Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male Wistar rats

We sought to ascertain whether pretreatment with troglitazone (20 days) cou ld prevent acute free fatty acid (FFA)-induced insulin resistance in male W istar rats. Animals were divided into three groups: 1) control, 2) FFA infu sion alone (FFA1), and 3) thiazolidinedione (TZD)-treated + FFA infusion (F FA1). Days before a hyperinsulinemic-euglycemic clamp, all animals were can nulated in the jugular vein (infusion) and carotid artery (sampling). Anima ls were allowed 5 days to recover from surgery and fasted 12 h before the e xperiment. Glucose (variable), insulin (40 mU . kg(-1) . min(-1)), and Lipo syn (heparinized 10% lipid emulsion) infusions were initiated simultaneousl y 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 grou ps. Interestingly, steady-state FFA levels were significantly lower in anim als 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 seco nd group of TZD-treated animals (TZD + FFA2) were infused with intralipid a t 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) co mpared with control rats. In addition, insulin receptor substrate-1 (IRS-1) phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase ac tivity was significantly reduced, 30-50%, in FFAI rats. TZD pretreatment pr evented the FFA-induced decrement in insulin signaling. Fatty acid transloc ase (FAT/CD36) also was significantly reduced (56%) in untreated FFA1 rats after the clamp but remained identical to control values for TZD-treated ra ts. In conclusion, acutely elevated FFA levels 1) induced a significant red uction in tracer-determined GDR paralleled by impaired tyrosine phosphoryla tion of IRS-1 and reduced IRS-1-associated PI 3-kinase activity and 2) indu ced a significant reduction in FAT/CD36 total protein. TZD pretreatment pre vented FFA-induced decrements in insulin action and prevented the reduction in FAT/CD36 protein.