A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene.
Open accessAbstract
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.
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Hyperinsulinemic hypoglycemia linked to a mutation of the insulin receptor and exercise-induced hyperinsulinemia are rare syndromes.
“Similarly, hyperinsulinemic hypoglycemia linked to a mutation of the insulin receptor (68) and exercise-induced hyperinsulinemia (69) are rare syndromes.”
From Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline (2009) · cites this paper as [68]
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- Authors
- Højlund, K., Hansen, T., Lajer, M., Henriksen, J. E., Levin, K., Lindholm, J., Pedersen, O., & Beck-Nielsen, H.
- Affiliations
- Odense University Hospital (DK)
- Steno Diabetes Center Copenhagen (DK)
- Department of Medicine, Division of Endocrinology, Holstebro Hospital, Holstebro, Denmark
- Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-06-01
- Volume
- 53
- Issue
- 6
- Pages
- 1592-1598
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2124427868
- Semantic Scholar
- 1e2ad689472cb19837f790e9cbb95c3ba369b1ee
- Cited by
- 130
- References
- 34
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 7 · 2020: 5 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 7 · 2015: 6 · 2014: 7 · 2013: 8 · 2012: 6
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Funders
- Novo Nordisk
- Odense Universitetshospital
- Novo Nordisk Fonden
- Diabetesforeningen
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- insulin receptor gene, postprandial hypoglycemia, insulin resistance, insulin clearance, genetic linkage, heterozygous mutation
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Glucose Tolerance Test, Haplotypes, Heterozygote, Humans, Hyperinsulinism, Hypoglycemia, Genetic Linkage, Lod Score, Middle Aged, Mutation, Pedigree, Phenotype, Receptor, Insulin, Glucose Clamp Technique, Exercise, Point Mutation
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