Relationship of Skeletal Muscle Insulin Resistance and Intramyocellular Lipid Accumulation

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It is well-established that intramyocellular triacylglycerol (IMTG) accumulation is associated with skeletal-muscle insulin resistance.10,56,73 However, it is unlikely that triacylglycerols are the culprit for reduced skeletal-muscle insulin action, but more likely they are an inert marker of other lipid intermediates known to suppress insulin sensitivity. An increase in the intramyocellular concentration of lipid intermediates such as fatty acyl-CoAs,50 ceramides,339 and diacylglycerols52 not only correlate with insulin resistance but also directly and indirectly alter insulin signaling.92 Considerable evidence linking increased skeletal-muscle lipid content to insulin resistance has been derived from animal studies employing acute and chronic high-fat diets.24 Fatty acid-induced insulin resistance appears to occur in concert with increased fatty acyl-CoAs.24 Moreover, insulin sensitivity is restored by treatments that reduce intramyocellular lipid accumulation (i.e., low-fat feeding and fasting).78 Similar findings have been observed in humans. Bachmann et al.8 reported significant increases in intramyocellular lipid content and reductions in insulin sensitivity following intravenous-lipid infusion. Ellis et al.31 demonstrated a negative correlation between insulin-mediated glucose disposal and fatty acyl-CoA content in skeletal muscle from a group of older men. Our laboratory observed blunted insulin-mediated glucose disposal in skeletal muscle from moderately and morbidly obese patients that was accompanied by elevated levels of intramyocellular fatty acyl-CoAs.50 After weight loss, insulin sensitivity was restored, and fatty acyl-CoA levels were also normalized.49 Thus, fatty acyl-CoAs, or a derived lipid, are related to, and possibly responsible for, muscle-insulin resistance.

Various intramyocellular lipid intermediates, such as fatty acyl-CoAs, ceramides, and diacylglycerols, inhibit specific steps in the insulin-signaling cascade.92 Ceramides activate a protein phosphatase that dephosphorylates Akt/PKB, resulting in inhibition of GLUT4 translocation and glycogen synthesis21- 68. Diacylglycerols have been implicated in the activation of PKC in various tissues.249299 Fatty acyl-CoAs have been shown to directly activate PKC in brain tissue15, 98, but these observations have yet to be observed in skeletal muscle. In models of high-fat exposure, intramyocellular fatty acyl-CoAs are elevated in concert with increased PKC activation.52 Moreover, fatty acyl-CoAs are also implicated in the indirect activation of PKC, as they are precursors for diacylglycerols formation. Diacylglycerol levels are elevated in many models of insulin resistance92, and these intermediates directly activate PKC,63,75

One of the difficulties with the lipotoxicity hypothesis of insulin resistance is the apparent paradox of increased IMTG in muscle of highly trained athletes, who are very insulin sensitive.37 However, the recent report by He, et al.43 may help to understand the role of muscle lipids in insulin resistance. They measured the size and quantity of mitochondria and lipid droplets in muscle from obese patients before and after weight loss and an endurance-exercise trial. After weight loss and exercise, the subjects improved insulin sensitivity by approximately 40 percent, but there was no change in the amount of intramuscular lipid. However, the mitochondria were larger, the lipid droplets were smaller, and the change in size of both mitochondria and lipid droplets correlated with the improvement in insulin sensitivity. They speculate that the smaller lipid droplets have a larger surface area that provides access for hydrolysis and utilization. In addition, the ratio of mitochondria to lipid droplets would also be important in the improved utilization of fat, which was characteristic of the subjects after weight loss and exercise.

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