Perspective:

The following are 10 points to remember from this review article:

1. Type 2 diabetes currently affects more than a third of a billion people worldwide and is the leading cause of end-stage renal disease, nontraumatic loss of limb, and blindness in working adults, with estimated annual worldwide health care costs exceeding half a trillion dollars.

2. Although impaired beta-cell function is ultimately responsible for the progression from normoglycemia to hyperglycemia, insulin resistance predates beta-cell dysfunction and plays a major role in the pathogenesis of type 2 diabetes.

3. The association between excess lipid storage in the form of obesity and insulin resistance has long been recognized, and proton (¹H) MRS studies have shown an even stronger relationship between intramyocellular lipid content and insulin resistance in muscle.

4. Accumulation of an intracellular lipid metabolite mediates insulin resistance associated with obesity and type 2 diabetes by causing defects in insulin signaling and reduced insulin-stimulated glucose-transport activity.

5. The most common cause of ectopic lipid deposition in skeletal muscle and the liver is a level of energy intake that exceeds the level of energy expenditure, resulting in spillover of energy storage from adipose tissue to the liver and skeletal muscle.

6. Studies show that ectopic accumulation of intracellular lipid leads to insulin resistance in muscle and the liver even in the absence of peripheral and visceral adiposity and that myocellular diacylglycerol (DAG)s are the lipid-derived metabolites responsible for triggering insulin resistance through activation of protein kinase C (PKC)ε in the liver and PKCθ in muscle.

7. Acquired mitochondrial dysfunction has been shown to be an important predisposing factor for ectopic lipid accumulation and insulin resistance in the elderly.

8. Preserving mitochondrial function by reducing mitochondrial oxidative damage may be a therapeutic target for preventing age-associated reduction in muscle mitochondrial function, insulin resistance in muscle, and type 2 diabetes in the elderly.

9. Macrophage-induced lipolysis, as opposed to alterations in circulating cytokines and hepatic gluconeogenic protein transcription, may be the major culprit in the transition from insulin resistance to impaired glucose tolerance and type 2 diabetes.

10. Increasing hepatic energy expenditure by promoting mitochondrial uncoupling could be a novel approach for treating the related epidemics of nonalcoholic fatty liver disease, the metabolic syndrome, and type 2 diabetes.