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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.

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. [ABSTRACT FROM AUTHOR]

We have previously shown, in rat-1 fibroblasts which stably overexpress high levels of human insulin receptor (HIR), that high glucose levels induce an inhibition of insulin receptor tyrosine kinase (IRK) activity [Berti, L., Mosthaf, L., Kellerer, M., Tippmer, S., Mushaek, J., Seffer, E., Seedorf, K., Häring, H. (1994) Jr. Biol. Chem. 269, 3381–3386]. This effect appears to be mediated through activation of protein kinase C and phosphorylation of the receptor β-subunit on threonine or serine residues. The aim of the present study was to determine whether the juxtamembrane region or the C-terminus tail of the receptor are involved in the IRK modulation by glucose. In these domains increased serine and threonine phosphorylation was observed after phorbol ester or insulin stimulation of cells, and a regulatory function for IRK activity seems conceivable. We used an antibody directed against one potential regulatory site in the C-terminus tail, i.e. PSer1315, to study the effect of glucose. An increased signal was detected in HIR from rat-1 fibroblasts treated with phorbol 12-myristate 13-acetate or glucose (25 mM). To investigate whether this site in the C-terminus is essential for glucose-dependent IRK inhibition, rat-1 fibroblasts stably overexpressing a C-terminus-truncated human insulin receptor lacking 43 amino acids (HIRΔCT) were studied in parallel with cells expressing the wild-type receptor. As described earlier, HIRΔCT has lost the ability to stimulate glucose uptake. Glucose (25 mM) inhibited the insulin effect on the autophosphorylation or both receptors to a similar extent. Thus, glucose (25 mM) stimulates phosphorylation of Ser1315, however, this appears not to mediate the inhibitory effect on IRK. To test whether serine residues 955⁄956 and 962⁄964 in the juxtamembrane region of the insulin receptor are involved in the inhibitory effect of glucose, 293 cells transiently transfected either with wild-type HIR or HIR with a juxtamembrane deletion spanning amino acids 954–965 [des-(954–965)-HIR] were studied in parallel. As described earlier, the des-(954–965)-HIR has lost the ability to stimulate PI-3 kinase. However, 25 mM glucose equally inhibited the insulin effect on tyrosine phosphorylation of the receptor. Together, the data suggest that the regulatory serine or threonine phosphorylation site(s) involved in the inhibitory effect of hyperglycemia are neither located in the C-terminus nor in the juxtamembrane region of the insulin receptor β subunit. [ABSTRACT FROM AUTHOR]