Excessive accumulation of
triglycerides and certain
fatty acid derivatives in skeletal muscle and other tissues appears to mediate many of the adverse effects of
insulin resistance syndrome. Although fatty diets and
obesity can promote such accumulation, deficient capacity for
fatty acid oxidation can also contribute in this regard. Indeed, in subjects who are
insulin resistant, diabetic, and/or obese,
fatty acid oxidation by skeletal muscle tends to be inefficient, reflecting decreased expression of mitochondria and mitochondrial
enzymes in muscle. This phenomenon is not corrected by
weight loss, is not simply reflective of subnormal physical activity, and is also seen in lean first-degree relatives of diabetics; thus, it appears to be primarily attributable to genetic factors. Recent studies indicate that decreased expression of
PPARgamma coactivator-1alpha (PGC-1alpha), a "master switch" which induces mitochondrial biogenesis by supporting the transcriptional activity of the
nuclear respiratory factors, may largely account for the diminished oxidative capacity of subjects prone to
insulin resistance. Thus, feasible measures which up-regulate PGC-1alpha may be useful for preventing and treating
insulin resistance and
obesity. These may include exercise training,
metformin and other agents which stimulate
AMP-activated kinase, high-dose
biotin, and
PPARdelta agonists. Drugs which are specific agonists for
PPARdelta show remarkable efficacy in rodent models of
insulin resistance, diabetes, and
obesity, and are currently being evaluated clinically.
Phytanic acid, a branched-chain
fatty acid found in omnivore diets, can also activate
PPARdelta, and thus should be examined with respect to its impact on mitochondrial biogenesis and
insulin sensitivity.