A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1

Background ATP-sensitive potassium (KATP) channels are major regulators of glucose-induced insulin secretion in pancreatic β cells. We have described a dominant heterozygous mutation—E1506K—in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of KATP-channel activity. We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation. Methods Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls. Findings Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12–32 pmol/L), and was almost completely lost in adulthood (n=11; 12–32 pmol/L). Furthermore, these heterozygous people had a substantial reduction in maximum glucose-stimulated insulin secretion during hyperglycemic clamp (carriers without diabetes 422 pmol/L; carriers with diabetes 97 pmol/L). By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0·07 in those without diabetes and 0·05 in those with the disorder; not significantly different from controls). Interpretation Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes. ATP-sensitive potassium (KATP) channels are major regulators of glucose-induced insulin secretion in pancreatic β cells. We have described a dominant heterozygous mutation—E1506K—in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of KATP-channel activity. We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation. Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls. Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12–32 pmol/L), and was almost completely lost in adulthood (n=11; 12–32 pmol/L). Furthermore, these heterozygous people had a substantial reduction in maximum glucose-stimulated insulin secretion during hyperglycemic clamp (carriers without diabetes 422 pmol/L; carriers with diabetes 97 pmol/L). By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0·07 in those without diabetes and 0·05 in those with the disorder; not significantly different from controls). Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes. A disease characterised by inappropriate and unregulated insulin secretion. Insulinotropic factors of the gut released by nutrients and stimulating insulin secretion. Regulates insulin secretion in the pancreatic β-cells Dominant SUR1 mutation causing autosomal dominant type 2 diabetesType 2 diabetes mellitus is common and increasing rapidly in incidence and prevalence. The disease has a strong genetic component; however, attempts to identify genes that contribute to the risk of the common polygenic form have met with little success. By contrast, major success has been achieved in identifying genes (six so far1) responsible for the rarer monogenetic forms of type 2 diabetes, particularly maturity onset diabetes of the young. Mutations in any of these genes result in primary β-cell defects but not defects in insulin action, long considered the hallmark of type 2 diabetes. Full-Text PDF