Common genetic variation in the human FNDC5 locus, encoding the novel muscle-derived 'browning' factor irisin, determines insulin sensitivity

PLoS One. 2013 Apr 25;8(4):e61903. doi: 10.1371/journal.pone.0061903. Print 2013.

Abstract

Aims/hypothesis: Recently, the novel myokine irisin was described to drive adipose tissue 'browning', to increase energy expenditure, and to improve obesity and insulin resistance in high fat-fed mice. Here, we assessed whether common single nucleotide polymorphisms (SNPs) in the FNDC5 locus, encoding the irisin precursor, contribute to human prediabetic phenotypes (overweight, glucose intolerance, insulin resistance, impaired insulin release).

Methods: A population of 1,976 individuals was characterized by oral glucose tolerance tests and genotyped for FNDC5 tagging SNPs. Subgroups underwent hyperinsulinaemic-euglycaemic clamps, magnetic resonance imaging/spectroscopy, and intravenous glucose tolerance tests. From 37 young and 14 elderly participants recruited in two different centres, muscle biopsies were obtained for the preparation of human myotube cultures.

Results: After appropriate adjustment and Bonferroni correction for the number of tested variants, SNPs rs16835198 and rs726344 were associated with in vivo measures of insulin sensitivity. Via interrogation of publicly available data from the Meta-Analyses of Glucose and Insulin-related traits Consortium, rs726344's effect on insulin sensitivity was replicated. Moreover, novel data from human myotubes revealed a negative association between FNDC5 expression and appropriately adjusted in vivo measures of insulin sensitivity in young donors. This finding was replicated in myotubes from elderly men.

Conclusions/interpretation: This study provides evidence that the FNDC5 gene, encoding the novel myokine irisin, determines insulin sensitivity in humans. Our gene expression data point to an unexpected insulin-desensitizing effect of irisin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / metabolism
  • Body Fat Distribution
  • Diabetes Mellitus, Type 2 / genetics
  • Female
  • Fibronectins / genetics*
  • Fibronectins / metabolism*
  • Gene Expression Regulation
  • Gene Frequency
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease / genetics
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Insulin Secretion
  • Male
  • Middle Aged
  • Muscle Fibers, Skeletal / metabolism*
  • Overweight / genetics
  • Overweight / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prediabetic State / genetics
  • Prediabetic State / metabolism
  • Reproducibility of Results

Substances

  • Blood Glucose
  • FNDC5 protein, human
  • Fibronectins
  • Insulin

Grants and funding

The study was supported in part by a grant (01GI0925) from the German Federal Ministry of Education and Research (BMBF) to the German Centre for Diabetes Research (DZD e.V.). Norbert Stefan is supported by a Heisenberg professorship from the Deutsche Forschungsgemeinschaft (STE 1096/3-1), Anna Krook by the Swedish Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.