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.
Diabetologia
; 54(9): 2381-91, 2011 Sep.
Article
em En
| MEDLINE
| ID: mdl-21695571
ABSTRACT
AIMS/HYPOTHESIS:
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/INTERPRETATION:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glicemia
/
Glucagon
/
Receptores de Glucagon
/
Células Secretoras de Glucagon
/
Peptídeo 1 Semelhante ao Glucagon
/
Obesidade
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Diabetologia
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos