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 if 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.
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