Evaluating the role of hypoleptinemia in impaired counterregulatory responses to hypoglycemia

项目摘要 低血糖并发症是人们达到健康血糖水平的主要障碍 糖尿病（PWD）这在很大程度上是由关于如何暴露的重大知识差距所决定的。 众所周知的风险因素，如复发性医源性低血糖，运动或酒精 消费，导致随后损害的反调节反应（CRR）， 低血糖因此，旨在减少PWD低血糖的临床干预措施仅限于 行为改变，如短期调整治疗方案，往往以牺牲 血糖控制下降。为了改善PWD的结局， 必须开发低血糖并发症的预防。该项目旨在开发预- 临床数据确定了预防低血糖并发症的药物靶点，从而 解决低血糖引起的PWD的显著治疗负担。PI最近 完成了一系列研究，表明瘦素信号在门控生理过程中的新作用。 对严重低血糖的反应。这项工作支持了我们的主要假设，即刺激降低 瘦素水平可通过引起“假性饥饿”来抑制对严重低血糖的反应。 表型。更重要的是，这一系列工作表明，阻止向一个 “饥饿”表型可防止CRR受损。该项目的总体目标是 明确确定低肽血症在CRR病理生理学损害中的作用， 开发临床前数据，确定预防低血糖的药物靶点， 并发症为了实现这些目标，PI组建了一个研究者团队， 在葡萄糖反调节、能量稳态和瘦素信号传导方面拥有丰富的专业知识， 具体目标如下：1）阐明低肽血症在改变葡萄糖反调节中的作用 在低血糖和饥饿的情况下。2)确定复发性低血糖的机制 引起低肽血症。3)确定瘦素治疗是否可以预防受损的低血糖 由已知会增加PWD低血糖并发症的条件诱导的反调节，例如 as exercise行使and alcohol酒精consumption消费.我们预计，我们提出的研究将证明， 低肽血症通过损害低血糖患者的CRR，在功能上增加了对低血糖的易感性。 生理和精神上相关的状态。如果是这样，这些结果将不仅确定第一个 内分泌机制驱动低血糖风险，但他们也将确定一个临床上易于处理的 用于预防低血糖的治疗。

PROJECT SUMMARY Hypoglycemic complications are the major barrier to achieving healthy blood glucose levels in persons with diabetes (PWD). This is largely predicated by a significant knowledge gap regarding how exposure to well-known risk factors, such as recurrent iatrogenic hypoglycemia, exercise, or alcohol consumption, leads to the subsequent impairment of the counterregulatory response (CRR) to hypoglycemia. Thus, clinical interventions aimed at reducing hypoglycemia in PWD are limited to behavioral modification, such as short-term adjustment of treatment regimens, often at the expense of decreased glycemic control. To improve outcomes for PWD, truly efficacious treatments for the prevention of hypoglycemic complications must be developed. This project is designed to develop pre- clinical data that identifies druggable targets for the prevention of hypoglycemic complications, thus addressing the significant treatment burden in PWD caused by hypoglycemia. The PI has recently completed a series of studies that suggest a novel role for leptin signaling in gating the physiological response to severe hypoglycemia. This work supports our principal hypothesis that stimuli that lower leptin levels may inhibit the response to severe hypoglycemia by evoking a “pseudostarvation” phenotype. More critically, this body of work suggests that interventions that prevent the transition to a “starvation” phenotype could prevent impairment of the CRR. The overarching goal of this project is to definitively establish the role of hypoleptinemia in the pathophysiological impairment of the CRR while developing pre-clinical data that identifies druggable targets for the prevention of hypoglycemic complications. In order to achieve these objectives, the PI has assembled a team of investigators with extensive expertise in glucose counterregulation, energy homeostasis, and leptin signaling to achieve the following specific aims: 1) Elucidate the role of hypoleptinemia in altering glucose counterregulation during hypoglycemia and starvation. 2) Ascertain the mechanisms by which recurrent hypoglycemia induces hypoleptinemia. 3) Determine whether leptin treatment can prevent impaired hypoglycemic counterregulation induced by conditions known to increase hypoglycemic complications in PWD, such as exercise and alcohol consumption. We anticipate that our proposed studies will demonstrate that hypoleptinemia functionally drives increased susceptibility to hypoglycemia by impairing the CRR in physiologically and translationally relevant states. If so, these results will not only identify the first endocrine mechanism driving hypoglycemic risk, but they will also identify a clinically tractable treatment for the prevention of hypoglycemia.