Non-alcoholic fatty liver disease and insulin resistance

Non-alcoholic fatty liver disease (NAFLD) is considered the most common chronic liver disease, with estimated prevalence of around 30% in the United States, and is a major risk factor for the development of non-alcoholic steatohepatitis, cirrhosis, and liver-related death. Hepatic insulin resistance frequently accompanies NAFLD. This chapter reviews model for the pathogenesis of insulin resistance in the skeletal muscle, and discusses how insulin resistance in skeletal muscle may promote the development of NAFLD. Hyperinsulinemic-euglycemic clamp studies indicated that lipid-induced muscle insulin resistance occurs by a mechanism independent of the Randle glucose-fatty acid cycle. One model in which to study the mechanism for lipid-induced hepatic insulin resistance is the liver-specific lipoprotein lipase overexpressing mouse. The specific role of protein kinase C-e (PKCe) in the pathogenesis of hepatic insulin resistance was assessed using antisense oligonucleotides against PKCe. The chapter describes knowledge regarding the measurement, regulation, and significance of gluconeogenesis in the development of type 2 diabetes mellitus.