Ectopic fat is an important cause for insulin resistance. The cause for ectopic fat storage is largely unkown, failure of fat cell proliferation, mitochondrial function and fat oxidation, endocrine hypothesis, and alterations in CD36 content in adipose tissue, muscle, and presumably liver might all contribute to the association between ectopic fat distribution and metabolic disease. However, many different mechanisms that explain insulin resistance in obesity have been proposed, More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatotic liver is also resistant to insulin in terms of stimulation of hepatic glucose production and inhibition of glycogen synthesis. Inflammation, endoplasmicreticulum stress and adipokines have roles in the pathogenesis of insulin resistance in liver and skeletal muscle. However, these do not change in lean insulin-resistant young and elderly individuals. In muscle and liver, the intracellular accumulation of lipids—namely, diacylglycerol—triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing.
