Muscle insulin resistance is linked to oxidative stress and decreased mitochondrial function. However, the exact cause of muscle insulin resistance is still unknown. Since offspring of patients with type 2 diabetes mellitus (T2DM) are susceptible to developing insulin resistance, they are ideal for studying the early development of insulin resistance. By using primary muscle cells derived from obese non-diabetic subjects with (FH+) or without (FH-) a family history of T2DM, we aimed to better understand the link between mitochondrial function, oxidative stress, and muscle insulin resistance. Insulin-stimulated glucose uptake and glycogen synthesis were normal in FH+ myotubes. Resting oxygen consumption rate was not different between groups. However, proton leak was higher in FH+ myotubes. This was associated with lower ATP content and decreased mitochondrial membrane potential in FH+ myotubes. Surprisingly, mtDNA content was higher in FH+ myotubes. Oxidative stress level was not different between FH+ and FH- groups. Reactive oxygen species content was lower in FH+ myotubes when differentiated in high glucose/insulin (25mM/150pM), which could be due to higher oxidative stress defenses (SOD2 expression and uncoupled respiration). The increased antioxidant defenses and mtDNA content in FH+ myotubes suggest the existence of compensatory mechanisms, which may provisionally prevent the development of insulin resistance.
Keywords: 2′,7′-dichlorfluorescein-diacetate; ANT; COX; CS; DCFH-DA; FCCP; FH; GSH; GSSG; HGI; IPAQ; IκKβ; JNK; LGI; Mitochondrial proton leak; Muscle; OCR; Oxidative phosphorylation; Oxidative stress; PPARγ; RMR; ROS; RQ; SOD2; T2DM; TMRE; UCP3; adenine nucleotide translocase; c-Jun N-terminal kinase; carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; citrate synthase; cytochrome C oxidase; family history; high glucose, high insulin differentiation medium; inhibitor of NF-κB kinase; international physical activity questionnaire; low glucose, low insulin differentiation medium; manganese superoxide dismutase; oxidized glutathione; oxygen consumption rates; peroxisome proliferator-activated receptor γ; reactive oxygen species; reduced glutathione; respiratory quotient; resting metabolic rate; tetramethylrhodamine ethyl ester; type 2 diabetes mellitus; uncoupling protein 3.
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