title: Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans.
abstract: At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a noncoding region near CDKN2A. The disease-associated alleles have been implicated in reduced β-cell function, but the underlying mechanism remains elusive. In mice, β-cell-specific loss of Cdkn2a causes hyperplasia, while overexpression leads to diabetes, highlighting CDKN2A as a candidate effector transcript. Rare CDKN2A loss-of-function mutations are a cause of familial melanoma and offer the opportunity to determine the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans. To test the hypothesis that such individuals have improved β-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched control subjects. Compared with control subjects, carriers displayed increased insulin secretion, impaired insulin sensitivity, and reduced hepatic insulin clearance. These results are consistent with a model whereby CDKN2A loss affects a range of different tissues, including pancreatic β-cells and liver. To test for direct effects of CDKN2A-loss on β-cell function, we performed knockdown in a human β-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrated that CDKN2A is an important regulator of glucose homeostasis in humans, thus supporting its candidacy as an effector transcript for type 2 diabetes-associated alleles in the region.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Aparna
authors.initials: A
authors.lastname: Pal
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Potjer
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Soren K
authors.initials: SK
authors.lastname: Thomsen
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Hui Jin
authors.initials: HJ
authors.lastname: Ng
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.affiliation: INSERM U1016, Institut Cochin, Université Paris Descartes, Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford, U.K.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: James
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, U.K.
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.affiliation: Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Godsland
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, U.K.
authors.forename: Julia
authors.initials: J
authors.lastname: Newton-Bishop
authors.affiliation: Leiden University Medical Centre, Department of Internal Medicine, Leiden, the Netherlands.
authors.forename: Hanno
authors.initials: H
authors.lastname: Pijl
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K. anna.gloyn@drl.ox.ac.uk.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D019942:Genes, p16 / Q000502:physiology*; D005951:Glucose Tolerance Test; D065669:Hepatobiliary Elimination; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin