JTT-501, a novel oral antidiabetic agent, improves insulin resistance in genetic and non-genetic insulin-resistant models.
1. We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxa  zolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. 2. JTT-501 (10-100 mg kg(-1) day(-1)) was administered orally to Zucker fatty rats for 7-21 days. In the high-fat fed rat model, JTT-501 (100 mg kg(-1) day(-1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. 3. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. 4. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.
Shibata
T
T
Japan Tobacco, Inc., Central Pharmaceutical Research Institute, Takatsuki, Osaka.
Matsui
K
K
Yonemori
F
F
Wakitani
K
K
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D020738:Leptin; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000235:genetics; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D007555:Isoxazoles; D020738:Leptin; D008055:Lipids; D011506:Proteins; D014280:Triglycerides; D011972:Receptor, Insulin; D005947:Glucose; C112329:JTT 501