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β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance
Open accessAbstract
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 p16 ink4a, 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.
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“No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in our previous publications8,22,49.”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [49]
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1 retracted
RETRACTED: Betatrophin: A Hormone that Controls Pancreatic β Cell Proliferation
Yi, P., Park, J.-S., & Melton, D. A. (2013) · Cell · doi:10.1016/j.cell.2013.04.008 · Cited by 449
Retractedlimma powers differential expression analyses for RNA-sequencing and microarray studies
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv007 · Cited by 40,458
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes
Butler, A. E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R. A., & Butler, P. C. (2003) · Diabetes · doi:10.2337/diabetes.52.1.102 · Cited by 4,011
Self-citationClearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670
Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., A. Saltness, R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., et al. (2016) · Nature · doi:10.1038/nature16932 · Cited by 2,876
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623
Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes
Segerstolpe, Å., Palasantza, A., Eliasson, P., Andersson, E.-M., Andréasson, A.-C., Sun, X., Picelli, S., Sabirsh, A., Clausen, M., Bjursell, M. K., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.020 · Cited by 1,550
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
p16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003
Self-citationRNA Sequencing of Single Human Islet Cells Reveals Type 2 Diabetes Genes
Xin, Y., Kim, J., Okamoto, H., Ni, M., Wei, Y., Adler, C., Murphy, A. J., Yancopoulos, G. D., Lin, C., & Gromada, J. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.018 · Cited by 684
Discovering statistically significant pathways in expression profiling studies
Tian, L., Greenberg, S. A., Kong, S. W., Altschuler, J., Kohane, I. S., & Park, P. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506577102 · Cited by 649
Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model
Finegood, D. T., Scaglia, L., & Bonner‐Weir, S. (1995) · Diabetes · doi:10.2337/diab.44.3.249 · Cited by 631
Self-citationJonas, J., Sharma, A., Hasenkamp, W. M., ILKOVA, H. M., Patanè, G., Laybutt, D. R., Bonner‐Weir, S., & Weir, G. C. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.20.14112 · Cited by 567
Self-citationFadista, J., Vikman, P. J., Ottosson-Laakso, E., Mollet, I. G., Esguerra, J. L. S., Taneera, J., Storm, P., Osmark, P., Ladenvall, C., Prasad, R. B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402665111 · Cited by 480
Barbieri, M., Bonafè, M., Franceschi, C., & Paolisso, G. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00296.2003 · Cited by 456
Beta cell hubs dictate pancreatic islet responses to glucose
Johnston, N. R., Mitchell, R. K., Haythorne, E., Pessoa, M. P., Semplici, F., Ferrer, J., Piemonti, L., Marchetti, P., Bugliani, M., Bosco, D., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.06.020 · Cited by 454
Apoptosis Participates in the Remodeling of the Endocrine Pancreas in the Neonatal Rat
Scaglia, L., Cahill, C. J., Finegood, D. T., & Bonner‐Weir, S. (1997) · Endocrinology · doi:10.1210/endo.138.4.5069 · Cited by 418
Self-citationOpposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency
Baker, D. J., Perez-Terzic, C., Jin, F., Pitel, K. S., Niederländer, N. J., Jeganathan, K., Yamada, S., Reyes, S., Rowe, L., Hiddinga, H. J., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1744 · Cited by 408
Human islets contain four distinct subtypes of β cells
Dorrell, C., Schug, J., Canaday, P. S., Russ, H. A., Tarlow, B., Grompe, M. T., Horton, T., Hebrok, M., Streeter, P. R., Kaestner, K. H., et al. (2016) · Nature Communications · doi:10.1038/ncomms11756 · Cited by 389
