title: JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, ameliorates impaired glucose and lipid metabolism in Zucker diabetic fatty rats.
abstract: OBJECTIVE
  Microsomal triglyceride transfer protein (MTP) takes part in the mobilization of triglyceride-rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT-130, a novel intestine-specific MTP inhibitor, on impaired glucose and lipid metabolism in Zucker diabetic fatty (ZDF) rats.
  
  
  METHODS
  Male ZDF rats were fed a regular powdered diet with or without JTT-130 as a food admixture (0.01-0.02%) for 6 weeks. Food intake, body weight, blood biochemical parameters, fecal lipid contents, hepatic lipid contents, tissue mRNA levels and glucose utilization in adipose tissues were assessed. An intraperitoneal glucose tolerance test (IPGTT) and histological analysis of the pancreas were performed.
  
  
  RESULTS
  JTT-130 treatment decreased food intake, glycated hemoglobin, plasma levels of glucose, triglycerides and total cholesterol, hepatic levels of triglycerides and cholesterol and hepatic mRNA levels of glucose-6-phosphatase, phosphoenolpyruvate carboxykinase and fructose-1,6-bisphosphatase. JTT-130 treatment increased fecal levels of free fatty acids and cholesterol, plasma levels of glucagon-like peptide-1 and peptide YY, mRNA levels of glucose transporter 4 (GLUT4) and lipoprotein lipase in adipose tissues and GLUT4 in muscle and glucose utilization in adipose tissues. Plasma insulin decreased after 2 weeks and increased after 4 weeks of JTT-130 treatment. Plasma glucose in the JTT-130-treated rats was lower with higher plasma insulin than in the control rats during the IPGTT. The islets of the JTT-130-treated rats were larger and contained more insulin than those of the control rats.
  
  
  CONCLUSIONS
  JTT-130 ameliorates impaired glucose and lipid metabolism in the ZDF rats thereby suggesting that JTT-130 could be useful for prevention and treatment of type 2 diabetes.
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan. takahiro.hata@jt.com
authors.forename: T
authors.initials: T
authors.lastname: Hata
authors.forename: Y
authors.initials: Y
authors.lastname: Mera
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.forename: Y
authors.initials: Y
authors.lastname: Ishii
authors.forename: Y
authors.initials: Y
authors.lastname: Kuroki
authors.forename: K
authors.initials: K
authors.lastname: Kakimoto
authors.forename: T
authors.initials: T
authors.lastname: Ohta
authors.forename: M
authors.initials: M
authors.lastname: Kakutani
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004435:Eating; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin; D007328:Insulin / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008314:Malonates / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001549:Benzamides; D002352:Carrier Proteins; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D006442:Glycated Hemoglobin; 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