title: A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene.
abstract: Recently, various subtypes of familial hyperinsulinemic hypoglycemia with an autosomal-dominant inheritance have been etiologically characterized. In the present study, we have delineated the genetics and metabolic phenotype of a novel form of hypoglycemia in a large pedigree with an apparent autosomal-dominant transmission. After initial investigations of the proband, her mother, and a sister, the study was extended to 19 family members in three generations. Glucose tolerance was assessed by a 5-h oral glucose tolerance test (OGTT) and insulin sensitivity by euglycemic-hyperinsulinemic clamp in six affected family members and six control subjects. To identify the genetic cause of hypoglycemia, linkage analysis and mutation analysis of genomic DNA from all family members were performed. All affected family members were characterized by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C-peptide ratio. The 5-h OGTT demonstrated hyperinsulinemic hypoglycemia, and the clamp studies showed reduced insulin sensitivity and clearance of serum insulin in affected family members compared with control subjects. Linkage analysis and subsequent mutation screening revealed a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate the coexistence of severe postprandial hypoglycemia, insulin resistance, and impaired insulin clearance and suggest that hypoglycemia should be considered as a phenotype linked to heterozygote mutations in the insulin receptor gene.
authors.affiliation: Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Kloevervaenget 6, DK-5000, Odense C, Denmark. k.hojlund@dadlnet.dk
authors.forename: Kurt
authors.initials: K
authors.lastname: Højlund
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Henriksen
authors.forename: Klaus
authors.initials: K
authors.lastname: Levin
authors.forename: Jörgen
authors.initials: J
authors.lastname: Lindholm
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Henning
authors.initials: H
authors.lastname: Beck-Nielsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015444:Exercise; D008040:Genetic Linkage; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000503:physiopathology; D007003:Hypoglycemia / Q000235:genetics* / Q000503:physiopathology; D008126:Lod Score; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D011972:Receptor, Insulin