Glucagon Pump Therapy for Post-Bariatric Hypoglycemia: Merging Physiology and Engineering

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Project Summary/Abstract Bariatric surgery is a potent treatment for obesity-related metabolic disease and markedly improves glucose control in T2D. However, along with this metabolic success comes an increased risk of severe hypoglycemia (termed post-bariatric hypoglycemia, or PBH), with estimated prevalence of up to 30% of patients after both gastric bypass and sleeve gastrectomy. Current therapies for PBH are limited and incompletely effective, and individuals with severe hypoglycemia and unawareness lack sufficient warning to treat before rapid onset of neuroglycopenia and impaired safety. Previous studies of PBH by our group and others have demonstrated potential drivers of hypoglycemia in this condition: (1) increased insulin secretion, linked to postprandial incretin secretion (including GLP1), (2) increased insulin-independent glucose uptake, (3) reduced secretion of glucagon and other counterregulatory hormones, and (4) altered intestinal metabolism. One promising approach to prevent and treat severe hypoglycemia in PBH is closed-loop glucagon therapy. In prior studies, we collaborated with engineering colleagues to develop and test a closed-loop system which utilized CGM in combination with a novel closed-loop algorithm to detect incipient meal-related hypoglycemia and deliver boluses of glucagon via a patch pump. Using a double-blind, placebo-controlled crossover pilot study in the clinical research unit, we demonstrated efficacy and safety of this closed-loop glucagon pump system, with increased nadir glucose after mixed meal and reduced need for rescue glucose. Buoyed by the success of these meal-focused studies, we now propose to further define glucagon sensitivity, secretion, and turnover and glycogen metabolism in PBH, in order to develop an enhanced, more effective, closed-loop glucagon algorithm and clinical therapeutic system responsive to glycemic excursions which occur not only during the postprandial period, but also during overnight hours and during/after activity. To achieve this goal, we have assembled a multidisciplinary team including clinical investigators with expertise in PBH and glucagon and glucose metabolism, and biomedical engineers with expertise and an established track record in closed-loop pump system development and clinical testing and implementation. Thus, the proposed studies will address an important knowledge and therapeutic gap in PBH, and provide four innovative deliverables to advance our understanding of and the clinical care of this challenging patient population: (1) key quantitative data for glucagon sensitivity, secretion and turnover and glycogen metabolism as contributors to hypoglycemia during postprandial, postabsorptive, and post-activity states in PBH, (2) development of an in silico model of the PBH patient, allowing implementation and testing of a novel CLG algorithm, (3) implementation of the CLG algorithm in a system driving on-body pump delivery of microdoses of glucagon guided by CGM data, and (4) after regulatory approval, completion of a pilot randomized outpatient, hotel-based clinical trial of the CLG system in patients with PBH.