title: 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 p16(INK4A) 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 (p16(INK4A)) and three other gene products, p14 alternate reading frame (p14(ARF)), p15(INK4B) 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.
authors.affiliation: AS7-2047, Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Kong
authors.affiliation: AS7-2047, Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA.
authors.forename: Rohit B
authors.initials: RB
authors.lastname: Sharma
authors.affiliation: Division of Endocrinology, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Benjamin U
authors.initials: BU
authors.lastname: Nwosu
authors.affiliation: AS7-2047, Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA. Laura.Alonso@umassmed.edu.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
mesh_terms: D000818:Animals; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: ANRIL; Ageing; Beta cell mass; CDKN2B-AS; Cdkn2A; Cdkn2B; Insulin secretion; Oncogene; Pancreatic beta cell; Proliferation; Review; Senescence; Tumour suppressor; p14; p14ARF; p15; p15INK4B; p16; p16INK4A