Free XXXX in @entity28 and @entity164 2 @entity6 : defining their role in the development of insulin resistance and beta-cell dysfunction.

@entity28 @entity6 @entity6334 @entity2368 @entity164 @entity1718 @entity413
Plasma free @entity1718 ( @entity6334 ) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma @entity6334 appear to have pathophysiological consequences. Elevated @entity6334 concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised @entity6334 in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that @entity6334 compete with @entity413 as the major energy substrate in cardiac muscle, leading to decreased @entity413 oxidation when @entity6334 are elevated. Recent data indicate that high plasma @entity6334 also have a significant role in contributing to insulin resistance. Elevated @entity6334 and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle @entity413 transport that may be mediated by a decrease in @entity2368 translocation. The resulting suppression of muscle @entity413 transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated @entity6334 may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous @entity413 production. @entity6334 also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that @entity6334 represent a crucial link between insulin resistance and beta-cell dysfunction and, as such, a reduction in elevated plasma @entity6334 should be an important therapeutic target in @entity28 and @entity164 2 @entity6 .
