Abstract
Background/Aims: Insulin resistance in type 2 diabetes results from a combination of hyperglycemia and elevated free fatty acid (FFA) concentrations. However, the individual effects of glucotoxicity and lipotoxicity on cell function have not been determined. Methods: To compare the effects of increased FFAs and glucose levels on the PARP-NAD-SIRT1 pathway, which modulates insulin sensitivity, we cultured HepG2 hepatocytes with 300 or 500 µM oleic acid (OA) or 30 mM glucose for 1-4 days. PARP activity, NAD level, SIRT1 expression and insulin receptor phosphorylation were determined. Results: PARP activity was higher while NAD level and SIRT1 expression were lower in OA-treated cells than in control cells. Insulin receptor phosphorylation in response to insulin stimulation was attenuated under OA stimulation. Compared to glucose, OA produced a more rapid effect on the PARP-NAD-SIRT1 pathway in HepG2 cells. The reduction in SIRT1 expression and insulin receptor phosphorylation was similar in cells treated with 500 μM OA for 1 day and those treated with 30 mM glucose for 4 days. In addition to PARP activation, the LXRα activator T0901317 also affected SIRT1 expression. Conclusion: FFAs modulated cellular function through multiple ways, and induced more rapid and more potent cytotoxicity than glucose.
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