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ATP-binding cassette sub-family C member 8 (Sulfonylurea receptor 1) [HRINS] [SUR] [SUR1]


A mouse model of human hyperinsulinism produced by the E1506K mutation in the sulphonylurea receptor SUR1.

Loss-of-function mutations in the KATP channel genes KCNJ11 and ABCC8 cause neonatal hyperinsulinism in humans. Dominantly inherited mutations cause less severe disease, which may progress to glucose intolerance and diabetes in later life (e.g., SUR1-E1506K). We generated a mouse expressing SUR1-E1506K in place of SUR1. KATP channel inhibition by MgATP was enhanced in both homozygous (homE1506K) and heterozygous (hetE1506K) mutant mice, due to impaired channel activation by MgADP. As a consequence, mutant β-cells showed less on-cell KATP channel activity and fired action potentials in glucose-free solution. HomE1506K mice exhibited enhanced insulin secretion and lower fasting blood glucose within 8 weeks of birth, but reduced insulin secretion and impaired glucose tolerance at 6 months of age. These changes correlated with a lower insulin content; unlike wild-type or hetE1506K mice, insulin content did not increase with age in homE1506K mice. There was no difference in the number and size of islets or β-cells in the three types of mice, or evidence of β-cell proliferation. We conclude that the gradual development of glucose intolerance in patients with the SUR1-E1506K mutation might, as in the mouse model, result from impaired insulin secretion due a failure of insulin content to increase with age.

MeSH Terms

  • Aging
  • Animals
  • Blood Glucose
  • Calcium
  • Disease Models, Animal
  • Heterozygote
  • Homozygote
  • Humans
  • Hyperinsulinism
  • Insulin
  • Insulin Secretion
  • Islets of Langerhans
  • KATP Channels
  • Mice
  • Potassium Channel Blockers
  • Sulfonylurea Receptors

Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence.

Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K( ) channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy. A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6%). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m(2)), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were >11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells. A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR)1 mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1 demonstrate 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. 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 beta-cell function is not clear, but it may involve mutation-induced increased beta-cell apoptosis related to increased metabolic demand.

MeSH Terms

  • ATP-Binding Cassette Transporters
  • Adult
  • Aging
  • Child
  • Diabetes Mellitus, Type 1
  • Exons
  • Female
  • Humans
  • Hyperinsulinism
  • Introns
  • Male
  • Mutation
  • Obesity
  • Parents
  • Pedigree
  • Potassium Channels, Inwardly Rectifying
  • Puberty
  • Receptors, Drug
  • Seizures
  • Siblings
  • Sulfonylurea Receptors