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J Biol Chem. 2017 Mar 3;292(9):3841-3853. doi: 10.1074/jbc.M116.754077. Epub 2017 Jan 18.

Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary β-Cell Dysfunction to Progressive Depletion of β-Cell Mass and Diabetes.

Author information

1
From the Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch and.
2
the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin, Madison, Wisconsin 53705.
3
the Mouse Metabolism Core Laboratory, NIDDK, National Institutes of Health, Clinical Research Center, Bethesda, Maryland 20892.
4
the Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos#3-09, Singapore 138673, Singapore.
5
the Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore, and.
6
the Department of Pharmacology and Brehm Center for Diabetes Research, University of Michigan Medical School, Ann Arbor, Michigan 48105.
7
From the Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch and ranes@mail.nih.gov.

Abstract

The failure of pancreatic islet β-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 pancreas-specific 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.

KEYWORDS:

CDK2; FOXO; beta cell (B-cell); beta cell function; beta cell mass; cell cycle; cyclin-dependent kinase (CDK); diabetes; foxo1

PMID:
28100774
PMCID:
PMC5339765
DOI:
10.1074/jbc.M116.754077
[Indexed for MEDLINE]
Free PMC Article

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