| First Author | Kawamori D | Year | 2017 |
| Journal | Diabetologia | Volume | 60 |
| Issue | 8 | Pages | 1442-1453 |
| PubMed ID | 28526921 | Mgi Jnum | J:244241 |
| Mgi Id | MGI:5913020 | Doi | 10.1007/s00125-017-4303-6 |
| Citation | Kawamori D, et al. (2017) GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in betaIRKO mice. Diabetologia 60(8):1442-1453 |
| abstractText | 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 (betaIRKO) 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 betaIRKO 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 betaIRKO 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. |
