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

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.

Genome-wide association study identifies novel type II diabetes risk loci in Jordan subpopulations

“…Recent studies demonstrate that in addition to regulation of glucose-sensing transcription, MLXIP plays an important role in Myc activation and subsequent metabolic pathway reprogramming ( Carroll et al, 2015 ). It is well known that Myc has important functions in the pathogenesis of diabetes, through both regulating cell cycle entry and maintaining expansion, regeneration and normal function of beta-cells ( Tiwari et al, 2016 ). It has been shown that abnormal activation of Myc resulted in decreased beta-cell differentiation, proliferation and reduced insulin secretion ( Cheung et al, 2010 ).…”

“…The pathological events that can lead to the development of T2D are diverse, such as deficiency and malfunction of beta-cells together with insulin resistance in multiple tissues, including liver and adipose tissues ( Tiwari et al, 2016 ). The likely underlying genes for the novel T2D signals that we identified through GWAS are key players of signaling pathways that could lead to the development of T2D.…”

Pancreatic β-cell rescue in diabetes by targeting Merlin

“…The loss of functional pancreatic β-cells, mainly by increased β-cell apoptosis is a central feature of both type 1 diabetes (T1D) and type 2 diabetes (T2D) [2][3][4][5]. Other possible causes of this reduced β-cell mass in diabetes include β-cell dedifferentiation [6,7] and failure of adaptive expansion due to impaired β-cell proliferation [8]. In T1D, selective β-cell destruction occurs through auto-immune-mediated processes; infiltration of activated CD 4+ /CD 8+ T cells, B cells, and macrophages in the pancreatic islets.…”

Peer Review #1 of "Genome-wide association study identifies novel type II diabetes risk loci in Jordan subpopulations (v0.1)"

“…344 The pathological events that can lead to the development of T2D are diverse, such as deficiency 345 and malfunction of beta-cells together with insulin resistance in multiple tissues, including liver 346 and adipose tissues (Tiwari et al 2016). The likely underlying genes for the novel T2D signals 347 that we identified through GWAS are key players of signaling pathways that could lead to the 348 development of T2D.…”