Role of GLP-1 in Congenital Hyperinsulinism

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Project Summary/Abstract Description This is a translational research study of the role of glucagon-like peptide-1 (GLP-1) in congenital hyperinsulinism (CHI), the most frequent cause of persistent hypoglycemia in children. 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. 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 hospitalization, high risk for life-threatening complications, and increased risk for diabetes mellitus and malabsorption. Our preliminary studies demonstrate that the GLP-1 receptor is constitutively active in islets of mice lacking KATP channels (SUR-1-/- mice) and that antagonism of the GLP-1 receptor by exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in these mice. The goal of this grant is to examine the effects of exendin-(9-39) on glucose metabolism of human subjects with KATPHI and to examine the mechanism whereby exendin-(9-39) inhibits insulin secretion in human and rodent islets lacking KATP channels. Our overall hypothesis is that antagonism of the GLP-1 receptor by exendin-(9-39) will increase fasting blood glucose levels, prevent protein-induced hypoglycemia and decrease glucose requirement to maintain euglycemia in subjects with KATPHI as a result of suppressed insulin secretion and increased glucagon levels, and that these effects are mediated by changes in cellular cAMP levels. Aim 1 is to examine the effects of exendin-(9-39) on (a) fasting blood glucose and (b) protein-induced hypoglycemia in subjects with KATPHI. Subjects will receive a continuous infusion of vehicle or exendin-(9-39) during fasting, during a protein challenge, and while following a normal daily routine to evaluate the effects of the peptide on glucose levels. Aim 2 is to examine the effects of exendin-(9-39) on glucose requirements to maintain euglycemia in infants with congenital hyperinsulinism unresponsive to medical therapy who are scheduled for a pancreatectomy. Subjects will receive a continuous infusion of exendin-(9-39) and glucose requirements to maintain blood glucose levels > 70 mg/dL during the infusion will be compared to baseline requirements. Aim 3 is to characterize metabolic fuel responsiveness of pancreatic islets isolated from human subjects with KATP hyperinsulinism and to examine the mechanism whereby exendin-(9-39) suppresses insulin secretion in pancreatic islets lacking KATP channels. The metabolic fuel responsiveness of islets isolated from surgical specimens of children with KATPHI and from SUR-1-/- mice and the effects of exendin-(9-39) on these responses will be examined by perifusion and batch incubation experiments. The results of this research will provide essential information for evaluating exendin-(9-39) as a potential therapeutic option for this devastating disorder and for understanding the basis of KATP-independent insulin secretion in normal humans.