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Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response

Sonia Klinger1, Carine Poussin, Marie-Bernard Debril

  • 1Institute of Physiology, University of Lausanne, Lausanne, Switzerland.

Diabetes
|November 21, 2007
PubMed
Abstract

Insights

Blocking specific cellular mechanisms enhances glucagon-like peptide-1 (GLP-1) effects on beta-cell proliferation. This research identifies negative regulators that limit GLP-1

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Glucagon-like peptide-1 (GLP-1) is a key factor for beta-cell growth and differentiation.
  • Augmenting GLP-1's effect on beta-cell mass is crucial for treating type 1 and type 2 diabetes.
  • Existing GLP-1 therapies have limited impact on increasing beta-cell mass.

Purpose of the Study:

  • To identify cellular mechanisms limiting GLP-1's proliferative effect on beta-cells.
  • To investigate whether blocking these mechanisms can enhance beta-cell proliferation.
  • To explore novel therapeutic targets for diabetes by modulating beta-cell mass.

Main Methods:

  • Examined GLP-1-regulated genes in beta TC-Tet cells using cDNA microarrays.
  • Reduced expression of identified genes using small heterogeneous RNA in beta-cell lines and primary mouse islets.
  • Measured beta-cell proliferation via [(3)H]thymidine and 5'-bromo-2'-deoxyuridine incorporation.

Main Results:

  • Identified four negative regulators of intracellular signaling activated by GLP-1: RGS2, CREM-alpha, ICERI, and DUSP14.
  • Knockdown of CREM-alpha or DUSP14, or dominant-negative DUSP14, increased beta-cell line proliferation.
  • Enhanced GLP-1-induced proliferation in primary beta-cells by blocking these negative regulators.

Conclusions:

  • The cAMP/protein kinase A/CREB and MAPK/ERK1/2 pathways additively control beta-cell proliferation.
  • Beta-cells possess evolved mechanisms that limit GLP-1-induced proliferation.
  • Blocking these inhibitory mechanisms potentiates GLP-1's positive effects on beta-cell mass.

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