GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in ßIRKO mice.
Diabetologia
; 60(8): 1442-1453, 2017 08.
Article
en En
| MEDLINE
| ID: mdl-28526921
ABSTRACT
AIMS/HYPOTHESIS:
We aimed to investigate potential interactions between insulin and glucagon-like peptide (GLP)-1 signalling pathways in the regulation of beta cell-cycle dynamics in vivo, in the context of the therapeutic potential of GLP-1 to modulate impaired beta cell function.METHODS:
Beta cell-specific insulin receptor knockout (ßIRKO) mice, which exhibit beta cell dysfunction and an age-dependent decrease in beta cell mass, were treated with the dipeptidyl peptidase-4 inhibitor vildagliptin. Following this, glucose homeostasis and beta cell proliferation were evaluated and underlying molecular mechanisms were investigated.RESULTS:
The sustained elevation in circulating GLP-1 levels, caused by treatment of the knockout mice with vildagliptin for 6 weeks, significantly improved glucose tolerance secondary to enhanced insulin secretion and proliferation of beta cells. Treating ßIRKO beta cell lines with the GLP-1 analogue, exendin-4, promoted Akt phosphorylation and protein expression of cyclins A, D1 and E two- to threefold, in addition to cyclin D2. Pancreases from the vildagliptin-treated ßIRKO mice exhibited increased cyclin D1 expression, while cyclin D2 expression was impaired. CONCLUSIONS/INTERPRETATION:
Activation of GLP-1 signalling compensates for impaired growth factor (insulin) signalling and enhances expression of cyclins to promote beta cell proliferation. Together, these data indicate the potential of GLP-1-related therapies to enhance beta cell proliferation and promote beneficial outcomes in models with dysfunctional beta cells.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Receptor de Insulina
/
Células Secretoras de Insulina
/
Péptido 1 Similar al Glucagón
/
Insulina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Diabetologia
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos