GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice
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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.
Beta cell-specific insulin receptor knockout (βIRKO) 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.
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 βIRKO 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 βIRKO mice exhibited increased cyclin D1 expression, while cyclin D2 expression was impaired.
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.
KeywordsBeta cell Cyclins DPP-4 inhibitor GLP-1 Insulin signalling Proliferation
Beta cell-specific insulin receptor knockout
cAMP response-element binding protein
Green fluorescent protein
Glucose-dependent insulinotropic peptide
Glucose-stimulated insulin secretion
Internal ribosome entry site
Krebs-Ringer bicarbonate buffer