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

Dan Kawamori1,2,3, Jun Shirakawa1, Chong Wee Liew1,4

  • 1Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Room 410, One Joslin Place, Boston, MA, 02215, USA.

Diabetologia
|May 21, 2017
PubMed
Abstract

Insights

Glucagon-like peptide (GLP)-1 signaling enhances beta cell proliferation in models with impaired insulin signaling. GLP-1 therapies may improve beta cell function and proliferation in dysfunctional beta cells.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Insulin and glucagon-like peptide (GLP)-1 signaling pathways are crucial for beta cell function.
  • Impaired beta cell function and mass contribute to metabolic diseases.
  • GLP-1-based therapies show potential for modulating beta cell function.

Purpose of the Study:

  • To investigate the interaction between insulin and GLP-1 signaling in regulating beta cell cycle dynamics.
  • To evaluate the therapeutic potential of GLP-1 in modulating impaired beta cell function in vivo.
  • To explore the molecular mechanisms underlying GLP-1's effects on beta cell proliferation.

Main Methods:

  • Beta cell-specific insulin receptor knockout (βIRKO) mice were treated with vildagliptin.
  • Glucose homeostasis and beta cell proliferation were assessed.
  • Molecular mechanisms involving Akt phosphorylation and cyclin expression were investigated in βIRKO cell lines and mouse pancreases.

Main Results:

  • Vildagliptin treatment improved glucose tolerance, insulin secretion, and beta cell proliferation in βIRKO mice.
  • GLP-1 analogue exendin-4 promoted Akt phosphorylation and cyclin A, D1, D2, and E expression in βIRKO cells.
  • Vildagliptin-treated βIRKO mice showed increased cyclin D1 but impaired cyclin D2 expression.

Conclusions:

  • GLP-1 signaling activation compensates for impaired insulin signaling, promoting beta cell proliferation.
  • GLP-1 enhances cyclin expression, crucial for cell cycle progression.
  • GLP-1-related therapies hold promise for enhancing beta cell proliferation and function in models of beta cell dysfunction.
Keywords:
Beta cellCyclinsDPP-4 inhibitorGLP-1Insulin signallingProliferation

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