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.