title: β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance.
abstract: We hypothesized that the known heterogeneity of pancreatic β cells was due to subpopulations of β cells at different stages of their life cycle with different functional capacities and that further changes occur with metabolic stress and aging. We identified new markers of aging in β cells, including IGF1R. In β cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16ink4a, p53BP1, and senescence-associated β-galactosidase. The new markers showed striking heterogeneity both within and between islets in both mouse and human pancreas. Acute induction of insulin resistance with an insulin receptor antagonist or chronic ER stress resulted in increased expression of aging markers, providing insight into how metabolic stress might accelerate dysfunction and decline of β cells. These novel findings about β cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions about the pathogenesis of type 2 diabetes.
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguayo-Mazzucato
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: van Haaren
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mruk
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Terence B
authors.initials: TB
authors.lastname: Lee
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Crawford
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Sullivan
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Johnson
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Aref
authors.initials: A
authors.lastname: Ebrahimi
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02115, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Dreyfuss
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Deursen
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA. Electronic address: susan.bonner-weir@joslin.harvard.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D016922:Cellular Senescence; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006462:Hemolytic Plaque Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013312:Stress, Physiological; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007328:Insulin; D012333:RNA, Messenger; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D049452:Green Fluorescent Proteins; D017526:Receptor, IGF Type 1; D005947:Glucose
keywords: aging markers; beta-cell heterogeneity; islets