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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.

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From the Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch and.
the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin, Madison, Wisconsin 53705.
the Mouse Metabolism Core Laboratory, NIDDK, National Institutes of Health, Clinical Research Center, Bethesda, Maryland 20892.
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.
the Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore, and.
the Department of Pharmacology and Brehm Center for Diabetes Research, University of Michigan Medical School, Ann Arbor, Michigan 48105.
From the Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch and


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.


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

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