Carriers of an inactivating beta-cell ATP-sensitive K(+) channel mutation have normal glucose tolerance and insulin sensitivity and appropriate insulin secretion.
OBJECTIVE
Insulin release from the pancreatic beta-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.


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.
Huopio
Hanna
H
Department of Pediatrics, University of Kuopio, Kuopio, Finland.
Vauhkonen
Ilkka
I
Komulainen
Jorma
J
Niskanen
Leo
L
Otonkoski
Timo
T
Laakso
Markku
M
D018528:ATP-Binding Cassette Transporters; D000328:Adult; D019943:Amino Acid Substitution; D002096:C-Peptide / Q000097:blood; D005260:Female; D006580:Genetic Carrier Screening; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D020125:Mutation, Missense; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014044:Tolbutamide