Low-grade inflammation associated with Type 2 Diabetes (T2DM) is postulated to exacerbate insulin resistance. We report that serum levels, as well as IL-13 secreted from cultured skeletal muscle, is reduced in T2DM versus normal glucose tolerant (NGT) subjects. IL-13 exposure increases skeletal muscle glucose uptake, oxidation and glycogen synthesis via an Akt-dependent mechanism. Expression of microRNA let-7a and let-7d, direct translational repressors of the IL-13 gene, was increased in skeletal muscle from T2DM patients. Overexpression of let-7a and let-7d in cultured myotubes reduced IL-13 secretion. Furthermore, basal glycogen synthesis was reduced in cultured myotubes exposed to an IL-13 neutralizing antibody. Thus, IL-13 is synthesized and released by skeletal muscle through a mechanism involving let-7 and this effect is attenuated in skeletal muscle from insulin resistant T2DM patients. In conclusion, IL-13 plays an autocrine role in skeletal muscle to increase glucose uptake and metabolism, suggesting a role in glucose homeostasis in metabolic disease.