FOXN3 hyperglycemic risk allele and insulin sensitivity in humans.

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  • Author(s): Erickson ML;Erickson ML; Karanth S; Karanth S; Ravussin E; Ravussin E; Schlegel A; Schlegel A
  • Source:
    BMJ open diabetes research & care [BMJ Open Diabetes Res Care] 2019 Aug 30; Vol. 7 (1), pp. e000688. Date of Electronic Publication: 2019 Aug 30 (Print Publication: 2019).
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Published by BMJ in partnership with the American Diabetes Association Country of Publication: England NLM ID: 101641391 Publication Model: eCollection Cited Medium: Print ISSN: 2052-4897 (Print) Linking ISSN: 20524897 NLM ISO Abbreviation: BMJ Open Diabetes Res Care
    • Publication Information:
      Original Publication: London : Published by BMJ in partnership with the American Diabetes Association
    • Subject Terms:
      Homozygote*; Biomarkers/*analysis ; Cell Cycle Proteins/*genetics ; Diabetes Mellitus, Type 2/*genetics ; Forkhead Transcription Factors/*genetics ; Hyperglycemia/*genetics ; Insulin/*metabolism ; Insulin Resistance/*genetics; Body Mass Index ; Case-Control Studies ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/pathology ; Female ; Follow-Up Studies ; Gene Frequency ; Humans ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; Risk Factors ; Sex Factors
    • 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/m 2 , 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.
      Competing Interests: Competing interests: None declared.
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    • Grant Information:
      P30 DK072476 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: FOXN3; GWAS; diabetes; euglycemic hyperinsulinemic clamp; human; liver
    • Accession Number:
      0 (Biomarkers)
      0 (Cell Cycle Proteins)
      0 (FOXN3 protein, human)
      0 (Forkhead Transcription Factors)
      0 (Insulin)
    • Publication Date:
      Date Created: 20190924 Date Completed: 20200422 Latest Revision: 20200422
    • Publication Date:
      20231215
    • Accession Number:
      PMC6731827
    • Accession Number:
      10.1136/bmjdrc-2019-000688
    • Accession Number:
      31543974