Abstract
Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional β-cell mass. Developmental differences, failure of adaptive expansion and loss of β-cells via β-cell death or de-differentiation have emerged as the possible causes of this reduced β-cell mass. We hypothesized that the proliferative response to mitogens of human β-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 β-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, p27kip1. Increasing nuclear abundance of p27kip1 by adenoviral delivery decreases the proliferative response of β-cells from non-diabetic donors, mimicking T2D β-cells. However, while both p27kip1 gene silencing and downregulation by Skp2 overexpression increased similarly the proliferative response of human β-cells, only Skp2 was capable of inducing a significant human β-cell expansion. Skp2 was also able to double the proliferative response of T2D β-cells. These studies define c-Myc as a central Skp2 target for the induction of cell cycle entry, expansion and regeneration of human T2D β-cells.
Highlights
Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional β-cell mass
Individuals[8], we explored the proliferative response of β-cells from T2D donors by overexpressing cdk[6] and cyclin D3 in human dispersed islets
Since p27kip[1] is an important cell cycle inhibitor in rodent β-cells, and since p27kip[1] overexpression is linked to T2D in rodent models, we questioned whether the reduction of proliferative response in T2D human β-cells correlates with an increased level of Immunolabelling for Ki67 is shown in red, insulin in white, and DAPI in blue. (D) Quantification of data in C at 72 hours after transduction
Summary
Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional β-cell mass. We demonstrate that the proliferative response of human β-cells from T2D donors in response to cdk[6] and cyclin D3 is dramatically impaired We show that this is accompanied by increased nuclear abundance of the cell cycle inhibitor, p27kip[1]. Studies in children and young adults suggest that it is possible that some people accrue lower than average β-cell mass during their first years of development[13,14] These individuals would require greater expansion of β-cell mass in response to insulin resistance. A second possibility is that if β-cell expansion can occur in adults, some individuals may not expand their β-cell mass as effectively as others in response to obesity and insulin resistance. By facilitating the formation and stabilizing the complex formed between D-cyclins and cdk[4]
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