Metabolic and Molecular Abnormalities in Response to Insulin and Exercise in Obesity and Type 2 Diabetes

BACKGROUND Insulin resistance (IR) plays a major role for the increased risk of cardiovascular disease (CVD) in obesity and type 2 diabetes (T2D). Targeted treatment of IR in affected tissues is, however, almost non-existing, except for weight-loss and physical activity. The central hypothesis of this proposal is that abnormalities in glucose and lipid metabolism as well as defects in molecular processes regulated by insulin and exercise can explain the link between IR, mitochondrial dysfunction and lipid accumulation observed in skeletal muscle in obesity and T2D. Focusing on these metabolic and molecular abnormalities, the major goal of our project is to discover novel targets for the treatment of IR and mimicking exercise, which can be used in the prevention and treatment of T2D and CVD.

T2D, obesity and other high risk conditions are characterized by IR in skeletal muscle, the major site of insulin-mediated glucose disposal (1-3). In T2D, failure of the pancreatic β-cells to compensate for this abnormality causes hyperglycemia, which further aggravates the risk of CVD. Despite extensive research, the exact metabolic and molecular mechanisms underlying IR are not fully understood. At the metabolic level, the investigators and others have demonstrated that IR in obesity and T2D is characterized by impaired insulin-stimulated glucose uptake and glucose storage, but also reduced insulin-mediated increase in glucose oxidation and attenuated suppression of lipid oxidation and circulating levels of free fatty acids (lipolysis) in response to insulin (2,3). At the molecular level these metabolic abnormalities are associated with reduced insulin signaling to glucose transport through IRS-1, PI3K, Akt, AS160 and RAC1 and to glycogen synthesis through impaired insulin action on glycogen synthase in skeletal muscle (1-10). Moreover, IR is consistently associated with accumulation of lipid content and different measures of mitochondrial dysfunction in skeletal muscle of patient with T2D, obesity and high-risk individuals (1-3,11,12).

In addition, there is accumulating evidence of increased glycolysis (13-15) and resistance to the beneficial effect of exercise in T2D and obesity (16-18). The changes in substrate metabolism in IR conditions seem to be associated with a specific metabolomic signature that includes increased circulating levels of branched-chain amino acids and α-hydroxybutyrate, and reduced levels of glycine (19-23). Finally, impaired adipose tissue expandability in T2D, obesity and other high risk conditions may play a role in the pathogenesis of IR and T2D by leading to increased secretion of inflammatory factors and overflow of free fatty acids to cause ectopic lipid deposition in liver and muscle (24). Genetic variants found to be associated with T2D, obesity and body composition in large GWAS-studies suggest a role for several transcriptional factors and signaling pathways in adipose tissue expansion and inflammation (25,26).

Effects of exercise: Physical activity plays a fundamental role in the prevention and treatment of T2D (27-29). Thus, meta-analysis of several long-term (> 8 weeks) exercise training studies have shown that exercise can improve body composition, insulin sensitivity and reduce Hb1Ac by approximately 0.67 % in patients with T2D (30). The beneficial effects of a single bout of moderate-intensity one-legged exercise include an immediate increase in muscle glucose uptake (31). This is followed by a more prolonged (<48 h) increase in insulin sensitivity to stimulate glucose uptake in both lean healthy and insulin-resistant obese and type 2 diabetic individuals (32-33). In addition, the cumulative effect of repeated exercise bouts (exercise training) increases insulin sensitivity and VO2max, and is further known to increase skeletal muscle mitochondrial content and function in both nondiabetic and diabetic subjects (34-37). Furthermore, there is evidence that exercise training improves pancreatic beta-cell function in individuals with T2D (38).

Exercise mode: The most appropriate exercise mode for IR individuals has not yet been established. A major problem in this respect is to find an effective mode of exercise (type, intensity and duration) which will ensure continued engagement (patient adherence) as well as continued beneficial effects on health (29). Thus, for IR individuals it is important to identify a mode of exercise that can safely and effectively maximize energy expenditure. This could be non-weight-bearing exercise modes such as cycling and rowing. Most studies so far have reported effects of acute exercise or endurance exercise training on stationery bikes. However, it has been shown that energy expenditure and fat oxidation during rowing is higher than during cycling (39,40). The strong association between IR, lipid accumulation and mitochondrial dysfunction in muscle makes fat-burning exercise of special interest (29,40). The contribution of fat oxidation to energy expenditure is highest during low- and moderate intensity exercise (45-65 % of VO2max) (41-43). Thus, the combination of cycling and rowing at moderate intensities could be an attractive exercise mode due to its non-weight-bearing nature and by the involvement of both lower and upper body muscle groups (29). In our studies, we will for the first time evaluate the effect and tolerability of a high intensity interval training protocol combining cycling and rowing on ergometers on insulin sensitivity, body composition, cardiorespiratory fitness, pancreatic beta-cell function and metabolic and molecular regulators of glucose uptake and energy metabolism in obesity and T2D versus weight-matched controls.