Chen, H., Gu, X., Su, I.-H., Bottino, R., Contreras, J. L., Tarakhovsky, A., & Kim, S. K. (2009) · Genes & Development · doi:10.1101/gad.1742509 · Cited by 366
p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion
Helman, A., Klochendler, A., Azazmeh, N., Gabai, Y., Horwitz, E., Anzi, S., Swisa, A., Condiotti, R., Granit, R. Z., Nevo, Y., et al. (2016) · Nature Medicine · doi:10.1038/nm.4054 · Cited by 351
Blum, B., Hrvatin, S., Schuetz, C., Bonal, C., Rezania, A., & Melton, D. (2012) · Nature Biotechnology · doi:10.1038/nbt.2141 · Cited by 349
The pancreatic islets in diabetes
Gepts, W., & LeCompte, P. M. (1981) · The American Journal of Medicine · doi:10.1016/0002-9343(81)90417-4 · Cited by 348
Formation of a human β-cell population within pancreatic islets is set early in life
Gregg, B. E., Moore, P. C., Demozay, D., Hall, B. A., Li, M., Husain, A., Wright, A. J., Atkinson, M. A., & Rhodes, C. J. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1206 · Cited by 344
Identification of proliferative and mature β-cells in the islets of Langerhans
Bader, E., Migliorini, A., Gegg, M., Moruzzi, N., Gerdes, J. M., Roscioni, S. S., Bakhti, M., Brandl, E., Irmler, M., Beckers, J., et al. (2016) · Nature · doi:10.1038/nature18624 · Cited by 338
Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice
Tschen, S.-I., Dhawan, S., Gurlo, T., & Bhushan, A. (2009) · Diabetes · doi:10.2337/db08-1651 · Cited by 331
Deletion of Nicotinamide Nucleotide Transhydrogenase
Freeman, H. C., Hugill, A., Dear, N. T., Ashcroft, F. M., & Cox, R. (2006) · Diabetes · doi:10.2337/db06-0358 · Cited by 325
Marselli, L., Thorne, J., Dahiya, S., Sgroi, D. C., Sharma, A., Bonner-Weir, S., Marchetti, P., & Weir, G. C. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011499 · Cited by 313
Self-citationGlucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells
Schuit, F. C., In't Veld, P. A., & Pipeleers, D. G. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.11.3865 · Cited by 308
Islet β cell mass in diabetes and how it relates to function, birth, and death
Weir, G. C., & Bonner‐Weir, S. (2013) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12031 · Cited by 296
Self-citationTransgenic mice with green fluorescent protein-labeled pancreatic β-cells
Hara, M., Wang, X., Kawamura, T., Bindokas, V. P., Dizon, R. F., Alcoser, S. Y., Magnuson, M. A., & Bell, G. I. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00321.2002 · Cited by 293
Changes in Age at Diagnosis of Type 2 Diabetes Mellitus in the United States, 1988 to 2000
Koopman, R. J. (2005) · The Annals of Family Medicine · doi:10.1370/afm.214 · Cited by 291
Heterogeneity and contact-dependent regulation of hormone secretion by individual B cells
Salomon, D., & Meda, P. (1986) · Experimental Cell Research · doi:10.1016/0014-4827(86)90354-x · Cited by 252
Perspective: Postnatal Pancreatic β Cell Growth
Bonner‐Weir, S. (2000) · Endocrinology · doi:10.1210/endo.141.6.7567 · Cited by 247
Self-citationMontanya, E., Nacher, V, Biarnés, M., & Soler, J. (2000) · Diabetes · doi:10.2337/diabetes.49.8.1341 · Cited by 220
Gotoh, M., Maki, T., Satomi, S., Porter, J., Bonner‐Weir, S., O’Hara, C., & Monaco, A. P. (1987) · Transplantation · doi:10.1097/00007890-198705000-00024 · Cited by 217
Self-citationHeterogeneity in Pancreatic β-cell Population
PIPELEERS, D. G. (1992) · Diabetes · doi:10.2337/diab.41.7.777 · Cited by 214
Bmi-1 regulates the Ink4a/Arf locus to control pancreatic β-cell proliferation
Dhawan, S., Tschen, S.-I., & Bhushan, A. (2009) · Genes & Development · doi:10.1101/gad.1742609 · Cited by 210
Avrahami, D., Li, C., Zhang, J., Schug, J., Avrahami, R., Rao, S., Stadler, M. B., Burger, L., Schübeler, D., Glaser, B., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.07.025 · Cited by 207
The role of aging upon β cell turnover
Kushner, J. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64095 · Cited by 167
Pancreatic beta cell heterogeneity in glucose-induced insulin secretion.
