A new antidiabetic agent (JTT-501) rapidly stimulates glucose disposal rates by enhancing insulin signal transduction in skeletal muscle |
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Authors: | H Maegawa T Obata T Shibata T Fujita S Ugi K Morino Y Nishio H Kojima H Hidaka M Haneda H Yasuda R Kikkawa A Kashiwagi |
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Institution: | (1) Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520–2192, Japan, JP;(2) Japan Tabacco Inc., Central Pharmaceutical Institute, Takatsuki, Osaka, 569–11, Japan, JP |
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Abstract: | Summary A newly synthesized antidiabetic agent, JTT-501 is an isoxazolidinedione rather than a thiazolidinedione. An oral dose of
JTT-501 (100 mg · kg–1· day–1) given to 12-week-old male Zucker fatty rats for 7 days led to the amelioration of both hyperinsulinaemia (40 % of non-treated)
and hypertriglyceridaemia (23 % of non-treated) as well as a 2.4-fold increased insulin sensitivity as determined by a euglycaemic
insulin clamp. In our study, we further evaluated the acute effect of JTT-501 on both the glucose infusion rates (GIR) and
insulin signalling in skeletal muscle. Male Sprague-Dawley (SD) rats aged 10 weeks were injected intravenously with JTT-501
(5 mg/kg) and then a euglycaemic insulin clamp was initiated and glucose infusion rates monitored for 150 min. We found that
this treatment increased the glucose infusion rate by 33 % during the last 30 min in SD rats. After the clamp had been initiated
for 30 min, the insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activities co-immunoprecipitated with insulin
receptor substrate 1 (IRS-1) were also enhanced, resulting in increased glycogen synthase activities in the soleus muscles.
Treatment with JTT-501 also enhanced the phosphorylation of insulin receptors and insulin receptor-substrate 1 rapidly as
well as the phosphatidylinositol 3-kinase activities, which were stimulated by a bolus injection of insulin. Similarly, JTT-501
stimulated the glucose infusion rate by 30 % and enhanced insulin signalling in Zucker fatty rats. In conclusion, a newly
developed isoxazolidinedione, JTT-501, rapidly potentiates the insulin sensitivity of skeletal muscle by enhancing insulin
signalling and could be useful for the treatment of insulin-resistant diabetic subjects. Diabetologia (1999) 42: 151–159]
Received: 2 June 1998 and in final revised form: 2 October 1998 |
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Keywords: | Euglycaemic insulin clamp insulin sensitizer isoxazolidinedione insulin signaling JTT-501 |
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