FOXN3 高血糖风险等位基因与人类胰岛素敏感性。

FOXN3 hyperglycemic risk allele and insulin sensitivity in humans.

机构信息

Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.

University of Utah Molecular Medicine Program and the Departments of Internal Medicine, Biochemistry, and Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

出版信息

BMJ Open Diabetes Res Care. 2019 Aug 30;7(1):e000688. doi: 10.1136/bmjdrc-2019-000688. eCollection 2019.

DOI:10.1136/bmjdrc-2019-000688

PMID:31543974

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6731827/

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 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, 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.

摘要

目的

FOXN3 基因内的 rs8004664 变异与人类空腹血糖显著且独立相关。我们之前曾表明，高血糖风险等位基因（A）增加原代人肝细胞中 FOXN3 的表达；斑马鱼肝脏中人类 FOXN3 的过表达会增加空腹血糖；而斑马鱼同源物的杂合缺失会降低空腹血糖。与这些模式生物的发现平行，我们发现 rs8004664 A|A 纯合子在口服葡萄糖耐量试验中胰高血糖素抑制作用减弱。在这里，我们测试了胰岛素敏感性与 rs8004664 变异之间的关联。

研究设计和方法

92 名参与者（49±13 岁，体重指数：32±6 kg/m，28 名患有 2 型糖尿病，64 名未患有 2 型糖尿病）在 rs8004664 处进行了基因分型。通过正葡萄糖高胰岛素钳夹技术测量胰岛素敏感性。

结果

“A”等位基因频率为 59%；保护性（G）等位基因频率为 41%（A|A：n=29；G|G：n=12；A|G：n=50）。钳夹法测量的葡萄糖处置率（GDR）不因基因型（F=0.046，p=0.96）或“A”等位基因携带者而不同（p=0.36）。女性 G|G 纯合子的胰岛素敏感性优于女性“A”等位基因携带者（GDR；G|G：9.9±3.0 与 A|A+A|G：7.1±3.0 mg/kg 去脂体重+17.7/min；p=0.04）。胰岛素敏感性不因基因型或“A”等位基因携带者而不同。