title: Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist.
abstract: OBJECTIVE
  Inhibition of transient receptor potential vanilloid 1 (TRPV1) suppresses calcitonin gene-related peptide (CGRP) secretion in pancreatic nerve fiber cells, thereby stimulating insulin secretion. We examined the effects of repeat administration of the TRPV1 antagonist N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamidte monohydrochloride (BCTC) to ob/ob mice, a model of type 2 diabetes with insulin resistance, on whole body glucose and lipid metabolism.
  
  
  METHODS
  We measured blood parameters, including levels of glucose, insulin, and triglycerides, and performed the oral glucose tolerance test (OGTT) after repeat administration of BCTC to ob/ob mice twice a day for four weeks.
  
  
  RESULTS
  We found that BCTC treatment reduced fasting glucose, triglyceride, and insulin levels in the whole body. The effects were comparable to that of pioglitazone, a major insulin-sensitizing agent. Further, we found that administration of BCTC significantly increased plasma insulin secretion in the OGTT, which differed from the effect of pioglitazone treatment.
  
  
  CONCLUSIONS
  Our study is the first to show the anti-diabetic pharmacological effects of the TRPV1 signal inhibitor BCTC. These findings suggest that TRPV1 antagonists may represent a new class of drugs effective in treating type 2 diabetes mellitus because of their dual effects as insulin sensitizers and secretagogues.
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. hirotsugu.tanaka@jp.astellas.com
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Shimaya
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kiso
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuramochi
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Shimokawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D011719:Pyrazines; D011725:Pyridines; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D015740:Calcitonin Gene-Related Peptide