title: p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion.
abstract: Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Aharon
authors.initials: A
authors.lastname: Helman
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Agnes
authors.initials: A
authors.lastname: Klochendler
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Narmen
authors.initials: N
authors.lastname: Azazmeh
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Gabai
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Horwitz
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Anzi
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Swisa
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Reba
authors.initials: R
authors.lastname: Condiotti
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Roy Z
authors.initials: RZ
authors.lastname: Granit
authors.affiliation: Computation Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Nevo
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Fixler
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Dorin
authors.initials: D
authors.lastname: Shreibman
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Zamir
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Sharona
authors.initials: S
authors.lastname: Tornovsky-Babeay
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.|Veteran Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.|Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.|Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ittai
authors.initials: I
authors.lastname: Ben-Porath
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D007328:Insulin; D047495:PPAR gamma; D058570:TOR Serine-Threonine Kinases; D005947:Glucose