Lipotoxicity in type 2 diabetic cardiomyopathy

As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy

Uncoupling protein 3 and physical activity: the role of uncoupling protein 3 in energy metabolism revisited

Uncoupling protein 3 and physical activity: the role of uncoupling protein 3 in energy metabolism revisited. Schrauwen P, Hesselink M. Nutrition and Toxicology Research Institute Maastricht, Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. [email protected] Physical activity influences energy metabolism in human subjects by increasing activity-induced energy expenditure and resting metabolic rate for several hours after exercise. On the other hand, physical activity increases mechanical energy efficiency, suggesting that trained subjects would need less energy for daily activities. The underlying mechanism by which physical activity influences energy metabolism is largely unknown. The skeletal muscle-specific homologue of uncoupling protein (UCP) 1, UCP3, could possibly play a major role in energy expenditure. UCP3 is, like UCP1, able to uncouple respiration from ATP production. A strong link or association between the UCP3 gene and energy metabolism was found. Furthermore, UCP3 mRNA expression is related to sleeping metabolic rate, and thyroid hormone, a powerful stimulator of energy expenditure, up regulates UCP3. Finally, mice overexpressing UCP3 are hyperphagic but lean. These findings indicated that UCP3 is related to energy metabolism and that UCP3 could have a role in the effect of physical activity on energy expenditure. Thus, acute exercise up regulates UCP3, whereas endurance training results in the down-regulation of UCP3 protein content. Only a minimal amount of physical activity is needed for down-regulation of UCP3. Moreover, there is very strong evidence that UCP3 is negatively related to mechanical energy efficiency, suggesting that the down-regulation of UCP3 with training increases mechanical energy efficiency. Taken together, although the exact function of UCP3 is still unknown, exercise and training studies clearly show that under certain circumstances UCP3 is strongly related to human energy metabolism, possibly as a secondary effect of its (yet) unknown primary function

The insulin-sensitizing effect of rosiglitazone in type 2 diabetes mellitus patients does not require improved in vivo muscle mitochondrial function.

Aims: To investigate whether improved in vivo mitochondrial function in skeletal muscle and intramyocellular lipids (IMCL) contribute to the insulin-sensitizing effect of rosiglitazone. Methods: Eight overweight type 2 diabetic patients (BMI= 29.3 +/- 1.1 kg/m(2)) were treated with rosiglitazone for 8 weeks. Before and after treatment, insulin sensitivity was determined by a hyperinsulinaemic-euglycaemic clamp. Muscular mitochondrial function (half-time of phosphocreatine recovery after exercise) and IMCL content were measured by magnetic resonance spectroscopy. Results: Insulin sensitivity improved after rosiglitazone (GIR: 19.9+/-2.8 to 24.8+/-2.1 micromol/kg/min (P<0.05)). In vivo mitochondrial function (PCr recovery half-time: 23.8+/-3.5 to 20.0+/-1.7 s (P=0.23)) and IMCL content (0.93+/-0.18% to 1.37+/-0.40%, p=0.34) did not change. Interestingly, the changes in PCr half-time correlated/tended to correlate with changes in fasting insulin (R(2)=0.50, P=0.05), and glucose (R(2)=0.43, p=0.08) levels. Changes in PCr half-time did not correlate with changes in GIR (R(2)=0.08, P=0.49). Conclusion: The rosiglitazone-enhanced insulin sensitivity does not require improved muscular mitochondrial function

Human uncoupling protein-3 and obesity: an update

Human uncoupling protein-3 and obesity: an update. Hesselink MK, Mensink M, Schrauwen P. Department of Movement Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands. [email protected] The cloning of the uncoupling protein (UCP)1 homologs UCP2 and UCP3 has raised considerable interest in the mechanism. The expression of UCP3 mainly in skeletal muscle mitochondria and the potency of the skeletal muscle as a thermogenic organ made UCP3 an attractive target for studies toward manipulation of energy expenditure to fight disorders such as obesity and type 2 diabetes. Overexpressing UCP3 in mice resulted in lean, hyperphagic mice. However, the lack of an apparent phenotype in mice lacking UCP3 triggered the search for alternative functions of UCP3. The observation that fatty acid levels significantly affect UCP3 expression has given UCP3 a position in fatty acid handling and/or oxidation. Emerging data indicate that the primary physiological role of UCP3 may be the mitochondrial handling of fatty acids rather than the regulation of energy expenditure through thermogenesis. It has been proposed that UCP3 functions to export fatty acid anions away from the mitochondrial matrix. In doing so, fatty acids are exchanged with protons, explaining the uncoupling activity of UCP3. The exported fatty acid anions may originate from hydrolysis of fatty acid esters by a mitochondrial thioesterase, or they may have entered the mitochondria as nonesterified fatty acids by incorporating into and flip-flopping across the mitochondrial inner membrane. Regardless of the origin of the fatty acid anions, this putative function of UCP3 might be of great importance in protecting mitochondria against fatty acid accumulation and may help to maintain muscular fat oxidative capacity