Schravendijk, C. F. H. V., Kiekens, R., & PIPELEERS, D. G. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36615-3 · Cited by 165
A novel high-affinity peptide antagonist to the insulin receptor
Schäffer, L., Brand, C. L., Hansen, B. F., Ribel, U., Shaw, A. C., Slaaby, R., & Sturis, J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.08.151 · Cited by 161
Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells
Aguayo-Mazzucato, C., Koh, A., Khattabi, I. E., Li, W.-D., Toschi, E., Jermendy, Á., Juhl, K., Mao, K., Weir, G., Sharma, A. J., et al. (2010) · Diabetologia · doi:10.1007/s00125-010-2026-z · Cited by 161
Self-citationKiekens, R., Veld, P. I. '. '., Mahler, T., Schuit, F., van de Winkel, M., & Pipeleers, D. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115551 · Cited by 161
Tornovsky-Babeay, S., Dadon, D., Ziv, O., Tzipilevich, E., Kadosh, T., Schyr, R. B., Hija, A., Stolovich-Rain, M., Furth‐Lavi, J., Granot, Z., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.007 · Cited by 150
Physiologic relevance of heterogeneity in the pancreatic beta-cell population
PIPELEERS, D. G., Kiekens, R., Ling, Z., Wilikens, A., & Schuit, F. C. (1994) · Diabetologia · doi:10.1007/bf00400827 · Cited by 150
β-cell dedifferentiation in diabetes is important, but what is it?
Weir, G. C., Aguayo‐Mazzucato, C., & Bonner‐Weir, S. (2013) · Islets · doi:10.4161/isl.27494 · Cited by 123
Self-citationShort Telomeres Compromise β-Cell Signaling and Survival
Guo, N., Parry, E. M., Li, L.-S., Kembou, F., Lauder, N., Hussain, M. A., Berggren, P.-O., & Armanios, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017858 · Cited by 100
Olsson, R. F., & Carlsson, P. (2011) · Diabetes · doi:10.2337/db09-0877 · Cited by 85
Restructuring of Pancreatic Islets and Insulin Secretion in a Postnatal Critical Window
Aguayo‐Mazzucato, C., Sánchez-Soto, C., Godinez-Puig, V., Gutiérrez‐Ospina, G., & Hiriart, M. (2006) · PLoS ONE · doi:10.1371/journal.pone.0000035 · Cited by 82
Self-citationActively Synthesizingβ-Cells Secrete Preferentially after Glucose Stimulation*
Bosco, D., & Meda, P. (1991) · Endocrinology · doi:10.1210/endo-129-6-3157 · Cited by 77
Functional Subpopulations of Individual Pancreatic B-Cells in Culture
Hiriart, M., & RAMIREZ-MEDELES, M. C. (1991) · Endocrinology · doi:10.1210/endo-128-6-3193 · Cited by 76
Bliss, C. R., & Sharp, G. W. (1992) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1992.263.5.e890 · Cited by 69
Cell cycle control of β-cell replication in the prenatal and postnatal human pancreas
Köhler, C. U., Olewinski, M., Tannapfel, A., Schmidt, W. E., Fritsch, H., & Meier, J. J. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00496.2010 · Cited by 64
Katsuta, H., Aguayo‐Mazzucato, C., Katsuta, R., Akashi, T., Hollister‐Lock, J., Sharma, A. J., Bonner‐Weir, S., & Weir, G. C. (2012) · Endocrinology · doi:10.1210/en.2012-1257 · Cited by 56
Self-citationNormal Relationship of β- and Non–β-Cells Not Needed for Successful Islet Transplantation
King, A., Fernandes, J. R., Hollister‐Lock, J., Nienaber, C. E., Bonner‐Weir, S., & Weir, G. C. (2007) · Diabetes · doi:10.2337/db07-0191 · Cited by 54
Self-citationExploring Functional β-Cell Heterogeneity In Vivo Using PSA-NCAM as a Specific Marker
Karaca, M., Castel, J., Tourrel‐Cuzin, C., Brun, M., Géant, A., Dubois, M., Catesson, S., Rodriguez, M., Luquet, S. H., Cattan, P., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005555 · Cited by 52
β-Cell adaptation in 60% pancreatectomy rats that preserves normoinsulinemia and normoglycemia
