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- Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary β-Cell Dysfunction to Progressive Depletion of β-Cell Mass and Diabetes.
Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary β-Cell Dysfunction to Progressive Depletion of β-Cell Mass and Diabetes.
Citation | “Loss Of Cyclin-Dependent Kinase 2 In The Pancreas Links Primary Β-Cell Dysfunction To Progressive Depletion Of Β-Cell Mass And Diabetes.”. The Journal Of Biological Chemistry, pp. 3841-3853. . |
Center | University of Michigan |
Author | So Yoon Kim, Ji-Hyeon Lee, Matthew J Merrins, Oksana Gavrilova, Xavier Bisteau, Philipp Kaldis, Leslie S Satin, Sushil G Rane |
Keywords | CDK2, FoxO, beta cell (B-cell), beta cell function, Beta cell mass, cell cycle, cyclin-dependent kinase (CDK), diabetes, FoxO1 |
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 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. |
Year of Publication |
2017
|
Journal |
The Journal of biological chemistry
|
Volume |
292
|
Issue |
9
|
Number of Pages |
3841-3853
|
Date Published |
12/2017
|
ISSN Number |
1083-351X
|
DOI |
10.1074/jbc.M116.754077
|
Alternate Journal |
J. Biol. Chem.
|
PMID |
28100774
|
PMCID |
PMC5339765
|
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