Evaluating the role of hypoleptinemia in impaired counterregulatory responses to hypoglycemia

评估低瘦素血症在低血糖反调节反应受损中的作用

• 批准号: 10586777
• 负责人: David Harry McDougal
• 金额: $ 36.45万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586777
• 关键词: Acute; Address; Adipose tissue; Adrenergic Agents; Alcohol consumption; Alcohols; Automobile Driving; Behavior Therapy; Blood Glucose; Clinical; Clinical Management; Corticotropin-Releasing Hormone Receptors; Data; Diabetes Mellitus; Dyslipidemias; Endocrine; Event; Exercise; Exposure to; FDA approved; Genetic; Glucose; Goals; Homeostasis; Hormones; Human; Hypoglycemia; Iatrogenesis; Impairment; Intervention; Knowledge; Leptin; Life Experience; Mediating; Metabolic; Patients; Persons; Phenotype; Physiological; Predisposition; Prevention; Recombinants; Recurrence; Research; Research Personnel; Risk; Risk Factors; Role; Series; Signal Transduction; Starvation; Stimulus; Strenuous Exercise; Testing; Treatment Protocols; Work; animal tissue; cold temperature; counterregulation; design; druggable target; efficacious treatment; glycemic control; improved outcome; nerve supply; novel; permissiveness; pharmacologic; pre-clinical; prevent; receptor; response

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.

项目概要 低血糖并发症是人类达到健康血糖水平的主要障碍 患有糖尿病（PWD）。这在很大程度上是由于关于如何暴露的巨大知识差距 众所周知的危险因素，例如复发性医源性低血糖、运动或酒精 消费，导致随后的反监管反应（CRR）受损 低血糖。因此，旨在减少残疾人低血糖的临床干预措施仅限于 行为改变，例如治疗方案的短期调整，通常以牺牲 血糖控制下降。为了改善残障人士的治疗结果，真正有效的治疗方法 必须制定低血糖并发症的预防措施。该项目旨在开发预 确定预防低血糖并发症的药物靶点的临床数据，因此 解决低血糖引起的残疾人的重大治疗负担。 PI 最近 完成了一系列研究，表明瘦素信号在门控生理学中的新作用 对严重低血糖的反应。这项工作支持我们的主要假设，即刺激会降低 瘦素水平可能通过引起“假性饥饿”来抑制对严重低血糖的反应 表型。更重要的是，这项工作表明，阻止向经济转型的干预措施 “饥饿”表型可以防止 CRR 受损。该项目的总体目标是 明确确定低瘦素血症在 CRR 病理生理损伤中的作用，同时 开发临床前数据，确定预防低血糖的药物靶标 并发症。为了实现这些目标，PI 组建了一个调查小组 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，以实现 以下具体目标： 1) 阐明低瘦素血症在改变葡萄糖反调节中的作用 低血糖和饥饿期间。 2) 确定复发性低血糖的机制 诱发低瘦血症。 3) 确定瘦素治疗是否可以预防低血糖受损 由已知会增加残疾人低血糖并发症的情况引起的反调节，例如 如运动和饮酒。我们预计我们提出的研究将证明 低瘦素血症通过损害 CRR 来功能性地增加对低血糖的易感性 生理和翻译相关状态。如果是这样，这些结果不仅会确定第一个 内分泌机制驱动低血糖风险，但他们也将确定临床上可处理的 预防低血糖的治疗。