intensive insulin therapy significantly increases the risk of coronary artery disease (> 90% after age 55) and hypoglycemia in T1D subjects. Here, we will perform experiments aimed at identifying the neurocircuitries and molecular mechanisms by which leptin administration ameliorates T1D; we believe that results from the experiments proposed in this application will pave the way to develop better therapeutic approaches against T1D without the risks of hypoglycemia and cardiovascular disease.