β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance

被引：157
作者：
Aguayo-Mazzucato, Cristina [1 ]
van Haaren, Mark [1 ]
Mruk, Magdalena [1 ]
Lee, Terence B., Jr. [1 ]
Crawford, Caitlin [1 ]
Hollister-Lock, Jennifer [1 ]
Sullivan, Brooke A. [1 ]
Johnson, James W. [1 ]
Ebrahimi, Aref [1 ]
Dreyfuss, Jonathan M. [1 ,2 ]
Van Deursen, Jan [3 ]
Weir, Gordon C. [1 ]
Bonner-Weir, Susan [1 ]
机构：
[1] Harvard Med Sch, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA
[2] Boston Univ, Dept Biomed Engn, Boston, MA 02115 USA
[3] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA
来源：
CELL METABOLISM | 2017年 / 25卷 / 04期
关键词：
PANCREATIC B-CELLS; INK4A/ARF EXPRESSION; SENESCENT CELLS; ISLETS; MASS; RATS; SUBPOPULATIONS; REGENERATION; REPLICATION; SECRETION;
D O I：
10.1016/j.cmet.2017.03.015
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
We hypothesized that the known heterogeneity of pancreatic beta cells was due to subpopulations of beta 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 beta cells, including IGF1R. In beta cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16(ink4a), p53BP1, and senescence-associated beta-galactosidase. The new markers showed striking heterogeneity both within and between islets in bothmouse 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 beta cells. These novel findings about beta 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.
引用
收藏
页码：898 / +
页数：18
相关论文
共 65 条
  • [1] Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells
    Aguayo-Mazzucato, C.
    Koh, A.
    El Khattabi, I.
    Li, W. -C.
    Toschi, E.
    Jermendy, A.
    Juhl, K.
    Mao, K.
    Weir, G. C.
    Sharma, A.
    Bonner-Weir, S.
    [J]. DIABETOLOGIA, 2011, 54 (03) : 583 - 593
  • [2] Restructuring of Pancreatic Islets and Insulin Secretion in a Postnatal Critical Window
    Aguayo-Mazzucato, Cristina
    Sanchez-Soto, Carmen
    Godinez-Puig, Victoria
    Gutierrez-Ospina, Gabriel
    Hiriart, Marcia
    [J]. PLOS ONE, 2006, 1 (01):
  • [3] Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function
    Avrahami, Dana
    Li, Changhong
    Zhang, Jia
    Schug, Jonathan
    Avrahami, Ran
    Rao, Shilpa
    Stadler, Michael B.
    Burger, Lukas
    Schuebeler, Dirk
    Glaser, Benjamin
    Kaestner, Klaus H.
    [J]. CELL METABOLISM, 2015, 22 (04) : 619 - 632
  • [4] Identification of proliferative and mature β-cells in the islets of Langerhans
    Bader, Erik
    Migliorini, Adriana
    Gegg, Moritz
    Moruzzi, Noah
    Gerdes, Jantje
    Roscioni, Sara S.
    Bakhti, Mostafa
    Brandl, Elisabeth
    Irmler, Martin
    Beckers, Johannes
    Aichler, Michaela
    Feuchtinger, Annette
    Leitzinger, Christin
    Zischka, Hans
    Wang-Sattler, Rui
    Jastroch, Martin
    Tschoep, Matthias
    Machicao, Fausto
    Staiger, Harald
    Haering, Hans-Ulrich
    Chmelova, Helena
    Chouinard, Julie A.
    Oskolkov, Nikolay
    Korsgren, Olle
    Speier, Stephan
    Lickert, Heiko
    [J]. NATURE, 2016, 535 (7612) : 430 - +
  • [5] Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency
    Baker, Darren J.
    Perez-Terzic, Carmen
    Jin, Fang
    Pitel, Kevin
    Niederlaender, Nicolas J.
    Jeganathan, Karthik
    Yamada, Satsuki
    Reyes, Santiago
    Rowe, Lois
    Hiddinga, H. Jay
    Eberhardt, Norman L.
    Terzic, Andre
    van Deursen, Jan M.
    [J]. NATURE CELL BIOLOGY, 2008, 10 (07) : 825 - 836
  • [6] Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
    Baker, Darren J.
    Childs, Bennett G.
    Durik, Matej
    Wijers, Melinde E.
    Sieben, Cynthia J.
    Zhong, Jian
    Saltness, Rachel A.
    Jeganathan, Karthik B.
    Verzosa, Grace Casaclang
    Pezeshki, Abdulmohammad
    Khazaie, Khashayarsha
    Miller, Jordan D.
    van Deursen, Jan M.
    [J]. NATURE, 2016, 530 (7589) : 184 - +
  • [7] Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
    Baker, Darren J.
    Wijshake, Tobias
    Tchkonia, Tamar
    LeBrasseur, Nathan K.
    Childs, Bennett G.
    van de Sluis, Bart
    Kirkland, James L.
    van Deursen, Jan M.
    [J]. NATURE, 2011, 479 (7372) : 232 - U112
  • [8] Insulin/IGF-I-signaling pathway:: an evolutionarily conserved mechanism of longevity from yeast to humans
    Barbieri, M
    Bonafè, M
    Franceschi, C
    Paolisso, G
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2003, 285 (05): : E1064 - E1071
  • [9] GLUCOSE-INDUCED INSULIN RELEASE IN ISLETS OF YOUNG-RATS - TIME-DEPENDENT POTENTIATION AND EFFECTS OF 2-BROMOSTEARATE
    BLISS, CR
    SHARP, GWG
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 263 (05): : E890 - E896
  • [10] Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3
    Blum, Barak
    Hrvatin, Sinisa
    Schuetz, Christian
    Bonal, Claire
    Rezania, Alireza
    Melton, Douglas A.
    [J]. NATURE BIOTECHNOLOGY, 2012, 30 (03) : 261 - 264
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