Autocrine role of interleukin-13 on skeletal muscle glucose metabolism in type 2 diabetic patients involves microRNA let-7

Abstract

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...

Myokines in insulin resistance and type 2 diabetes

“…IL-13 was recently identified as a novel myokine that is released by human myotubes [28]. Interestingly, type 2 diabetic individuals have significantly reduced serum levels of IL-13 compared with controls, and myotubes from these patients secrete 75% less IL-13 than myotubes from controls.…”

“…Interestingly, type 2 diabetic individuals have significantly reduced serum levels of IL-13 compared with controls, and myotubes from these patients secrete 75% less IL-13 than myotubes from controls. Furthermore, Jiang et al suggested a role for IL-13 in skeletal muscle glucose metabolism by showing that treatment of myotubes with this protein increased basal glucose uptake and oxidation and glycogen synthesis (Table 1) [28]. Moreover, a study using IL-13-deficient mice has suggested an implication for IL-13 in suppression of hepatic glucose production [29].…”

“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”

microManaging glucose and lipid metabolism in skeletal muscle: Role of microRNAs

“…Loss of function of Lin28 increases let-7 expression and induces insulin resistance in mouse models [34]. In cultured primary myotubes derived from T2D patients, let-7a is increased when compared to healthy subjects and may play a role in the regulation of glucose metabolism by targeting IL-13 [35]. The H19 long non-coding RNA has also been shown to regulate the let-7 family bioavailability [36] and is reduced in human and rodent diabetic skeletal muscle [37].…”

Promoter hypermethylation of let-7a-3 is relevant to its down-expression in diabetic nephropathy by targeting UHRF1

“…However, recent studies have showed that the let-7 family is a potential target for regulating glucose metabolism and insulin synthesis/secretion in patients with type 2 DM (Frost and Olson, 2011), and the mechanism may be related to the regulation by targeting lin28 pathway . Let-7a and let-7d could affect glucose metabolism in the skeletal muscle of type 2 DM patients by regulating IL-13 (Jiang et al, 2013). Up-regulation of let-7c could induce fibrosis by suppressing TGF-β1, and the expressions of let-7c targets were dysregulated in human renal fibrosis (Brennan et al, 2013).…”