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Original Articles

TNF-α-Induced Insulin Resistance In Vivo and Its Prevention by Troglitazone

  1. Philip D G Miles,
  2. Oreste M Romeo,
  3. Katsuya Higo,
  4. Aaron Cohen,
  5. Karim Rafaat and
  6. Jerrold M Olefsky
  1. Departments of Surgery, University of California San Diego
  2. Departments of Medicine, University of California San Diego
  3. San Diego VA Medical Center, Division of Endocrinology and Metabolism La Jolla, California
  1. Address correspondence and reprint requests to Dr. Philip D.G. Miles, Department of Surgery (8400), UCSD Medical Center, 200 West Arbor Dr., San Diego, CA 92103. E-mail: pmiles{at}ucsd.edu.
Diabetes 1997 Nov; 46(11): 1678-1683. https://doi.org/10.2337/diab.46.11.1678
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Abstract

Tumor necrosis factor (TNF)-α may play a role in the insulin resistance of obesity and NIDDM. Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsu-linemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of TNF-α-induced insulin resistance, glucose turnover was assessed in rats infused with cytokine and pretreated with troglitazone. Normal male Sprague-Dawley rats were fed normal powdered food with or without troglitazone as a food admixture (0.2%). After ∼10 days, rats were infused with TNF-a for 4–5 days, producing a plasma concentration of 632 ± 30 pg/ml. In vivo insulin action was measured by the euglycemic-hyperinsulinemic clamp technique at a sub-maximal (24 μmol · kg−1 · min−1) and maximal insulin infusion rate (240 μmol · kg−1 · min−1). TNF-α infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 ± 10 vs. 141 ± 4 μmol · kg−1 · min−1 P < 0.05), maximal GDR (175 ± 8 vs. 267 ± 6 μmol · kg−1 · min−1 P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 ± 39 vs. 406 ± 32 pmol ATP/pmol IR, P < 0.05). It also led to a marked increase in basal insulin (90 ± 24 vs. 48 ± 6 pmol/1, P < 0.05) and free fatty acid (FFA) concentration (2.56 ± 0.76 vs. 0.87 ± 0.13 mmol/1, p < 0.01). Troglitazone treatment completely prevented the TNF-α-induced decline in submaximal GDR (133 ± 16 vs. 141 ± 4 umol · kg−1 · min−1, NS) and maximal GDR (271 ± 19 vs. 267 ± 6 μmol · kg1 · min1, NS). The hyperlipidemia was partially corrected by troglitazone (1.53 ± 0.28 vs. 0.87 ± 0.13 mmol/1, P < 0.05), while IR-TKA and insulin concentration remained unaffected by the drug. Troglitazone restores insulin action possibly by lowering the FFA concentration of the blood and/or by stimulating glucose uptake at an intracellular point distal to insulin receptor autophosphorylation in muscle. If TNF-α plays a role in the development of the obe-sity/NIDDM syndrome, troglitazone may prove useful in its treatment.

  • Received April 13, 1997.
  • Revision received June 24, 1997.
  • Accepted June 24, 1997.
  • Copyright © 1997 by the American Diabetes Association

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November 1997, 46(11)
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TNF-α-Induced Insulin Resistance In Vivo and Its Prevention by Troglitazone
Philip D G Miles, Oreste M Romeo, Katsuya Higo, Aaron Cohen, Karim Rafaat, Jerrold M Olefsky
Diabetes Nov 1997, 46 (11) 1678-1683; DOI: 10.2337/diab.46.11.1678

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TNF-α-Induced Insulin Resistance In Vivo and Its Prevention by Troglitazone
Philip D G Miles, Oreste M Romeo, Katsuya Higo, Aaron Cohen, Karim Rafaat, Jerrold M Olefsky
Diabetes Nov 1997, 46 (11) 1678-1683; DOI: 10.2337/diab.46.11.1678
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