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
We thank C. R. Kahn and R. Suzuki (Joslin Diabetes Center, Boston, MA, USA) for discussions, A. J. Kurpad (Joslin Diabetes Center) for technical assistance and H. Li, Z. Fu and G. Sankaranarayanan (Specialized Assay Core, DERC, Joslin Diabetes Center, Boston, MA, USA) for assays.
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
DK is the recipient of a Research Fellowship (Manpei Suzuki Diabetes Foundation, Japan) and a JDRF Post-doctoral Fellowship. JS is the recipient of a Research Fellowship (the Japan Society for the Promotion of Science [JSPS] and the Uehara Memorial Foundation, Japan). This work was supported in part by NIH DK67536 (RNK), NIH DK103215 (RNK), NIH DK55523 (RNK), 5P30DK36836 (Joslin DERC Specialized Assay and Advanced Microscopy Cores), K99DK090210 (CWL), R00DK090210 (CWL) and the Novartis Institutes for Biomedical Research Inc. (RNK). The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.
Duality of interest
AD is an employee of the Novartis Institutes for Biomedical Research Inc. BB was an employee of the Novartis Institutes for Biomedical Research Inc. and is an employee of Zafgen Inc. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.
DK, JS and RNK planned the experiments, researched data, wrote the manuscript and reviewed/edited the manuscript. CWL, JH and TM acquired and analysed the researched data. CWL, JH, TM, AD and BB provided materials and contributed to study design, interpretation of the data and editing the article. All authors approved the manuscript for publication. DK and RNK are the guarantors of this work, had full access to all the data, and take full responsibility for the integrity of data and the accuracy of data analysis.
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