Glucagon-mediated glycemic effect in humans with and without rerouted gut after bariatric surgery

Glucagon plays an important role in glucose physiology, but the full range of its hormonal actions in humans is not completely understood. Gastric bypass surgery (GB) and sleeve gastrectomy (SG) induce durable weight loss and reverse type 2 diabetes. The glycemic effects of GB and, to lesser degree, SG is associated with much faster nutrient emptying from stomach pouch/stomach to the gut resulting in larger glucose excursion and lower nadir glucose levels as well as greater insulin and proglucagon peptides (glucagon-like peptide 1 [GLP-1] and glucagon) secretion. The glycemic effect of GB is exaggerated in a subgroup of patients who develop a devastating complication of hypoglycemia after this surgery. Dysregulated glucagon response to meal and hypoglycemia is well documented after GB and SG. However, the glycemic effects of hyperglucagonemia during prandial hyperglycemia or the hepatic action of glucagon during hypoglycemia or hyperglycemia in absence of nutrient stimuli after these procedures is largely unknown. We have previously found that prandial counterregulatory glucose response to hypoglycemia induced by supraphysiological insulin doses is impaired after GB or SG despite hyperglucagonemia. Therefore, we hypothesize that hepatic action of glucagon during both hypoglycemia or hyperglycemia under physiological conditions is smaller in GB and SG compared to non-operated controls (CN), particularly in post-GB hypoglycemic patients. We test this hypothesis in Aim 1 by measuring the effect of exogenous glucagon infusion during pancreatic clamp producing hyperglucagonemia that mimics prandial glucagon profile of GB or SG on endogenous glucose production during separate hypoglycemic and hyperglycemic conditions in absence of meal stimuli. Further, recent studies in rodent models have suggested that glucagon is essential in nutrient-induced insulin secretion or insulin action via glucagon or GLP-1 receptor. Therefore, it is conceivable that improved glucose tolerance and prandial hyperinsulinemia after bariatric surgery that previously attributed to GLP-1R signal can also reflect insulinotropic effect of hyperglucagonemia after GB or SG. We test this hypothesis in Aim 2 by measuring post-mixed-meal glycemic effects of disrupted glucagon signal by administration of glucagon receptor antagonist (REMD-477). We expect a larger glycemic effect, mediated by insulin secretion or action, after GB and SG, particularly in those with GB-related hypoglycemia. Four groups of subjects will be studied: patients with GB-related hypoglycemia, asymptomatic GB and SG individuals, and non-operated controls. The PI has considerable experience in conducting clinical trials in these cohorts. Physiological insights into glucagon action in humans is critical in guiding glucagon-based drug development to treat hypoglycemia and hyperglycemia. Also, understanding of glycemic effects of bariatric surgeries based on glucagon action is critical for development of personalized therapeutic options to optimize antidiabetic effects of GB or SG and mitigate glucose abnormalities, such as post-bariatric hypoglycemia.