This review focuses on the effect of increases in intracellular diacylglycerol content on hepatic and skeletal muscle insulin resistance associated with obesity and type 2 diabetes. Overnutrition is the most common cause for increased intracellular diacylglycerol content, which is due to an imbalance between fatty acid delivery and intracellular fatty acid oxidation and storage. Moreover, this increase in diacylglycerol content lead to activation of protein kinase C (PKC) isoforms in skeletal muscle or liver, which in turn decreases insulin-stimulated IRS1/IRS2 tyrosine phosphorylation, PI3K activation and downstream insulin signalling. Consequently, there is a reduction of insulin-stimulated GLUT4 translocation to the plasma membrane, resulting in decreased muscle glycogen synthesis. As for the liver, this results in decreased hepatic glycogen synthesis, and increased hepatic gluconeogenesis. Therefore, the diacyglycerol-mediated insulin resistance is another interesting molecular mechanism to better understand the pathogenesis of type 2 diabetes and to find new targets for effective therapeutic strategies.
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