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© 2001 by the American Diabetes Association, Inc.
Thiazolidinedione Treatment Prevents Free Fatty Acid–Induced Insulin Resistance in Male Wistar Rats
1 Department of Medicine, University of California, San Diego, La Jolla, California
2 Veterans Administration, San Diego Health Care System, Research Service, San Diego, California
We sought to ascertain whether pretreatment with troglitazone (20 days) could prevent acute free fatty acid (FFA)–induced insulin resistance in male Wistar rats. Animals were divided into three groups: 1) control, 2) FFA infusion alone (FFA1), and 3) thiazolidinedione (TZD)-treated + FFA infusion (FFA1). Days before a hyperinsulinemic-euglycemic clamp, all animals were cannulated in the jugular vein (infusion) and carotid artery (sampling). Animals were allowed 5 days to recover from surgery and fasted 12 h before the experiment. Glucose (variable), insulin (40 mU · kg-1 · min-1), and Liposyn (heparinized 10% lipid emulsion) infusions were initiated simultaneously and continued from 0–120 min. Steady-state glucose, 8.3 ± 0.14 mmol/l, and insulin concentrations, 7.3 ± 2.45 nmol/l, were the same between groups. Interestingly, steady-state FFA levels were significantly lower in animals pretreated with TZD compared with FFA alone (1.83 ± 0.26 vs. 2.96 ± 0.25 mmol/l; P = 0.009), despite matched intralipid infusion rates. A second group of TZD-treated animals (TZD + FFA2) were infused with intralipid at a higher infusion rate (44%) to match the arterial concentrations of FFA1. The glucose infusion and insulin-stimulated glucose disposal rates (GDRs) were significantly decreased (40%) for untreated Liposyn infused (FFA1) compared with control rats. In addition, insulin receptor substrate-1 (IRS-1) phosphorylation and IRS-1–associated phosphatidylinositol (PI) 3-kinase activity was significantly reduced, 30–50%, in FFA1 rats. TZD pretreatment prevented the FFA-induced decrement in insulin signaling. Fatty acid translocase (FAT/CD36) also was significantly reduced (56%) in untreated FFA1 rats after the clamp but remained identical to control values for TZD-treated rats. In conclusion, acutely elevated FFA levels 1) induced a significant reduction in tracer-determined GDR paralleled by impaired tyrosine phosphorylation of IRS-1 and reduced IRS-1–associated PI 3-kinase activity and 2) induced a significant reduction in FAT/CD36 total protein. TZD pretreatment prevented FFA-induced decrements in insulin action and prevented the reduction in FAT/CD36 protein.
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