PUBLICATION
FOXN3 hyperglycemic risk allele and insulin sensitivity in humans
- Authors
- Erickson, M.L., Karanth, S., Ravussin, E., Schlegel, A.
- ID
- ZDB-PUB-190924-1
- Date
- 2019
- Source
- BMJ open diabetes research & care 7: e000688 (Journal)
- Registered Authors
- Karanth, Santhosh, Schlegel, Amnon
- Keywords
- FOXN3, GWAS, diabetes, euglycemic hyperinsulinemic clamp, human, liver
- MeSH Terms
-
- Biomarkers/analysis*
- Body Mass Index
- Case-Control Studies
- Cell Cycle Proteins/genetics*
- Cross-Sectional Studies
- Diabetes Mellitus, Type 2/genetics*
- Diabetes Mellitus, Type 2/pathology
- Female
- Follow-Up Studies
- Forkhead Transcription Factors/genetics*
- Gene Frequency
- Homozygote*
- Humans
- Hyperglycemia/genetics*
- Insulin/metabolism*
- Insulin Resistance/genetics*
- Male
- Middle Aged
- Prognosis
- Prospective Studies
- Risk Factors
- Sex Factors
- PubMed
- 31543974 Full text @ BMJ Open Diabetes Res Care
Citation
Erickson, M.L., Karanth, S., Ravussin, E., Schlegel, A. (2019) FOXN3 hyperglycemic risk allele and insulin sensitivity in humans. BMJ open diabetes research & care. 7:e000688.
Abstract
Objective The rs8004664 variation within the FOXN3 gene is significantly and independently associated with fasting blood glucose in humans. We have previously shown that the hyperglycemia risk allele (A) increases FOXN3 expression in primary human hepatocytes; over-expression of human FOXN3 in zebrafish liver increases fasting blood glucose; and heterozygous deletion of the zebrafish ortholog foxn3 decreases fasting blood glucose. Paralleling these model organism findings, we found that rs8004664 A|A homozygotes had blunted glucagon suppression during an oral glucose tolerance test. Here, we test associations between insulin sensitivity and the rs8004664 variation.
Research design and methods 92 participants (49±13 years, body mass index: 32±6 kg/m2, 28 with and 64 without type 2 diabetes mellitus) were genotyped at rs8004664. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp technique.
Results The "A" allele frequency was 59%; the protective (G) allele frequency was 41% (A|A: n=29; G|G: n=12; A|G: n=50). Clamp-measured glucose disposal rate (GDR) was not different by genotype (F=0.046, p=0.96) or by "A" allele carrier (p=0.36). Female G|G homozygotes had better insulin sensitivity compared to female "A" allele carriers (GDR; G|G: 9.9±3.0 vs A|A+A|G: 7.1±3.0 mg/kg fat-free mass+17.7/min; p=0.04). Insulin sensitivity was not different by genotype or by "A" allele carriers.
Conclusion The rs8004664 variation within the FOXN3 gene may modulate insulin sensitivity in women.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping