Role of JTT-501, a new insulin sensitiser, in restoring impaired GLUT4 translocation in adipocytes of rats fed a high fat diet

J. Terasaki, M. Anai, M. Funaki, T. Shibata, K. Inukai, T. Ogihara, H. Ishihara, H. Katagiri, Y. Onishi, H. Sakoda, Y. Fukushima, Y. Yazaki, M. Kikuchi, Y. Oka, T. Asano

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24 Citations (Scopus)

Abstract

JTT-501 is an insulin-sensitising compound with an isoxazolidinedione rather than a thiazolidionedione structure. Sprague-Dawley rats fed a high fat diet for 2 weeks were used as an animal model of insulin resistance, and JTT-501 was administered for the final week of the diet. An euglycaemic glucose clamp study showed that the glucose infusion rate (GIR) required to maintain euglycaemia was 57% lower in rats fed a high fat diet than in control rats, and that JTT-501 treatment restored the reduction in GIR produced by the high fat diet. To explain the mechanisms underlying the effects of a high fat diet and JTT-501 treatment, epididymal fat pads were excised and used in the analysis of insulin action. The high fat diet caused: (1) a 58% decrease in insulin receptor substrate-1 (IRS-1) content with a 58% decrease in IRS-1 tyrosine phosphorylation; (2) reductions of 56% and 73% respectively in insulin-induced maximal PI 3-kinase activation in anti- phosphotyrosine and anti-IRS-1 antibody immunoprecipitates; (3)a 46% reduction in the glucose transporter protein, GLUT4 content and, consequently, (4)severely impaired insulin-induced GLUT4 translocation to the plasma membrane and glucose uptake in adipocytes. JTT-501 treatment restored appreciably the protein content and tyrosine phosphorylation level of IRS-1. Insulin-stimulated PI 3-kinase activation was also restored in anti- phosphotyrosine and anti-IRS-1 antibody immunoprecipitates. As reflected by these improvements in insulin signalling, JTT-501 treatment improved considerably insulin-induced GLUT4 translocation to the plasma membrane as well as insulin-induced glucose uptake. However, JTT-501 had no effect on the decrease in GLUT4 content produced by the high fat diet. These observations suggest that JTT-501 enhances insulin signalling and may be effective in reducing insulin resistance.

Original languageEnglish
Pages (from-to)400-409
Number of pages10
JournalDiabetologia
Volume41
Issue number4
DOIs
Publication statusPublished - 1998
Externally publishedYes

Keywords

  • Adipocyte
  • GLUT4
  • High fat diet
  • Insulin sensitiser
  • Isoxazolidinedione
  • JTT- 501
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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