Carriers of an Inactivating β-Cell ATP-Sensitive K+ Channel Mutation Have Normal Glucose Tolerance and Insulin Sensitivity and Appropriate Insulin Secretion

Carriers of an Inactivating β-Cell ATP-Sensitive K + Channel Mutation Have Normal Glucose Tolerance and Insulin Sensitivity and Appropriate Insulin Secretion Hanna Huopio , MD 1 , Ilkka Vauhkonen , MD 2 , Jorma Komulainen , MD 1 , Leo Niskanen , MD 2 , Timo Otonkoski , MD 3 and Markku Laakso , MD 2 1 Department of Pediatrics, University of Kuopio, Kuopio, Finland 2 Department of Medicine, University of Kuopio, Kuopio, Finland 3 Transplantation Laboratory, Haartman Institute, University of Helsinki, and the Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland Abstract OBJECTIVE —Insulin release from the pancreatic β-cells is controlled by ATP-sensitive K + (K ATP ) channels, which consist of a hetero-octameric complex of four sulfonylurea receptor 1 (SUR1) and four Kir6.2 proteins. Mutations in the SUR1 gene are the major cause of congenital hyperinsulinemia (CHI). Despite the hereditary nature of CHI, studies of glucose homeostasis in heterozygous relatives of CHI patients are lacking. Theoretically, in the heterozygous state of the SUR1 gene mutation, only 1 of 16 K ATP channels consists of entirely normal subunits. The aim of our study was to investigate in vivo the glucose homeostasis of heterozygous SUR1 mutation carriers. RESEARCH DESIGN AND METHODS —We studied 8 parents of CHI patients, all 8 of whom were heterozygous for the inactivating SUR1 mutation V187D, and 10 matched control subjects. We evaluated glucose tolerance and insulin secretory capacity with oral and intravenous glucose tests, rates of whole-body glucose uptake with hyperinsulinemic-euglycemic clamps, C-peptide response to hypoglycemia during hyperinsulinemic-hypoglycemic clamp, and function of the K ATP channels with intravenous tolbutamide test. RESULTS —Carriers of the V187D substitution had normal glucose tolerance, normal tissue sensitivity to insulin, and no signs of inappropriate insulin secretion. The normal insulin response to tolbutamide indicated that heterozygosity for the V187D mutation did not impair K ATP channel function. CONCLUSIONS —We conclude that the heterozygous carriers of the SUR1 mutation had normal glucose metabolism and insulin secretion, indicating that carriers of recessive K ATP channel mutations are unlikely to be at an increased risk of hypoglycemia or other disturbances in glucose metabolism. CHI, congenital hyperinsulinemia KATP, ATP-sensitive K+ channel IVGTT, intravenous glucose tolerance test OGTT, oral glucose tolerance