Role of the fatty liver (NAFLD) in the pathogenesis and treatment of Type II Diabetes
Several prospective studies have shown that fat accumulation in the liver due to non-alcoholic causes (NAFLD) preceeds and predicts type 2 diabetes and cardiovascular disease independent of obesity and even fat distribution, although individuals with a fatty liver tend to be more abdominally obese than those without. All components of the metabolic syndrome also correlate with liver fat independent of obesity. Both genetic and acquired factors regulate liver fat content. The heritability of liver fat based on twin studies is ~60%. The rs738409[G] allele in the PNPLA3 (adiponutrin) gene strongly associates with increased liver fat content in 3 different ethnic groups, also in Finns. Of acquired factors, changes in body weight markedly and rapidly change liver fat. Of dietary factors, diets rich in saturated fat and those stimulating de novo lipogenesis appear harmful. Regarding the mechanisms of fat accumulation in the liver, peripheral lipolysis is increased independent of obesity in subjects with NAFLD. In such subjects, adipose tissue in inflamed and insulin resistant and characterized by an excess of ceramides which could be mediators of high fat induced insulin resistance. In the human liver, there is an excess of triglycerides which contain saturated fatty acids, consistent with tracer studies that both increased adipose tissue lipolysis and de novo lipogenesis (which produces saturated fatty acids) contribute to excess fat accumulation in the liver. Liver fat content and inflammation can be reduced by PPARγ agonists. This effect is unlikely to be direct s PPARγ2 expression is increased and likely to involve adiponectin from adipose tissue. The main target of adiponectin is the liver and its circulating concentrations are markedly increased by PPARγ agonist therapy. Indeed patients who are very resistant to insulin because of a fatty liver or who have inflammatory changes in addition to increased fat content (NASH) might form a subgroup which benefit from PPARγ treatment. Liver fat is also the best preodctor of insulin requirements in type 2 diabetes. Simple equations to predict liver fat based on routinely available clinical data have recently been developed.