Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells

Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional beta-cell mass. Developmental differences, failure of adaptive expansion and loss of beta-cells via beta-cell death or dedifferentiation have emerged as the possible causes of this reduced beta-cell mass. We hypothesized that the proliferative response to mitogens of human beta-cells from T2D donors is reduced, and that this might contribute to the development and progression of T2D. Here, we demonstrate that the proliferative response of human beta-cells from T2D donors in response to cdk6 and cyclin D3 is indeed dramatically impaired. We show that this is accompanied by increased nuclear abundance of the cell cycle inhibitor, p27(kip1). Increasing nuclear abundance of p27(kip1) by adenoviral delivery decreases the proliferative response of beta-cells from non-diabetic donors, mimicking T2D beta-cells. However, while both p27(kip1) gene silencing and downregulation by Skp2 overexpression increased similarly the proliferative response of human beta-cells, only Skp2 was capable of inducing a significant human beta-cell expansion. Skp2 was also able to double the proliferative response of T2D beta-cells. These studies define c-Myc as a central Skp2 target for the induction of cell cycle entry, expansion and regeneration of human T2D beta-cells.