title: Common genetic variation in the human FNDC5 locus, encoding the novel muscle-derived 'browning' factor irisin, determines insulin sensitivity.
abstract: OBJECTIVE
  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
  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.
authors: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
authors: Harald
authors: H
authors: Staiger
authors: Anja
authors: A
authors: Böhm
authors: Mika
authors: M
authors: Scheler
authors: Lucia
authors: L
authors: Berti
authors: Jürgen
authors: J
authors: Machann
authors: Fritz
authors: F
authors: Schick
authors: Fausto
authors: F
authors: Machicao
authors: Andreas
authors: A
authors: Fritsche
authors: Norbert
authors: N
authors: Stefan
authors: Cora
authors: C
authors: Weigert
authors: Anna
authors: A
authors: Krook
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Martin Hrabě
authors: MH
authors: de Angelis
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D050218:Body Fat Distribution; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D050177:Overweight / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D001786:Blood Glucose; C577593:FNDC5 protein, human; D005353:Fibronectins; D007328:Insulin
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