Mitochondrial dysfunction in type II diabetes: Role of mitochondrial ROS and effect of exercise
Mitochondria generate reactive oxygen species (ROS). Dysregulated mitochondrial ROS production results in oxidative stress compromising mitochondrial structure and function. In animal models, mitochondrial oxidative stress leads to development of insulin resistance, a main feature of type II diabetes.
The aims of this project are to demonstrate the connection between mitochondrial oxidative stress and insulin resistance in humans and to explore the mitochondrial adaptations whereby exercise training ameliorates insulin sensitivity in patients with type II diabetes.
Recent evidence indicates that mitochondria-derived oxidative stress causes insulin resistance in cultured cells and animal models. However, it is unknown whether dysregulated mitochondrial ROS production plays a causal role in human insulin resistance. Chronic treatment with mitochondria-targeted antioxidant ameliorates lipid-induced insulin resistance in rodents, suggesting that mitochondria-targeted antioxidant supplementation may represent a viable strategy to manipulate mitochondrial ROS and possibly alter insulin sensitivity in humans.
Physical exercise is a well-established intervention to promote beneficial mitochondrial adaptations and improves insulin sensitivity. Notably, aerobic exercise training decreases mitochondrial ROS emission while increasing insulin sensitivity in insulin resistant individuals. Nevertheless, it is unclear whether the exercise training-induced reduction in mitochondrial ROS emission contributes to the improved insulin sensitivity.
The project consists of a two-phase human study assessing changes in insulin sensitivity in response to acute and chronic manipulation of skeletal muscle mitochondrial ROS. By using an innovative experimental approach integrating in vivo manipulation of mitochondrial ROS along with gold-standard measurements of insulin-stimulated glucose uptake, we expect to provide the first evidence of a link between mitochondrial oxidative stress and insulin resistance in humans while identifying the mitochondrial adaptive mechanisms whereby exercise training possibly improves insulin-dependent glucose regulation in patients with type II diabetes.
The project is supported by the Novo Nordisk Foundation.
Postdoc Matteo Fiorenza
Associate Professor Morten Hostrup
Professor Jens Bangsbo