Islet biology, the CDKN2A/B locus and type 2 diabetes risk

Abstract

Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16INK4A to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16INK4A) and three other gene products, p14 alternate reading frame (p14ARF), p15INK4B and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

CDKN2A/B T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene Expression and Proliferation in Human Islets

“…Age-Dependent Gene Expression Increase of p14, p16, and ANRIL but Not p15 or MTAP In many tissues, including islets, some CDKN2A/B locus genes increase with advancing age (9,10,32). In this cohort of human islets, expression of p14, p16, and ANRIL showed a modest positive correlation with donor age, whereas p15 and MTAP did not ( Fig.…”

“…SNPs at the CDKN2A/B genomic locus impact risk of T2D and related diseases, such as gestational diabetes mellitus, cystic fibrosis-related diabetes, and posttransplant diabetes, across ethnicities and cultures, suggesting a central diabetogenic mechanism (9). Multiple SNPs in different linkage blocks at the CDKN2A/B locus confer T2D risk (9); mechanisms impacting risk remain unknown. The CDKN2A/B locus encodes four genes ( Fig.…”

“…A fourth SNP, rs564398, ;100,000 base pairs upstream of these, falls within exon 2 of ANRIL. These SNPs were identified in large population studies seeking to identify genomic regions associated with T2D risk (12)(13)(14) (more details have previously been published [9]). The three downstream SNPs are mostly associated with T2D risk and not other diseases; the rs564398 SNP is also associated with coronary heart disease and glaucoma (15).…”

“…Intriguingly, given the aging and senescence roles played by CDKN2A/B genes, the impact of rs10811661 on T2D risk was influenced by subject age (18). SNPs at this locus also influence insulin sensitivity and biology of other metabolic tissues, demonstrating the complexity of even a single genomic locus on T2D biology (9).…”

<p>Is there a CDKN2A-centric network in pancreatic ductal adenocarcinoma?</p>

“…22 CDKN2A involves the function regulation of islets, fat, muscle, liver and immune cells, and even the whole process of uterine development. 23 CDKN2A affects the risk of human vascular disease, including coronary artery disease, aneurysm, ischemic stroke, glaucoma, Alzheimer's disease, endometriosis and periodontitis. 16,24 Additionally, CDKN2A mutations are involved in a variety of cancers.…”