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)
- author
- Kim, So Yoon
; Lee, Ji Hyeon
; Merrins, Matthew J.
; Gavrilova, Oksana
; Bisteau, Xavier
; Kaldis, Philipp
LU
; Satin, Leslie S.
and Rane, Sushil G.
- publishing date
- 2017-03-03
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 292
- issue
- 9
- pages
- 13 pages
- publisher
- American Society for Biochemistry and Molecular Biology
- 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
- 2024-02-15 21:23:55
@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 = {{American Society for Biochemistry and Molecular Biology}},
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}},
}