Oxidative stress has been implicated in glucose toxicity. We tested the hypothesis that certain antioxidants may prevent insulin-resistant glucose transport that develops in adipocytes after sustained exposure to high glucose, provided insulin is present. The antioxidant α-lipoic acid has been proposed as an insulin sensitizer. 3T3-L1 adipocytes were preincubated 18 hours in media containing insulin (0.6 nmol/L) with low (5 mmol/L) or high (25 mmol/L) glucose with or without α-lipoate, dihydrolipoate (each 0.1 to 0.5 mmol/L), or N-acetylcysteine (1 to 5 mmol/L). After extensive re-equilibration in insulin and antioxidant-free media, basal and maximally insulin-stimulated (100 nmol/L) glucose transport was measured. Insulin was quantified by radioimmunoassay. Preincubation with α-lipoate and dihydrolipoate but not N-acetylcysteine increased subsequent basal glucose transport; the effect was much smaller than that of acute maximal insulin stimulation. Preincubation in high glucose without antioxidants inhibited acutely insulin-stimulated glucose transport by 40% to 50% compared with low glucose. This down-regulation was partially or completely prevented by each antioxidant. In cell-free media, the 2 reductants, dihydrolipoate and N-acetylcysteine, rapidly decreased immunoreactive insulin, but α-lipoate was ineffective. However, during incubation with adipocytes, α-lipoate, and dihydrolipoate promoted the decline in immunoreactive insulin nearly equally. Because insulin and high glucose are synergistic in inducing insulin resistance in this model, the reduction in immunoreactive insulin probably contributed to the protective effect of the antioxidants. 3T3-L1 adipocytes efficiently metabolize α-lipoate to dihydrolipoate, which may be released into the medium. The stimulation of glucose transport by α-lipoic acid may represent redox effects in subcellular compartments that are accessible to dihydrolipoate.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism