title: Increased proton leak and SOD2 expression in myotubes from obese non-diabetic subjects with a family history of type 2 diabetes.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Céline
authors.initials: C
authors.lastname: Aguer
authors.forename: Melissa
authors.initials: M
authors.lastname: Pasqua
authors.forename: A Brianne
authors.initials: AB
authors.lastname: Thrush
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moffat
authors.forename: Michael
authors.initials: M
authors.lastname: McBurney
authors.forename: Karen
authors.initials: K
authors.lastname: Jardine
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Brittany
authors.initials: B
authors.lastname: Beauchamp
authors.forename: Robert
authors.initials: R
authors.lastname: Dent
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology / Q000378:metabolism*; D011522:Protons; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D004272:DNA, Mitochondrial; D011522:Protons; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
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