Xiao C, Giacca A, Lewis GF. Short-term oral ␣-lipoic acid does not prevent lipid-induced dysregulation of glucose homeostasis in obese and overweight nondiabetic men. Prolonged elevation of plasma free fatty acids (FFAs) induces insulin resistance and impairs pancreatic ␤-cell adaptation to insulin resistance. The mechanisms whereby lipid induces these impairments are not fully defined but may involve oxidative stress, inflammation, and endoplasmic reticulum stress. ␣-Lipoic acid (ALA), a

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... ly used health supplement with antioxidant, anti-inflammatory, and AMPK-activating properties, has been shown to have therapeutic value in type 2 diabetes and its complications. Here we examined the effects of ALA on insulin sensitivity and secretion in humans under the conditions of 24-h iv lipid infusion to elevate plasma FFAs. Eight overweight and obese male subjects underwent four randomized studies each, 4 -6 wk apart: 1) SAL, 2-wk oral placebo followed by 24-h iv infusion of saline; 2) IH, 2-wk placebo followed by 24-h iv infusion of intralipid plus heparin to raise plasma FFAs approximately twofold; 3) IH ϩ ALA, 2-wk ALA (1,800 mg/day) followed by 24-h infusion of intralipid plus heparin; and 4) ALA, 2-wk ALA followed by 24-h infusion of saline. Insulin secretion rates (ISR) and insulin sensitivity were assessed with a 2-h, 20-mmol/l hyperglycemic clamp and a hyperinsulinemic euglycemic clamp, respectively. ISR was not significantly different between treatments. Lipid infusion impaired insulin sensitivity with and without ALA pretreatment. These results indicate that ALA, administered orally at this dose for 2 wk, does not protect against lipid-induced insulin resistance in overweight and obese humans.