The role of diminished CNS hypoglycemia sensing in postbariatric hypoglycemia - PROJECT SUMMARY / ABSTRACT: Rates of obesity continue to rise across the world, hastening the need for new and improved treatment interventions. Currently, bariatric surgery is the most effective strategy to induce and sustain significant weight loss for individuals with obesity. However, this treatment option is often accompanied with metabolic complications, most notably postbariatric hypoglycemia (PBH). Latest estimates suggest that PBH occurs in ~30% of patients, after both Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG). Despite the high prevalence of PBH, many patients do not experience the symptoms that should normally alert them of hypoglycemia. If untreated, severe hypoglycemia can lead to accidents, brain damage, and even sudden death. Thus, PBH is a serious issue that often goes unnoticed and therefore cannot be easily treated until we increase our understanding of the causes and mechanisms. The dramatic changes in feeding behavior after bariatric surgery and the lack of neurological symptoms in response to hypoglycemia clearly implicate altered brain function, but very little is known about how bariatric surgery alters the central circuits regulating feeding and glucose homeostasis. Recent work suggests that bariatric surgery reduces counterregulatory responses (CRR) and that dysregulated hypothalamic response to hypoglycemia may be involved. However, there are currently no effective treatment strategies for PBH, and more preclinical work is needed to identify therapeutic targets. In our lab, we have found that mouse models of VSG recapitulate key features of PBH, including postprandial and prolonged insulin-induced hypoglycemia. Overall, our data suggest that CRR signaling is dysregulated after VSG, and we will investigate neuronal mechanisms which may be underlying these deficits. The current proposal aims to study whether the glycemic threshold for CRR hormone release, glucoprivic feeding, and brain activation is shifted lower after VSG, and to identify the hypothalamic circuits and molecular mechanisms that may contribute. To accomplish this research objective, we will utilize glucose clamp strategies to characterize the glycemic threshold for CRR hormone release, and we will perform dose-response studies to investigate dynamics of glucoprivic hunger and hypothalamic activation (Aim 1). In Aim 2 we will perform stereotaxic surgeries to manipulate ventromedial hypothalamus signaling to determine the mechanisms contributing to PBH. By investigating how VSG dysregulates central glucoregulatory mechanisms, the current project will identify new therapeutic targets that could help mitigate or prevent PBH, thus making bariatric surgery safer for a broader range of patients.
