| Metabolic syndrome is a complex condition that presents with obesity, cardiovascular disease and diabetes mellitus. Insulin resistance is thought to be one of the underlying pathways to metabolic syndrome. Mitochondrial function is a central feature of metabolic regulation. The mitochondria are responsible for generating the majority of the cell's energy from the fats and carbohydrates we consume. Impaired mitochondrial function has been linked with insulin resistance although its exact mechanism is still unknown. To better understand the connection between mitochondrial function and insulin resistance we examined transgenic mice that have defects in mitochondrial antioxidant defense (MnSOD and NNT), defects in oxidative phosphorylation enzyme activity (ND6 and COI), and defects in ATP/ADP transport (ANT1 and ANT2). We placed these mice on a high fat diet and monitored their weight gain, blood glucose and insulin levels, and their glucose tolerance. The MnSOD, ND6 and COI defects do not seem to significantly impact glucose and insulin metabolism. The pancreatic β-cell specific ANT2 defect (RIP-Cre, Ant2flox) showed significantly reduced insulin levels and impaired glucose tolerance, although additional studies reveal that the main factor in glucose intolerance is due to the RIP-Cre, not the inactivated Ant2..;Interestingly, deficiency in the heart, muscle, brain isoform of ANT (Ant1 -/-) revealed a significant hyperproliferation of mitochondrial mass and enzyme activity. State II respiration was increased in Ant1 -/- muscle; ADP-stimulated state III respiration was decreased, and ROS production was increased. In addition, the mice had lower insulin levels while maintaining euglycemia, increased glucose tolerance and overall increased glucose uptake. This result gives evidence to a compensation effect of mitochondria by acting as a sink for excess reducing equivalents during metabolic challenge. |
