title: Mechanism of action of hypoglycemic effects of an intestine-specific inhibitor of microsomal triglyceride transfer protein (MTP) in obese rats.
abstract: Diminished insulin sensitivity in the peripheral tissues and failure of pancreatic beta cells to secrete insulin are known major determinants of type 2 diabetes mellitus. JTT-130, an intestine-specific microsomal transfer protein inhibitor, has been shown to suppress high fat-induced obesity and ameliorate impaired glucose tolerance while enhancing glucagon-like peptide-1 (GLP-1) secretion. We investigated the effects of JTT-130 on glucose metabolism and elucidated the mechanism of action, direct effects on insulin sensitivity and glucose-stimulated insulin secretion in a high fat diet-induced obesity rat model. Male Sprague Dawley rats fed a high-fat diet were treated with a single administration of JTT-130. Glucose tolerance, hyperglycemic clamp and hyperinsulinemic-euglycemic testing were performed to assess effects on insulin sensitivity and glucose-stimulated insulin secretion, respectively. Plasma GLP-1 and tissue triglyceride content were also determined under the same conditions. A single administration of JTT-130 suppressed plasma glucose elevations after oral glucose loading and increased the disposition index while elevating GLP-1. JTT-130 also enhanced glucose-stimulated insulin secretion in hyperglycemic clamp tests, whereas increased insulin sensitivity was observed in hyperinsulinemic-euglycemic clamp tests. Single-dose administration of JTT-130 decreased lipid content in the liver and skeletal muscle. JTT-130 demonstrated acute and direct hypoglycemic effects by enhancing insulin secretion and/or insulin sensitivity.
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Sakata
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Katsumi
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Mera
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Yukiharu
authors.initials: Y
authors.lastname: Kuroki
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nashida
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kakutani
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: takeshi.ota@jt.com.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D059305:Diet, High-Fat; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000494:pharmacology* / Q000627:therapeutic use; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001549:Benzamides; D001786:Blood Glucose; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D008314:Malonates; D014280:Triglycerides; C556241:diethyl 2-((3-dimethylcarbamoyl-4-((4'-trifluoromethylbiphenyl-2-carbonyl)amino)phenyl)acetyloxymethyl)-2-phenylmalonate; C106092:microsomal triglyceride transfer protein; D052216:Glucagon-Like Peptide 1
keywords: Glucose-stimulated insulin secretion; High fat-induced obesity; Insulin sensitivity; JTT-130; Microsomal triglyceride transfer protein