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Signal transducer and activator of transcription 3 (STAT3) is involved in cytokine- and nutrient-induced insulin resistance. The role of STAT3 in the development of skeletal muscle insulin resistance and type 2 diabetes (T2D) pathogenesis is incompletely defined. We tested the hypothesis that STAT3 signaling contributes to skeletal muscle insulin resistance in T2D. Protein abundance and phosphorylation of STAT3 signaling molecules were determined in skeletal muscle biopsy specimens from BMI- and age-matched overweight individuals with normal glucose tolerant (NGT) and T2D patients. The direct role of STAT3 in the development of lipid-induced skeletal muscle insulin resistance was determined using small interfering (si) RNA. Phosphorylated STAT3, phosphorylated Janus kinase 2 (JAK2), and suppressor of cytokine signaling 3 (SOCS3) protein abundance was increased in skeletal muscle from T2D patients. STAT3 phosphorylation positively correlated with free fatty acid level and measures of insulin sensitivity in NGT but not T2D patients. Palmitate exposure led to a constitutive phosphorylation of STAT3, increased protein abundance of SOCS3, and development of insulin resistance in L6 myotubes. These effects were prevented by siRNA-mediated STAT3 silencing. In summary, STAT3 is constitutively phosphorylated in skeletal muscle from T2D patients. STAT3 gene silencing prevents lipid-induced insulin resistance in cultured myotubes. Collectively, our results implicate excessive STAT3 signaling in the development of skeletal muscle insulin resistance in T2D. Diabetes 62:457-465, 2013
The link between obesity and insulin resistance in type 2 diabetes (T2D) pathogenesis is increasingly appreciated (1). For instance, aberrant crosstalk between metabolically active organs in obese individuals can cause peripheral insulin resistance and increase T2D risk. In addition, obesity-induced elevations in circulating triglyceride and free fatty acid (FFA) levels are implicated in the development of skeletal muscle insulin resistance (1). Several factors secreted from adipose tissue (so-called adipocytokines) can also influence insulin action in skeletal muscle (2). Candidate adipokines, including tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and adiponectin, orchestrate interorgan communication between adipose tissue and skeletal muscle and influence insulin sensitivity (3). Signals emanating from the cytokineresponsive Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway are involved in adipokine-mediated crosstalk between adipocytes and liver or skeletal muscle (4-6). However, the role of STAT3 in the development of skeletal muscle insulin resistance in humans is inconclusive (7-9).
STAT3, a transcription factor expressed in multiple...