TNF-α-induced insulin resistance in vivo and its prevention by troglitazone

Philip D G Miles, Oreste M. Romeo, Katsuya Higo, Aaron Cohen-Gadol, Karim Rafaat, Jerrold M. Olefsky

Research output: Contribution to journalArticle

190 Citations (Scopus)

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 hyperinsulinemia 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-α 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 submaximal (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 fmol ATP/fmol IR, P <0.05). It also led to a marked increase in basal insulin (90 ± 24 vs. 48 ± 6 pmol/l, P <0.05) and free fatty acid (FFA) concentration (2.56 ± 0.76 vs. 0.87 ± 0.13 mmol/l, P <0.01). Troglitazone treatment completely prevented the TNFα-induced decline in submaximal GDR (133 ± 16 vs. 141 ± 4 μmol · kg- 1 · min-1, NS) and maximal GDR (271 ± 19 vs. 267 ± 6 μmol · kg-1 · min-1, NS). The hyperlipidemia was partially corrected by troglitazone (1.53 ± 0.28 vs. 0.87 ± 0.13 mmol/l, 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 obesity/NIDDM syndrome, troglitazone may prove useful in its treatment.

Original languageEnglish (US)
Pages (from-to)1678-1683
Number of pages6
JournalDiabetes
Volume46
Issue number11
StatePublished - Nov 1997
Externally publishedYes

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troglitazone
Insulin Resistance
Tumor Necrosis Factor-alpha
Insulin
Glucose
Type 2 Diabetes Mellitus
Nonesterified Fatty Acids
Obesity
Food
Glucose Clamp Technique
Insulin Receptor
Hyperinsulinism
Hyperlipidemias
Hypoglycemic Agents
Pharmaceutical Preparations
Sprague Dawley Rats
Animal Models
Adenosine Triphosphate

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Miles, P. D. G., Romeo, O. M., Higo, K., Cohen-Gadol, A., Rafaat, K., & Olefsky, J. M. (1997). TNF-α-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes, 46(11), 1678-1683.

TNF-α-induced insulin resistance in vivo and its prevention by troglitazone. / Miles, Philip D G; Romeo, Oreste M.; Higo, Katsuya; Cohen-Gadol, Aaron; Rafaat, Karim; Olefsky, Jerrold M.

In: Diabetes, Vol. 46, No. 11, 11.1997, p. 1678-1683.

Research output: Contribution to journalArticle

Miles, PDG, Romeo, OM, Higo, K, Cohen-Gadol, A, Rafaat, K & Olefsky, JM 1997, 'TNF-α-induced insulin resistance in vivo and its prevention by troglitazone', Diabetes, vol. 46, no. 11, pp. 1678-1683.
Miles PDG, Romeo OM, Higo K, Cohen-Gadol A, Rafaat K, Olefsky JM. TNF-α-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes. 1997 Nov;46(11):1678-1683.
Miles, Philip D G ; Romeo, Oreste M. ; Higo, Katsuya ; Cohen-Gadol, Aaron ; Rafaat, Karim ; Olefsky, Jerrold M. / TNF-α-induced insulin resistance in vivo and its prevention by troglitazone. In: Diabetes. 1997 ; Vol. 46, No. 11. pp. 1678-1683.
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