Advanced

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

Kim, So Yoon ; Lee, Ji Hyeon ; Merrins, Matthew J. ; Gavrilova, Oksana ; Bisteau, Xavier ; Kaldis, Philipp LU ; Satin, Leslie S. and Rane, Sushil G. (2017) In Journal of Biological Chemistry 292(9). p.3841-3853
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
292
issue
9
pages
13 pages
publisher
ASBMB
external identifiers
  • pmid:28100774
  • scopus:85014626813
ISSN
0021-9258
DOI
10.1074/jbc.M116.754077
language
English
LU publication?
no
id
27ce0e08-8299-4c22-ac71-dc9020fb44de
date added to LUP
2019-09-18 10:15:22
date last changed
2019-12-03 02:18:58
@article{27ce0e08-8299-4c22-ac71-dc9020fb44de,
  abstract     = {<p>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.</p>},
  author       = {Kim, So Yoon and Lee, Ji Hyeon and Merrins, Matthew J. and Gavrilova, Oksana and Bisteau, Xavier and Kaldis, Philipp and Satin, Leslie S. and Rane, Sushil G.},
  issn         = {0021-9258},
  language     = {eng},
  month        = {03},
  number       = {9},
  pages        = {3841--3853},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Loss of cyclin-dependent kinase 2 in the pancreas links primary β-cell dysfunction to progressive depletion of β-cell mass and diabetes},
  url          = {http://dx.doi.org/10.1074/jbc.M116.754077},
  doi          = {10.1074/jbc.M116.754077},
  volume       = {292},
  year         = {2017},
}