Increased susceptibility to oxidative damage in post-diabetic human myotubes.
OBJECTIVE
Obesity is an important risk factor for the development of type 2 diabetes, but not all obese individuals develop this complication. The clinical signs of type 2 diabetes can often be reversed with weight loss; however, it is unknown whether the skeletal muscle oxidative stress associated with type 2 diabetes remains after weight loss. We hypothesised that chronic exposure to high glucose and insulin would re-elicit impaired metabolism in primary myotubes from patients with a history of type 2 diabetes.


METHODS
Obese participants with or without type 2 diabetes completed a standardised weight loss protocol, following which all participants were euglycaemic and had similar indices of insulin sensitivity. Satellite cells were isolated from muscle biopsies and differentiated under low or high glucose and insulin conditions (HGI).


RESULTS
Cells from participants with no history of type 2 diabetes showed robust increases in mitochondrial content, citrate synthase and cytochrome c oxidase activities when exposed to HGI. This increase in oxidative capacity was absent in cells from patients with a history of type 2 diabetes. High glucose and insulin caused increased oxidative damage in cells from the latter, despite higher superoxide dismutase expression. Cells from patients with a history of type 2 diabetes were unable to decrease mitochondrial membrane potential in response to HGI, potentially due to lower levels of uncoupling protein-3.


CONCLUSIONS
This is the first report to note that primary myotubes from patients with a history of type 2 diabetes are unable to adapt to a hyperglycaemic-hyperinsulinaemic challenge. We have demonstrated that impaired mitochondrial biogenesis and an inability to manage oxidative stress define a muscle phenotype at risk of obesity-associated type 2 diabetes.
Costford
S R
SR
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
Crawford
S A
SA
Dent
R
R
McPherson
R
R
Harper
M-E
ME
D000328:Adult; D001823:Body Composition; D015992:Body Mass Index; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000453:epidemiology* / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications* / Q000178:diet therapy*; D018384:Oxidative Stress; D014280:Triglycerides / Q000378:metabolism; D000071247:Uncoupling Protein 3; D015431:Weight Loss
D006442:Glycated Hemoglobin; D006003:Glycogen; D007004:Hypoglycemic Agents; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D014280:Triglycerides; D000071247:Uncoupling Protein 3; C000604392:UCP3 protein, human
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