Diabetologia

, Volume 60, Issue 8, pp 1442–1453

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

  • Dan Kawamori
  • Jun Shirakawa
  • Chong Wee Liew
  • Jiang Hu
  • Tomoaki Morioka
  • Alokesh Duttaroy
  • Bryan Burkey
  • Rohit N. Kulkarni
Article

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.

Keywords

Beta cell Cyclins DPP-4 inhibitor GLP-1 Insulin signalling Proliferation 

Abbreviations

βIRKO

Beta cell-specific insulin receptor knockout

CDK

Cyclin-dependent kinase

CHX

Cycloheximide

CREB

cAMP response-element binding protein

DPP-4

Dipeptidyl peptidase-4

Ex-4

Exendin-4

GFP

Green fluorescent protein

GIP

Glucose-dependent insulinotropic peptide

GLP-1

Glucagon-like peptide-1

GSIS

Glucose-stimulated insulin secretion

HH3

Histone H3

IRES

Internal ribosome entry site

KRBB

Krebs-Ringer bicarbonate buffer

Supplementary material

125_2017_4303_MOESM1_ESM.pdf (607 kb)
ESM(PDF 607 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Dan Kawamori
    • 1
    • 2
    • 3
  • Jun Shirakawa
    • 1
  • Chong Wee Liew
    • 1
    • 4
  • Jiang Hu
    • 1
  • Tomoaki Morioka
    • 1
    • 5
  • Alokesh Duttaroy
    • 6
  • Bryan Burkey
    • 7
  • Rohit N. Kulkarni
    • 1
    • 8
    • 9
  1. 1.Section of Islet Cell and Regenerative BiologyJoslin Diabetes CenterBostonUSA
  2. 2.Department of Metabolic Medicine, Graduate School of MedicineOsaka UniversityOsakaJapan
  3. 3.Medical Education Center, Faculty of MedicineOsaka UniversityOsakaJapan
  4. 4.Department of Physiology and BiophysicsUniversity of Illinois at ChicagoChicagoUSA
  5. 5.Department of Metabolism, Endocrinology and Molecular Medicine, Graduate School of MedicineOsaka City UniversityOsakaJapan
  6. 6.Cardiovascular & Metabolic DiseasesNovartis Institutes for Biomedical Research, Inc.CambridgeUSA
  7. 7.Zafgen Inc.BostonUSA
  8. 8.Department of Medicine, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  9. 9.Harvard Stem Cell InstituteBostonUSA

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