Role of Oral vs Injectable Glucagon Suppressors

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DESCRIPTION (provided by applicant): The Artificial Pancreas (AP) closed loop (CL), glucose-sensitive insulin delivery in patients with insulin deficient type 1 diabetes (T1DM) holds promise in restoring euglycemia and thus decreasing long-term complication related to diabetes. Major impediments to the AP application are post-prandial hyperglycemia and post-absorptive hypoglycemia. Glucagon, an alpha cell hormone is a first-line counter-regulatory hormone released during hypoglycemia increases hepatic glucose production and is normally suppressed in the post-prandial period. In diabetes, in addition to insulin deficiency there is glucagon dysregulation. Paradoxical hyperglucagonemia and hyperglycemia after a meal and failure of glucagon to increase in response to hypoglycemia make AP treatment difficult with insulin monotherapy or more complicated if there were dual or triple hormonal infusion required. For the last decade we have investigated various glucagon suppressors' amylin, GLP-1 and sitagliptin to combat this problem. We have demonstrated that exenatide, an injectable glucagon like peptide-1 (GLP-1) receptor analog is very effective in reducing post-prandial hyperglycemia in the CL setting. Currently we are comparing exenatide to liraglutide (another long acting GLP-1 analog) in CL setting. We propose a novel approach to combating both hyper and hypoglycemia by introducing adjuvant sitagliptin, an FDA approved drug, which is given once daily as a pill. Sitagliptin acts by inhibiting dipeptidyl peptidase 4 (DPP4) the enzyme that metabolizes GLP-1 and increasing endogenous GLP-1. GLP-1 suppresses post-prandial hyperglycemia. In protocol 1, we will test 2 doses of sitagliptin to study its effect on post-prandal hyperglycemia and hyperglucagonemia in the CL setting. Vildagliptin (DPP4 inhibitor not US approved) increases glucagon in response to insulin- induced-hypoglycemia. Sitagliptin remains to be tested for this effect. In protocol 2, we will compare the effect of exenatide vs. sitaglipti on glucagon secretion during a hyperinsulinemic hypoglycemic clamp. Lastly, in protocol 3, we will compare the effects of exenatide to sitagliptin in the closed loop system to determine which analog is most beneficial to patients. The overarching goal of this application is to find the best and simplest way to overcome hyper and hypoglycemia associated with the treatment of diabetes. Medtronic, a leader in the development of closed-loop system technology for glucose control and Dr. Heptulla have pioneered adjunctive treatment of T1DM with the use of glucagon suppressors. These protocols aim to understand the pathogenesis and treatment of glucagon dysregulation in diabetes. They aim to simplify treatment and use the best glucagon suppressor for glucose regulation in AP.