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

被引：170

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

页码：898 / +

页数：18

共 65 条

[1] Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells [J].

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. .

DIABETOLOGIA, 2011, 54 (03) :583-593

[2] Restructuring of Pancreatic Islets and Insulin Secretion in a Postnatal Critical Window [J].

Aguayo-Mazzucato, Cristina ;

Sanchez-Soto, Carmen ;

Godinez-Puig, Victoria ;

Gutierrez-Ospina, Gabriel ;

Hiriart, Marcia .

PLOS ONE, 2006, 1 (01)

[3] Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function [J].

Avrahami, Dana ;

Li, Changhong ;

Zhang, Jia ;

Schug, Jonathan ;

Avrahami, Ran ;

Rao, Shilpa ;

Stadler, Michael B. ;

Burger, Lukas ;

Schuebeler, Dirk ;

Glaser, Benjamin ;

Kaestner, Klaus H. .

CELL METABOLISM, 2015, 22 (04) :619-632

[4] Identification of proliferative and mature β-cells in the islets of Langerhans [J].

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 .

NATURE, 2016, 535 (7612) :430-+

[5] Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency [J].

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. .

NATURE CELL BIOLOGY, 2008, 10 (07) :825-836

[6] Naturally occurring p16Ink4a-positive cells shorten healthy lifespan [J].

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. .

NATURE, 2016, 530 (7589) :184-+

[7] Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders [J].

Baker, Darren J. ;

Wijshake, Tobias ;

Tchkonia, Tamar ;

LeBrasseur, Nathan K. ;

Childs, Bennett G. ;

van de Sluis, Bart ;

Kirkland, James L. ;

van Deursen, Jan M. .

NATURE, 2011, 479 (7372) :232-U112

[8] Insulin/IGF-I-signaling pathway:: an evolutionarily conserved mechanism of longevity from yeast to humans [J].

Barbieri, M ;

Bonafè, M ;

Franceschi, C ;

Paolisso, G .

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 [J].

BLISS, CR ;

SHARP, GWG .

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 [J].

Blum, Barak ;

Hrvatin, Sinisa ;

Schuetz, Christian ;

Bonal, Claire ;

Rezania, Alireza ;

Melton, Douglas A. .

NATURE BIOTECHNOLOGY, 2012, 30 (03) :261-264

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