Endocrine Abstracts

Ectopic lipid deposition in liver and skeletal muscle plays a major role in the pathogenesis of insulin resistance and type 2 diabetes (T2D). Furthermore, nonalcoholic fatty liver disease (NAFLD) is a major predisposing factor for nonalcoholic steatohepatitis (NASH) and hepatocellular cancer and is an independent risk factor of cardiovascular disease. Understanding the cellular and molecular mechanisms by which ectopic lipid promotes insulin resistance in liver and identifying the key lipid mediators in this process is therefore of great interest. Recent studies have identified diacylglycerols, as a molecular trigger for lipid-induced hepatic insulin resistance through activation of PKC-epsilon (PKCe) resulting in phosphorylation of insulin receptor Thr1160 and inhibition of insulin receptor kinase activity. In addition, alterations in hepatic acetyl-CoA, an allosteric activator of pyruvate carboxylase, have been shown to mediate insulin suppression of hepatic gluconeogenesis as well as promote increased rates of hepatic gluconeogenesis in patients with poorly controlled T2D. In support of these mechanisms recent studies have demonstrated the potential utility and safety of liver-targeted hepatic mitochondrial uncoupling as a novel therapeutic approach to treat NAFLD, NASH and T2D in rodent and non-human primates and reverse hepatic insulin resistance and diabetes by decreasing hepatic DAG-PKCe activity and reducing hepatic acetyl-CoA content.