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Novel de novo mutation in SUR1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence

¹Division of Pediatric Endocrinology, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
²Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, OR 97239, USA
³Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel

Background: Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4^th decade of life in non-pancreatectomized patients.

Clinical data and methods: A 10.5y old female presented with new onset, antibody-negative diabetes (HbA1^C-10.6%). She was born large for gestational age (5Kg) to a non-diabetic mother, and developed frequent hypoglycemic episodes, which persisted until age 3y, responding initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal, obese (BMI-30.2kg/m²), with a partially controlled convulsive disorder (since age 1y) and poor school performance. Glucose levels were >11.1mmol/l throughout 72 hours of continuous glucose monitoring, with low insulin secretion during IVGTT. KCNJ11 and ABCC8 mutation analysis was performed and the mutation identified was characterized in COSm6 cells.

Results: A novel, de novo heterozygous ABCC8 (SUR1) mutation (R370S) was identified in the patient's DNA but not in that of either parent. Co-transfection of Kir6.2 and mutant SUR1 demonstrated that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy.

Conclusions: This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in-vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in β-cell function is not clear, but it may be due to mutation-induced increased β-cell apoptosis related to increased metabolic demand.

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