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Diabetologia
Published in: Diabetologia 8/2017

01-08-2017 | Article

GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice

Authors: Dan Kawamori, Jun Shirakawa, Chong Wee Liew, Jiang Hu, Tomoaki Morioka, Alokesh Duttaroy, Bryan Burkey, Rohit N. Kulkarni

Published in: Diabetologia | Issue 8/2017

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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 (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.

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 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.

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.
Appendix
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Metadata
Title
GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice
Authors
Dan Kawamori
Jun Shirakawa
Chong Wee Liew
Jiang Hu
Tomoaki Morioka
Alokesh Duttaroy
Bryan Burkey
Rohit N. Kulkarni
Publication date
01-08-2017
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 8/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-017-4303-6

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