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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.
- diabetes
- GWAS
- FOXN3
- human
- euglycemic hyperinsulinemic clamp
- liver
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Footnotes
Contributors MLE analyzed and interpreted data, and drafted manuscript. SK conceptualized study, collected and interpreted data, and edited the manuscript. ER conceptualized study, collected and interpreted data, and edited the manuscript. AS conceptualized study, collected and interpreted data, and edited the manuscript. ER is the guarantor of the study, having full access to all study data; he had the final responsibility for data integrity, accuracy of data analysis, and decision to submit for publication. All authors have approved the final version of this manuscript.
Funding This study was funded in part from the National Institutes of Health (grants P30DK072476; ER), and funds from the University of Utah Molecular Medicine Program and University of Utah School of Medicine, Department of Internal Medicine (AS).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study was performed in accordance with the principles contained within the Declaration of Helsinki. The protocol was approved by the Institutional Review Board of the Pennington Biomedical Research Center. All participants provided informed, written consent prior to study participation.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.