Effects of conjugated linoleic acid and lipoic acid on insulin action in insulin-resistant obese zucker rats

Insulin-resistant conditions such as pre-diabetes and type 2 diabetes are characterized by defects in the ability of insulin to activate glucose transport in skeletal muscle. One animal model that has proven useful in elucidating the multifactorial etiology of skeletal muscle insulin resistance is the obese Zucker (fa/fa) rat, characterized by complete leptin resistance, massive central obesity, hyperinsulinemia, dyslipidemia, and oxidative stress (the imbalance between exposure of tissue to an oxidant stress and cellular antioxidant defenses). Studies published by our research group addressed the utility of two nutriceutical compounds, conjugated linoleic acid (CLA) and alpha-lipoic acid (ALA), both of which possess antioxidant properties, in improving the metabolic conditions of obese Zucker rats. These studies indicate that chronic administration of the R-enantiomer of ALA (R-ALA) to obese Zucker rats improved whole-body insulin sensitivity and enhanced the insulin-stimulated skeletal muscle glucose transport system, at least in part by up-regulation of IRS-1- dependent insulin signaling. CLA treatment of obese Zucker rats improved glucose tolerance and insulin-stimulated glucose transport activity, attributable exclusively to the trans-10, cis-12 isomer and associated with reductions in oxidative stress and muscle lipid levels. Significant interactions exist between CLA and R-ALA for enhancement of insulin action on skeletal muscle glucose transport in the obese Zucker rat, also ascribed to reductions in muscle oxidative stress and lipid storage. Collectively, these investigations support the fundamental concept that oxidative stress is an important component of the etiology of insulin resistance that can be beneficially modulated by antioxidant interventions, including CLA and ALA.