title: JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, improves hyperglycemia and dyslipidemia independent of suppression of food intake in diabetic rats.
abstract: We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group. RESULTS. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment. CONCLUSIONS. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.
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: Makoto
authors.initials: M
authors.lastname: Ito
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: Tomohiko
authors.initials: T
authors.lastname: Sasase
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yamamoto
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.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048909:Diabetes Complications / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000097:blood / Q000378:metabolism; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008314:Malonates / Q000627:therapeutic use*; D009765:Obesity / Q000150:complications; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001549:Benzamides; D002352:Carrier Proteins; D005765:Gastrointestinal Agents; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008314:Malonates; 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