title: Chronic treatment with a glucagon receptor antagonist lowers glucose and moderately raises circulating glucagon and glucagon-like peptide 1 without severe alpha cell hypertrophy in diet-induced obese mice.
abstract: OBJECTIVE
  Antagonism of the glucagon receptor (GCGR) represents a potential approach for treating diabetes. Cpd-A, a potent and selective GCGR antagonist (GRA) was studied in preclinical models to assess its effects on alpha cells.
  
  
  METHODS
  Studies were conducted with Cpd-A to examine the effects on glucose-lowering efficacy, its effects in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor, and the extent and reversibility of alpha cell hypertrophy associated with GCGR antagonism in mouse models.
  
  
  RESULTS
  Chronic treatment with Cpd-A resulted in effective and sustained glucose lowering in mouse models in which endogenous murine Gcgr was replaced with human GCGR (hGCGR). Treatment with Cpd-A also led to stable, moderate elevations in both glucagon and glucagon-like peptide 1 (GLP-1) levels, which were completely reversible and not associated with a hyperglycaemic overshoot following termination of treatment. When combined with a DPP-4 inhibitor, Cpd-A led to additional improvement of glycaemic control correlated with elevated active GLP-1 levels after glucose challenge. In contrast to Gcgr-knockout mice in which alpha cell hypertrophy was detected, chronic treatment with Cpd-A in obese hGCGR mice did not result in gross morphological changes in pancreatic tissue.
  
  
  CONCLUSIONS
  A GRA lowered glucose effectively in diabetic models without significant alpha cell hypertrophy during or following chronic treatment. Treatment with a GRA may represent an effective approach for glycaemic control in patients with type 2 diabetes, which could be further enhanced when combined with DPP-4 inhibitors.
authors.affiliation: Merck, RY80N-A58, 126 East Lincoln Avenue, Rahway, NJ, USA. yingjun_mu@merck.com
authors.forename: J
authors.initials: J
authors.lastname: Mu
authors.forename: G
authors.initials: G
authors.lastname: Jiang
authors.forename: E
authors.initials: E
authors.lastname: Brady
authors.forename: Q
authors.initials: Q
authors.lastname: Dallas-Yang
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Woods
authors.forename: E
authors.initials: E
authors.lastname: Zycband
authors.forename: M
authors.initials: M
authors.lastname: Wright
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Lu
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.forename: R
authors.initials: R
authors.lastname: Sinharoy
authors.forename: M L
authors.initials: ML
authors.lastname: Candelore
authors.forename: S A
authors.initials: SA
authors.lastname: Qureshi
authors.forename: D-M
authors.initials: DM
authors.lastname: Shen
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: E R
authors.initials: ER
authors.lastname: Parmee
authors.forename: B B
authors.initials: BB
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced; D004041:Dietary Fats / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000097:blood*; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D050416:Glucagon-Secreting Cells / Q000473:pathology*; D006984:Hypertrophy; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood* / Q000209:etiology / Q000473:pathology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D018027:Receptors, Glucagon; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon