Regulation of skeletal muscle sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) by metabolic stress and diabetes.

Sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) is involved in cellular stress responses linked to obesity and type 2 diabetes. We determined the role of SNARK in response to metabolic stress and insulin action on glucose and lipid metabolism in skeletal muscle. Vastus lateralis skeletal muscle biopsies were obtained from normal glucose tolerant (n = 35) and type 2 diabetic (n = 31) men and women for SNARK expression studies. Primary myotube cultures were derived from biopsies obtained from normal glucose tolerant individuals for metabolic studies. SNARK (also known as NUAK2) mRNA expression was unaltered between normal glucose tolerant individuals and type 2 diabetic patients. SNARK expression was increased in skeletal muscle from obese (BMI >31 kg/m(2)) normal glucose tolerant individuals and type 2 diabetic patients (1.4- and 1.4-fold, respectively, p < 0.05) vs overweight (BMI <28 kg/m(2)) normal glucose tolerant individuals and type 2 diabetic patients. SNARK mRNA was increased in myotubes exposed to palmitate (12-fold; p < 0.01), or TNF-alpha (25-fold, p < 0.05), but not to oleate, glucose or IL-6, whereas expression of the AMP-activated protein kinase alpha2 subunit was unaltered. Small interfering (si)RNA against SNARK reduced mRNA and protein in myotubes by 61% and 60%, respectively (p < 0.05). SNARK siRNA was without effect on basal or insulin-stimulated glucose uptake or lipid oxidation, and insufficient to rescue TNF-alpha- or palmitate-induced insulin resistance. Skeletal muscle SNARK expression is increased in human obesity, and in response to metabolic stressors, but not type 2 diabetes. Partial SNARK depletion failed to modify either glucose or lipid metabolism, or protect against TNF-alpha- or palmitate-induced insulin resistance in primary human myotubes.