role of interleukin-13 on skeletal muscle glucose metabolism in type 2 diabetic patients involves microRNA let-7. Am J Physiol Endocrinol Metab 305: E1359 -E1366, 2013. First published October 8, 2013 doi:10.1152/ajpendo.00236.2013.-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, are reduced in T2DM vs. normal glucosetolerant (NGT) subjects. IL-13 exposure increases skeletal muscle glucose uptake, oxidation, and glycogen synthesis via an Aktdependent mechanism. Expression of microRNA let-7a and let-7d, which are 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.cytokines; diabetes; glucose metabolism; lipid metabolism; gene expression THE ROLE OF SKELETAL MUSCLE-DERIVED FACTORS or "myokines" as signaling molecules and the link to metabolic homeostasis are not completely described. The most extensively studied myokines include interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1, which exert biological effects on glucose and lipid metabolism via autocrine, paracrine, and endocrine mechanisms (11,34). However, the role of IL-13 in the development of insulin resistance and type 2 diabetes mellitus (T2DM) is unclear.IL-13 is secreted by activated Th2 cells and classified as an anti-inflammatory cytokine due to its ability to suppress the secretion of several macrophage and monocyte-derived inflammatory cytokines (6, 7). Hence, IL-13 counteracts several cytokines linked to the development of insulin resistance in T2DM (27,45). IL-13 is a major mediator of airway hyperresponsiveness and mucus hypersecretion, two fundamental responses in the clinical manifestation of asthma (20). IL-13-deficient mice display an impaired antigen-specific immunoglobulin G response but are otherwise viable with no reported disturbances in appearance or behavior (29). Thus, IL-13 displays disparate biological functions, ultimately promoting either anti-inflammatory or pathological responses, the latter primarily in lung. Of metabolic relevance is that IL-13 is required for alternative activation towards the anti-inflammatory M2 macrophage phenotype in adipose tissue, resulting in enhanced insulin sensitivity in mice fed a high-fat diet (22). Recent evidence implicates a role for IL-13 in controlling hepatic glucose production (41).There is a growing appreciation for the role of microRNAs (mi...

miRNAs are noncoding RNAs representing an important class of gene expression modulators. Extracellular circulating miRNAs are both candidate biomarkers for disease pathogenesis and mediators of cell-to-cell communication. We examined the miRNA expression profile of total serum and serum-derived exosome-enriched extracellular vesicles in people with normal glucose tolerance or type 2 diabetes. In contrast to total serum miRNA, which did not reveal any differences in miRNA expression, we identified differentially abundant miRNAs in patients with type 2 diabetes using miRNA expression profiles of exosome RNA (exoRNA). To validate the role of these differentially abundant miRNAs on glucose metabolism, we transfected miR-20b-5p, a highly abundant exoRNA in patients with type 2 diabetes, into primary human skeletal muscle cells. miR-20b-5p overexpression increased basal glycogen synthesis in human skeletal muscle cells. We identified AKTIP and STAT3 as miR-20b-5p targets. miR-20b-5p overexpression reduced AKTIP abundance and insulin-stimulated glycogen accumulation. In conclusion, exosome-derived extracellular miR-20b-5p is a circulating biomarker associated with type 2 diabetes that plays an intracellular role in modulating insulin-stimulated glucose metabolism via AKT signaling.

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miRNAs regulate protein abundance and control diverse aspects of cellular processes and biological functions in metabolic diseases, such as obesity and type 2 diabetes (T2D). Let (lethal)-7 miRNAs specifically targets genes associated with T2D and have been implicated in the regulation of peripheral glucose metabolism, yet the direct regulators of let-7 miRNA expression are unknown. In the present study, we report on a putative promoter region for the let-7a-1, let-7f-1 and let-7d gene cluster on chromosome 9 and characterize the promoter activity of this novel area. We show that promoter activity and let-7 miRNA expression is dynamically regulated in response to different factors including serum, glucose, tumour necrosis factor (TNF)-α and caffeine. These findings will contribute to understanding the interaction between precise promoter elements to control the transcription and translation of let-7 miRNA genes.