Evaluating the role of hypoleptinemia in impaired counterregulatory responses to hypoglycemia

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.