A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1^−/− mouse model of KATP hyperinsulinism

Abstract

Loss-of-function mutations of the ß-cell ATP-sensitive potassium channels (K_ATP) cause the most common and severe form of congenital hyperinsulinism (K_ATPHI), a disorder of ß-cell function characterized by severe hypoglycemia. Children with K_ATPHI are typically unresponsive to medical therapy and require pancreatectomy for intractable hypoglycemia. We tested the hypothesis that inhibition of insulin receptor signaling may prevent hypoglycemia in K_ATPHI. To test this hypothesis, we examined the effect of an antibody allosteric inhibitor of the insulin receptor, XMetD, on fasting plasma glucose in a mouse model of K_ATPHI (SUR-1^-^/^- mice). SUR-1^-^/^- and wild-type mice received twice weekly intraperitoneal injections of either XMetD or control antibody for 8 wks. Treatment with XMetD significantly decreased insulin sensitivity, and increased hepatic glucose output and fasting plasma glucose. These findings support the potential use of insulin receptor antagonists as a therapeutic approach to control the hypoglycemia in congenital hyperinsulinism.