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Irisin, a novel myocyte-secreted hormone mediating beneficial effects of exercise on metabolism, is supposed to be an ideal therapeutic target for metabolic disorders such as obesity and diabetes. Here, we investigated the potential effects of metformin and glibenclamide, two antidiabetic medicines, on irisin release in mouse.Wild-type and diabetic obese db/db mice were administrated with metformin and glibenclamide for 2 weeks, and cultured C2C12 myotubes were treated by metformin. Expression of irisin precursor FNDC5 was measured and blood irisin concentration was detected. AMP-activated protein kinase (AMPK) was blocked by chemical inhibitor compound C or knocking down with specific siRNA.The mRNA and protein expression of FNDC5 in skeletal muscle and blood irisin concentrations were lower in diabetic db/db mice than those in wild-type mice. Metformin and glibenclamide decreased blood glucose in db/db mice. Metformin, but not glibenclamide, increased intramuscular FNDC5 mRNA/protein expression and blood irisin levels. Additionally, the reductions of blood glucose and body weight in metformin-treated db/db mice were positively associated with blood irisin concentrations. In C2C12 myotubes, metformin upregulated intracellular FDNC5 mRNA/protein expression and promoted irisin release. Although metformin activated AMPK signalling in skeletal muscle cells, disrupting of AMPK signalling by chemical inhibitor or siRNA-mediated knockdown did not abolish the promoting effect of metformin on irisin release.Metformin promotes irisin release from murine skeletal muscle into blood, independently of AMPK pathway activation. Our results suggest that stimulation of irisin may be a novel molecular mechanism of metformin which is widely used for treatment of metabolic disorders.