Other
19 Authors
- Mu J,
- Shen X,
- Brady E,
- Li Z,
- Parmee ER,
- Zhang F,
- Candelore ML,
- Liu F,
- Lu K,
- Shen DM,
- Zhu L,
- Woods J,
- Wright M,
- Qureshi SA,
- Sinharoy R,
- Jiang G,
- Zhang BB,
- Zycband E,
- Dallas-Yang Q
| First Author | Mu J | Year | 2011 |
| Journal | Diabetologia | Volume | 54 |
| Issue | 9 | Pages | 2381-91 |
| PubMed ID | 21695571 | Mgi Jnum | J:174844 |
| Mgi Id | MGI:5141329 | Doi | 10.1007/s00125-011-2217-2 |
| Citation | Mu J, et al. (2011) 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 |
| abstractText | 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. |
