Figure 9

The influence of liver-specific glucokinase knockout on the myocardium. The liver-specific glucokinase knockout mouse experiences long-term hyperglycemia, which induced decreased levels of insulin receptor. Disrupting the early signaling events in the insulin pathway also has downstream effects on other proteins including Akt and AMPK, ultimately leading to insulin resistance and attenuated glucose uptake. Fatty acid synthesis increased in cardiomyocyte by decreased AMPK phosphorylation and subsequent increased ACC activity. Increased glucose stimulates NADPH oxidase expression. NADPH oxidase-derived superoxide generation then contributes to mitochondrial dysfunction, leading to a further increase in superoxide generation. Insulin resistance, increasing fatty acid synthesis and oxidative stress induced cardiomyocyte hypertrophy and fibrosis.