Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male wistar rats.
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.
Hevener
A L
AL
Department of Medicine, University of California, San Diego, La Jolla, California 92093-0673, USA.
Reichart
D
D
Janez
A
A
Olefsky
J
J
D000818:Animals; D018955:CD36 Antigens; D002839:Chromans / Q000494:pharmacology*; D004655:Emulsions; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D054709:Lecithins; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D018482:Muscle, Skeletal / Q000187:drug effects; D027361:Organic Anion Transporters; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D012450:Safflower Oil; D013024:Soybean Oil; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists; D000077288:Troglitazone; D014443:Tyrosine / Q000378:metabolism
D018955:CD36 Antigens; D002839:Chromans; D004655:Emulsions; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D054709:Lecithins; D008024:Ligands; D008562:Membrane Glycoproteins; D027361:Organic Anion Transporters; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C031435:safflower oil, soybean oil, lecithin emulsion; D014443:Tyrosine; D013024:Soybean Oil; D012450:Safflower Oil; D000077288:Troglitazone; D005947:Glucose