BACKGROUND: Stable glucagon-like peptide-1 (GLP-1) mimetics, such as the GLP-1 analogue liraglutide, are approved for treatment of type 2 diabetes. GLP-1 has a spectrum of anti-diabetic effects that are of possible utility in the treatment of more severe forms of diabetes.METHODS: The present study has evaluated the effect of once daily liraglutide injection (25 nmol/kg bw) for 15 days on metabolic control, islet architecture, and islet morphology in C57BL/KsJ db/db mice.RESULTS: Liraglutide had no appreciable effects on body weight, food intake, and non-fasting glucose and insulin concentrations. However, HbA1c was significantly (p <0.001) decreased, and oral glucose tolerance improved in liraglutide treated db/db mice. Pancreatic insulin content was increased (p <0.05) compared with saline controls, and the ratio of pancreatic insulin to glucagon in liraglutide mice was similar to lean mice. Although liraglutide did not alter islet number or area, the proportion of beta cells per islet was significantly increased (p <0.05) and alpha cells decreased (p <0.05), with normalization of islet architecture. In harmony with this, cell proliferation was significantly (p <0.001) augmented and apoptosis reduced (p <0.001) in liraglutide treated mice. Expression of pancreatic islet glucose-dependent insulinotropic polypeptide immunoreactivity was observed in lean control and, particularly, liraglutide treated db/db mice, whereas control db/db mice exhibited little glucose-dependent insulinotropic polypeptide staining.CONCLUSION: These data reveal that stable GLP-1 analogues exert important beneficial effects on pancreatic islet architecture and beta-cell turnover, indicating that they may be useful in the treatment of severe forms of diabetes with islet degeneration.