Liu, Y. Q., Nevin, P. W., & Leahy, J. L. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.1.e68 · Cited by 51
Ling, Z., Wang, Q., Stangé, G. M., Veld, P. I. '., & PIPELEERS, D. G. (2006) · Diabetes · doi:10.2337/diabetes.55.01.06.db05-0820 · Cited by 43
Schuppin, G. T., Bonner‐Weir, S., Montaña, E., Kaiser, Ν., & Weir, G. C. (1993) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/bf02633963 · Cited by 39
Self-citationBeta-Cell Failure, Stress, and Type 2 Diabetes
Kaufman, R. J. (2011) · New England Journal of Medicine · doi:10.1056/nejmcibr1109442 · Cited by 35
Islet Amyloid Polypeptide and Diabetes
Westermark, G. T., & Westermark, P. (2013) · Current Protein and Peptide Science · doi:10.2174/13892037113149990050 · Cited by 28
Peng, S., Zhu, L., Chen, M., Zhang, M., Li, D.-Z., Fu, Y., Chen, S., & Wei, C. (2009) · Endocrinology · doi:10.1210/en.2008-1731 · Cited by 27
Hiriart, M., Sánchez-Soto, M. C., Ramirezmedeles, M. C., & Malaisse, W. J. (1995) · Biochemical and Molecular Medicine · doi:10.1006/bmme.1995.1019 · Cited by 9
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Self-citationThe role of macrophages in obesity-associated islet inflammation and β-cell abnormalities
Ying, W., Fu, W., Lee, Y. S., & Olefsky, J. M. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0286-3 · Cited by 410
Obesity and ageing: Two sides of the same coin
Tam, B. T., Morais, J. A., & Santosa, S. (2020) · Obesity Reviews · doi:10.1111/obr.12991 · Cited by 274
Inflammageing and metaflammation: The yin and yang of type 2 diabetes
Prattichizzo, F., Nigris, V. D., Spiga, R., Mancuso, E., Sala, L. L., Antonicelli, R., Testa, R., Procopio, A. D., Olivieri, F., & Ceriello, A. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.10.003 · Cited by 255
Single-nucleus and in situ RNA-sequencing reveal cell topographies in the human pancreas
Tosti, L., Hang, Y., Debnath, O., Tiesmeyer, S., Trefzer, T., Steiger, K., Ten, F. W., Lukassen, S., Ballke, S., Kühl, A. A., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.11.010 · Cited by 228
Metadata
- Authors
- Aguayo-Mazzucato, C., van Haaren, M., Mruk, M., Lee, T. B., Crawford, C., Hollister-Lock, J., Sullivan, B. A., Johnson, J. W., Ebrahimi, A., Dreyfuss, J. M., Van Deursen, J., Weir, G. C., & Bonner-Weir, S.
- Affiliations
- Joslin Diabetes Center (US)
- Boston University (US)
- Mayo Clinic (US)
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 25
- Issue
- 4
- Pages
- 898-910.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5471618
- OpenAlex
- W2604579271
- Cited by
- 198
- References
- 66
- Citations by year
- 2026: 9 · 2025: 25 · 2024: 19 · 2023: 26 · 2022: 20 · 2021: 25 · 2020: 24 · 2019: 25 · 2018: 19 · 2017: 6
- FWCI
- 20.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- NIH (R01 DK093909, P30 DK036836, P30 DK057521)
- Diabetes Research and Wellness Foundation
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- beta-cell heterogeneity, IGF-1 receptor, insulin resistance, islet heterogeneity, cellular senescence, p16INK4a, senescence-associated β-galactosidase, endoplasmic reticulum stress, insulin receptor antagonist, type 2 diabetes pathogenesis, metabolic stress
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Adolescent, Adult, Aged, Aging, Animals, Diabetes Mellitus, Type 2, Female, Flow Cytometry, Glucose, Hemolytic Plaque Technique, Humans, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Middle Aged, RNA, Messenger, Stress, Physiological, Biomarkers, Cellular Senescence, Receptor, IGF Type 1, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Insulin-Secreting Cells, Young Adult
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