| First Author | Kim SY | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 9 | Pages | 3841-3853 |
| PubMed ID | 28100774 | Mgi Jnum | J:241385 |
| Mgi Id | MGI:5901982 | Doi | 10.1074/jbc.M116.754077 |
| Citation | Kim SY, et al. (2017) Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary beta-Cell Dysfunction to Progressive Depletion of beta-Cell Mass and Diabetes. J Biol Chem 292(9):3841-3853 |
| abstractText | The failure of pancreatic islet beta-cells is a major contributor to the etiology of type 2 diabetes. beta-Cell dysfunction and declining beta-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 beta-cell dysfunction to the progressive deterioration of beta-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 beta-cell metabolism and perturbed mitochondrial structure. Persistent insulin secretion defects culminate in progressive deficits in beta-cell proliferation, reduced beta-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 beta-cell mass that occur in response to age- and diet-induced stress. Thus, CDK2 serves as an important nexus linking primary beta-cell dysfunction to progressive beta-cell mass deterioration in diabetes. |
