Loss of cyclin-dependent kinase 2 in the pancreas links primary β-cell dysfunction to progressive depletion of β-cell mass and diabetes

Research output: Contribution to journalArticle

Abstract

The failure of pancreatic isletβ-cells is a major contributor to the etiology of type 2 diabetes.β-Cell dysfunction and declining β-cell mass are two mechanisms that contribute to this failure, although it is unclear whether they are molecularly linked. Here, we show that the cell cycle regulator, cyclin-dependent kinase 2 (CDK2), couples primary β-cell dysfunction to the progressive deterioration of β-cell mass in diabetes. Mice with pancreasspecific deletion of Cdk2 are glucose-intolerant, primarily due to defects in glucose-stimulated insulin secretion. Accompanying this loss of secretion are defects in β-cell metabolism and perturbed mitochondrial structure. Persistent insulin secretion defects culminate in progressive deficits in β-cell proliferation, reduced β-cell mass, and diabetes. These outcomes may be mediated directly by the loss of CDK2, which binds to and phosphorylates the transcription factor FOXO1 in a glucose-dependent manner. Further, we identified a requirement for CDK2 in the compensatory increases in β-cell mass that occur in response to age- and diet-induced stress. Thus, CDK2 serves as an important nexus linking primary β-cell dysfunction to progressive β-cell mass deterioration in diabetes.

Details

Authors
  • So Yoon Kim
  • Ji Hyeon Lee
  • Matthew J. Merrins
  • Oksana Gavrilova
  • Xavier Bisteau
  • Philipp Kaldis
  • Leslie S. Satin
  • Sushil G. Rane
External organisations
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • University of Wisconsin-Madison
  • A*Star Institute of Molecular and Cell Biology (IMCB)
  • National University of Singapore
  • University of Michigan
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Pages (from-to)3841-3853
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number9
Publication statusPublished - 2017 Mar 3
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes