Effect of exendin-(9-39) on glucose metabolism in subjects with hyperinsulinism

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DESCRIPTION (provided by applicant): Congenital hyperinsulinism (CHI) is a genetic disorder of pancreatic (-cell function characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if inadequately treated. In children, CHI is the most common cause of persistent hypoglycemia. Mutations in five genes have been associated with CHI: the sulfonylurea receptor (SUR-1), an inward rectifying potassium channel (Kir6.2), glucokinase (GCK), glutamate dehydrogenase (GLUD-1), and the mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC). Loss-of-function mutations in the KATP channel (composed by two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of HI (KATPHI). Most patients are unresponsive to available medical therapy and require partial pancreatectomy to control the hypoglycemia, resulting in prolonged hospital stays, high risk for life-threatening complications, and increased risk for diabetes mellitus and malabsorption. The KATP-sensitive channels couple the metabolic state of the (-cell to membrane potential by sensing changes in intracellular ATP concentration. In addition to its role in glucose-stimulated insulin secretion in (-cells, recent studies suggest that the KATP channels may play a role in glucose sensing and secretion of glucagon-like peptide-1 (GLP-1) by intestinal L-cells. As part of a career development award we are testing the hypothesis that abnormal GLP-1 secretion in KATPHI plays a role in the dysregulated insulin secretion. In this application we propose to study the effect of the GLP-1 receptor (GLP-1r) antagonist, exendin-(9-39), on glucose metabolism in subjects with KATPHI. Exendin-(9-39), acts as a specific and competitive antagonist of the GLP-1r increasing plasma glucagon levels and suppressing insulin. In normal subjects, exendin-(9-39) raises fasting plasma glucose levels. In an animal model of KATPHI we have shown that exendin-(9-39) significantly ameliorates the fasting hypoglycemia. Our overall hypothesis is that antagonism of the GLP-1 receptor by exendin-(9-39) will increase fasting blood glucose levels and decrease glucose requirement to maintain euglycemia in subjects with KATP HI as a result of suppressed insulin secretion and increased glucagon levels. This is an open label pilot study with a goal to enroll 10 subjects with KATPHI. The hypothesis will be tested in the following aims: 1) To evaluate the dose of exendin-(9-39) required to elevate fasting blood glucose levels in subjects with KATP HI. We will examine the effect of exendin-(9-39) administered intravenously at three different doses: 100, 300, and 500 pmol/kg/min on fasting blood glucose levels in subjects with KATPHI. 2) To examine the effect of GLP-1 receptor antagonism on glucose requirements to maintain euglycemia in subjects with KATP HI. We will assess glucose requirements to maintain euglycemia after an overnight fast in subjects with KATPHI in the presence of exendin-(9-39) or vehicle. If our hypothesis proves true, antagonism of the GLP-1r by exendin-(9-39) will be a potential therapeutic option for these subjects. To date, there is no effective medical therapy for subjects with congenital hyperinsulinism due to mutations in the KATP channel, therefore, the studies proposed here are important to further our understanding of the pathophysiology of this disorder and to evaluate the potential therapeutic applications of GLP-1 receptor antagonists in the treatment of this condition.