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) cause the most common and severe form of congenital hyperinsulinism (KHI), a disorder of ß-cell function characterized by severe hypoglycemia. Children with KHI 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 KHI. 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 KHI (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.

Update of variants identified in the pancreatic β‐cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

“…Although sulphonylureas provide a safe and effective treatment for the majority of individuals with K ATP channel NDM, for patients with CHI, pharmacological management of the condition is not always successful. Current efforts are, therefore, focusing on the development of new pharmacological treatments for this condition (Banerjee, De Leon, & Dunne, 2017; De Leon et al, 2008; Ng, Tang, Seeholzer, Zou, & De Leon, 2018; Patel et al, 2018; Powell et al, 2011; Senniappan et al, 2014).…”

Therapies and outcomes of congenital hyperinsulinism‐induced hypoglycaemia

“…Another current drug is a specific insulin receptor allosteric antibody that reduces insulin action [47]. Soluble glucagon is now available for the treatment of diabetes and ready for trial in CHI.…”

“…Soluble glucagon is now available for the treatment of diabetes and ready for trial in CHI. Another current drug is a specific insulin receptor allosteric antibody that reduces insulin action [47]. Alternative drug targets are also in the process of exploration.…”

A view at postbariatric hypoglycemia by endocrinologist

“…В исследованиях было показано, что у здоровых добровольцев однократная доза XMetD приводила к значительному повышению концентрации глюкозы в плазме после приема пищи и ослаблению снижения уровня глюкозы после введения экзогенного инсулина [61,62]. У мышей с дефектом АТФ-чувствительных калиевых каналов и гипогликемией натощак применение XMetD значительно повышало уровень глюкозы в плазме натощак за счет прямого воздействия на чувствительность к инсулину [63]. Исследования в отношении эффективности данного препарата для лечения постбариатрических гипогликемий не проводились.…”