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

Loss-of-function mutations of the ss-cell ATP-sensitive potassium channels (K-ATP) cause the most common and severe form of congenital hyperinsulinism (KATPHI), a disorder of ss-cell function characterized by severe hypoglycemia. Children with KATPHI 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 KATPHI. 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 KATPHI (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.