Abstract Mitochondrial dysfunctions in skeletal muscle have been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We have investigated the structure and functions of muscle mitochondria during the development of high fat and high sucrose diet-induced insulin resistance in mice. We found that mitochondrial dysfunctions were not present in glucose intolerant mice, whereas altered mitochondrial biogenesis, structure and functions were observed in muscle of diabetic mice. Furthermore, we demonstrated that muscle oxidative stress is one of the major determinants of these mitochondrial alterations since 1) there was an increase of ROS production specifically in skeletal muscle of hyperglycaemic and hyperlipidaemic diet-induced diabetic mice, 2) ROS production was also associated with mitochondrial alterations in muscle of hyperglycaemic streptozotocin-treated mice, 3) in this model, normalization of glycaemia or treatment with an antioxidant decreased muscle ROS production and restored mitochondrial integrity, and 4) glucose- or lipid-induced ROS production in muscle cells altered mitochondrial density and functions, and these effects were blocked by antioxidant treatment. Consequently, mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice.
