Retributions of a sedentary lifestyle: Impact on insulin sensitivity and diabetes — lessons learned from studies on muscle mitochondria

Altered fuel metabolism is the main metabolic derangement in diabetes, and mitochondria are the predominant sites of fuel metabolism.

K Sreekumaran Nair, M.D., Ph.D., an endocrinology consultant at Mayo Clinic's campus in Rochester, Minnesota, and his colleagues have been focusing their research on understanding the role of mitochondria in the pathogenesis of diabetes.

Dr. Nair's studies have shown that insulin deprivation temporarily results in increased energy consumption, but this increased energy is not fully translated within the mitochondria into adenosine triphosphate (ATP), the chemical form of energy that cells use.

Dr. Nair explains: "This inefficient fuel utilization by mitochondria during insulin deficiency appears to be the cause of increased formation of reactive oxygen species (ROS), which cause irreversible damage to newly synthesized proteins. Proteins are involved in most body functions, and damaged proteins may explain the decline in many of the biological functions of the body. Obese women who are insulin resistant also have excessive ROS emissions, which potentially can damage proteins and other cellular components."

It has been shown that muscle mitochondrial biogenesis is enhanced by insulin when supplemented by amino acids and glucose. However, in individuals with type 2 diabetes, unlike in controls without diabetes, increasing insulin from baseline levels to high physiological levels failed to increase muscle ATP production.

Moreover, it has been shown that insulin-resistant states, such as polycystic ovary syndrome (PCOS) in women, lead to altered muscle mitochondrial function. Skeletal muscle mitochondrial couplings and phosphorylation efficiencies are significantly lower in women with PCOS who have insulin resistance than in lean women with insulin sensitivity.

Women with PCOS also exhibit high levels of oxidative stress in skeletal muscle, as demonstrated by a higher production of ROS. It has been shown that higher ROS emission reduces insulin sensitivity. After three months of an aerobic exercise training program, women with PCOS displayed enhanced insulin sensitivity concurrent to the improvement of muscle mitochondrial coupling and phosphorylation efficiencies, as well as a reduction in ROS emission.

Dr. Nair's research has also shown that muscle mitochondrial capacity to produce ATP declines with age in people who are sedentary. Muscle mitochondrial capacity to produce ATP is a major determinant of maximal aerobic or exercise capacity.

Dr. Nair notes: "Maximal exercise capacity is a more powerful predictor of mortality than other established risk factors for cardiovascular disease. Studies have shown that mortality in chronic diseases, such as diabetes, hypertension, obesity and hyperlipidemia, substantially increases in people with a lower maximal exercise capacity.

"Research we performed at Mayo Clinic has found that a decline in the capacity of muscle to produce ATP is associated with a decline in many ATP-dependent processes such as protein turnover, which is critical to maintaining protein mass and quality. As a result, the mass and functional quality of the muscle also declines, further deteriorating the maximal exercise capacity. This decline in muscle mass and strength also causes further lowering of insulin sensitivity and increases the incidence of diabetes, hypertension, hyperlipidemia and cardiovascular-related death."

Dr. Nair continues: "Elderly people who maintain a high-level aerobic exercise program and prevent fat gain have a level of insulin sensitivity that is similar to young people. Moreover, elderly people who maintain a high-level exercise program also prevent age-related declines in muscle mitochondrial proteins and their functions. Exercise also enhances protein turnover, especially muscle protein synthesis, which is likely to contribute to the prevention of age-related declines in muscle proteins and muscle wasting. Research has also shown that weight training increases muscle strength, mass and synthesis of contractile proteins, irrespective of age."

Overall, these research programs have shown that the age-related increase in diabetes could be largely prevented by a regular exercise program as well as a reduction in caloric intake to prevent fat gain. High-fat meals reduce insulin sensitivity and likely increase emission of ROS.

Dr. Nair's research has also shown that in people with high insulin resistance, exercise not only increases their mitochondrial respiration but also reduces excess ROS emissions, thus potentially preventing deleterious effects on cellular functions. This decline in ROS emissions is also associated with an enhancement of insulin sensitivity and supports other experimental data showing that increased ROS emissions can reduce insulin sensitivity. Exercise also enhances the body's antioxidant capacity, further preventing the adverse effects of oxidative stress.

Dr. Nair's laboratory has also demonstrated that regular aerobic exercise as well as combined aerobic and resistant exercise training programs not only improve insulin sensitivity but also prevent age-related decreases in muscle mitochondrial ATP production.

Dr. Nair concludes: "These exercise training programs also have been shown to enhance whole-body and muscle mitochondrial oxidative capacity, which contributes to a reduction in mortality related to many diseases, including diabetes, hypertension and hyperlipidemia. Although some early studies have shown that a reduction in muscle mitochondrial oxidative capacity is related to insulin resistance, this association is not consistent, and the cause-effect relationship between muscle mitochondrial oxidative capacity and insulin sensitivity has not been fully established."

Dr. Nair cautions: "Implementing exercise programs and caloric restriction in real life is not straightforward. Additionally, many people with various disabilities, especially joint problems, cannot exercise. Therefore, there is a need to understand the various mechanistic pathways that are enhanced by exercise so that future research can target those pathways for drug discoveries that can offer similar benefits as exercise. The goal of the metabolic basis for type 2 diabetes and aging research in our laboratory is to focus on this translational objective to work toward an improvement in human health."