title: Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight.
abstract: OBJECTIVE
  To test the antidiabetic efficacy of ibipinabant, this new cannabinoid receptor 1 (CB1) antagonist was compared with food-restriction-induced weight loss, rosiglitazone (4 mg/kg) and rimonabant (3 and 10 mg/kg), using parameters of glycaemic control in male Zucker diabetic fatty (ZDF) rats.
  
  
  METHODS
  Body weight, food and water intake, fasted and non-fasted glucose and insulin, glucose tolerance and glycosylated haemoglobin (HbA1c) were all assessed over the course of the 9-week study. Pancreatic insulin content and islet area were also evaluated.
  
  
  RESULTS
  At the end of the study, vehicle-treated ZDF rats were severely hyperglycaemic and showed signs of β-cell decline, including dramatic reductions in unfasted insulin levels. Ibipinanbant (10 mg/kg) reduced the following relative to vehicle controls: fasting glucose (-61%), glucose excursion area under the curve (AUC) in an oral glucose tolerance test (OGTT, -44%) and HbA1c (-50%). Furthermore, non-fasting insulin, islet area and islet insulin content were all increased (71, 40 and 76%, respectively) relative to vehicle controls by the end of the study. All of these effects were similar to those of rimonabant and rosiglitazone, where ibipinabant was slightly more effective than rimonabant at the lowest dose and somewhat less effective than rosiglitazone at all doses. These antidiabetic effects appear independent of weight loss because none of the parameters above were consistently improved by the comparable weight loss induced by food restriction.
  
  
  CONCLUSIONS
  Ibipinabant may have weight loss-independent antidiabetic effects and may have the potential to attenuate β-cell loss in a model of progressive β-cell dysfunction.
authors.affiliation: Department of Metabolic Research, Bristol-Myers Squibb Co., Hopewell, NJ, USA.
authors.forename: K
authors.initials: K
authors.lastname: Rohrbach
authors.forename: M A
authors.initials: MA
authors.lastname: Thomas
authors.forename: S
authors.initials: S
authors.lastname: Glick
authors.forename: E N
authors.initials: EN
authors.lastname: Fung
authors.forename: V
authors.initials: V
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Watson
authors.forename: P
authors.initials: P
authors.lastname: Gregory
authors.forename: J
authors.initials: J
authors.lastname: Antel
authors.forename: M A
authors.initials: MA
authors.lastname: Pelleymounter
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D031204:Caloric Restriction; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D000578:Amidines; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D011720:Pyrazoles; C569626:ibipinabant