The Pivotal Role of the Western Diet, Hyperinsulinemia, Ectopic Fat, and Diacylglycerol-Mediated Insulin Resistance in Type 2 Diabetes.

Genetic background, the "Western diet", and environment may all contribute to hyperinsulinemia. Hyperinsulinemia can precede and cause insulin resistance. In situations of fuel overload, insulin resistance limits the amount fuel (glucose and fatty acids) entering insulin-sensitive tissues. When energy intake is chronically greater than energy expenditure, the capacity of the subcutaneous fat tissues to store fat can be overpowered. If subcutaneous fat tissues are no longer able to accommodate excess energy, there will be spillover of lipids. Excess calories will be stored as ectopic fat (triglycerides) in the liver, pancreas, and skeletal muscle. Growing evidence suggests that ectopic fat deposition directly causes insulin resistance and pancreatic beta cell dysfunction. Overnutrition and ectopic fat increase diacylglycerol (DAG) accumulation in fat cells, hepatocytes, and skeletal muscle cells. A unifying hypothesis proposes that translocated DAG into the plasma membrane induces insulin resistance in all these three cell types. In addition, ectopic fat accumulation in the pancreas induces beta-cell dysfunction. Introducing a negative energy balance by bariatric surgery or a very low-calorie diet (VLCD) reduces ectopic fat depositions from the liver and pancreas and decreases intracellular DAG content: both are effective treatments to restore insulin sensitivity, normalize metabolism, and put type 2 diabetes in remission.