Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Endocrine
Published in: Endocrine 2/2016

01-11-2016 | Original Article

Inhibition of tumor suppressor p53 preserves glycation-serum induced pancreatic beta-cell demise

Authors: Y. Li, T. Zhang, Q. Huang, Y. Sun, X. Chang, H. Zhang, Y. Zhu, X. Han

Published in: Endocrine | Issue 2/2016

Login to get access

Abstract

Tumor suppressor p53 is a transcriptional factor that determines cell fate in response to multiple stressors, such as oxidative stress and endoplasmic reticulum stress, in the majority of cells. However, its role in pancreatic beta cells is not well documented. Our previous research has revealed that glycation-serum (GS) induced pancreatic beta-cell demise through the AGEs-RAGE pathway. In the present study, we investigated the role of p53 in GS-related beta-cell demise. Using pancreatic islets beta-cell line INS-1 cells, we found that with GS treatment, the transcriptional activity of p53 was significantly evoked due to the increased amount of nuclear p53 protein. Resveratrol (RSV) was capable of further enhancing this transcriptional ability and consequently increased the population of dead beta cells under GS exposure. In contrast, inhibiting this transcriptional activity via p53 interference greatly protected beta cells from the damage provoked by GS, as well as damage strengthened by RSV. However, the pharmacological activation of PPARγ with troglitazone (TRO) only suppressed GS-induced, not RSV-induced, p53 activity. Moreover, the activation of PPARγ greatly preserved beta cells from GS-induced death. This protective effect recurred due to improved mitochondrial function with Bcl2 overexpression. Further, p53 activation could induce cellular apoptosis in primary rat islets. Our findings explore the broader role of p53 in regulating pancreatic beta-cell demise in the presence of GS and may provide a therapeutic target for the treatment and prevention of diabetes.
Appendix
Available only for authorised users
Literature
1.
Z. Fu, E.R. Gilbert, D. Liu, Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr. Diabetes Rev. 9, 25–53 (2013)CrossRefPubMedPubMedCentral
2.
S. Cernea, M. Dobreanu, Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. Biochemia Medica 23, 266–280 (2013)CrossRefPubMedPubMedCentral
3.
Y. Hirasawa, Y. Matsui, S. Ohtsu, K. Yamane, T. Toyoshi, K. Kyuki, T. Sakai, Y. Feng, T. Nagamatsu, Involvement of hyperglycemia in deposition of aggregated protein in glomeruli of diabetic mice. Eur. J. Pharmacol. 601, 129–135 (2008)CrossRefPubMed
4.
K. Nowotny, T. Jung, A. Hohn, D. Weber, T. Grune, Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 5, 194–222 (2015)CrossRefPubMedPubMedCentral
5.
J. O’Brien, P.A. Morrissey, Nutritional and toxicological aspects of the Maillard browning reaction in foods. Crit. Rev. Food Sci. Nutr. 28, 211–248 (1989)CrossRefPubMed
6.
R. Ramasamy, S.J. Vannucci, S.S. Yan, K. Herold, S.F. Yan, A.M. Schmidt, Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15, 16R–28R (2005)CrossRefPubMed
7.
H. Vlassara, G.E. Striker, Advanced glycation end products in diabetes and diabetic complications. Endocrinol. Metab. Clin. N. Am. 42, 697–719 (2013)CrossRef
8.
R. Pokupec, M. Kalauz, N. Turk, Z. Turk, Advanced glycation end products in human diabetic and non-diabetic cataractous lenses. Graefes. Arch. Clin. Exp. Ophthalmol. 241, 378–384 (2003)CrossRefPubMed
9.
O. Sandu, K. Song, W. Cai, F. Zheng, J. Uribarri, H. Vlassara, Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. Diabetes 54, 2314–2319 (2005)CrossRefPubMed
10.
E.J. Gallagher, D. LeRoith, E. Karnieli, The metabolic syndrome-from insulin resistance to obesity and diabetes. Endocrinol. Metab. Clin. N. Am. 37, 559–579 (2008)CrossRef
11.
W. Cai, M. Ramdas, L. Zhu, X. Chen, G.E. Striker, H. Vlassara, Oral advanced glycation end products (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. Proc. Natl. Acad. Sci. USA 109, 15888–15893 (2012)CrossRefPubMedPubMedCentral
12.
G. Luciano Viviani, A. Puddu, G. Sacchi, A. Garuti, D. Storace, A. Durante, F. Monacelli, P. Odetti, Glycated fetal calf serum affects the viability of an insulin-secreting cell line in vitro. Metabolism. 57, 163–169 (2008)CrossRefPubMed
13.
X. Kong, G.D. Wang, M.Z. Ma, R.Y. Deng, L.Q. Guo, J.X. Zhang, J.R. Yang, Q. Su, Sesamin ameliorates advanced glycation end products-induced pancreatic beta-cell dysfunction and apoptosis. Nutrients 7, 4689–4704 (2015)CrossRefPubMedPubMedCentral
14.
J. Uribarri, W. Cai, M. Ramdas, S. Goodman, R. Pyzik, X. Chen, L. Zhu, G.E. Striker, H. Vlassara, Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011)CrossRefPubMedPubMedCentral
15.
16.
C. Luevano-Contreras, M.E. Garay-Sevilla, K. Wrobel, J.M. Malacara, K. Wrobel, Dietary advanced glycation end products restriction diminishes inflammation markers and oxidative stress in patients with type 2 diabetes mellitus. J. Clin. Biochem. Nutr. 52, 22–26 (2013)CrossRefPubMed
17.
A. Puddu, R. Sanguineti, A. Durante, A. Nencioni, F. Mach, F. Montecucco, G.L. Viviani, Glucagon-like peptide-1 triggers protective pathways in pancreatic beta-cells exposed to glycated serum. Mediat. Inflamm. 2013, 317120 (2013)
18.
T. Shu, Y. Zhu, H. Wang, Y. Lin, Z. Ma, X. Han, AGEs decrease insulin synthesis in pancreatic beta-cell by repressing Pdx-1 protein expression at the post-translational level. PLoS ONE 6, e18782 (2011)CrossRefPubMedPubMedCentral
19.
Y. Zhu, T. Shu, Y. Lin, H. Wang, J. Yang, Y. Shi, X. Han, Inhibition of the receptor for advanced glycation end products (RAGE) protects pancreatic beta-cells. Biochem. Biophys. Res. Commun. 404, 159–165 (2011)CrossRefPubMed
20.
L. Jiang, J.H. Hickman, S.J. Wang, W. Gu, Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle 14, 2881–2885 (2015)CrossRefPubMedPubMedCentral
21.
N. Sen, Y.K. Satija, S. Das, PGC-1alpha, a key modulator of p53, promotes cell survival upon metabolic stress. Mol. Cell 44, 621–634 (2011)CrossRefPubMed
22.
S.E. Thomas, E. Malzer, A. Ordonez, L.E. Dalton, E.F. van ‘t Wout, E. Liniker, D.C. Crowther, D.A. Lomas, S.J. Marciniak, p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress. J. Biol. Chem. 288, 7606–7617 (2013)CrossRefPubMedPubMedCentral
23.
24.
Z. Li, M. Ni, J. Li, Y. Zhang, Q. Ouyang, C. Tang, Decision making of the p53 network: death by integration. J. Theor. Biol. 271, 205–211 (2011)CrossRefPubMed
25.
S. Zhang, J. Liu, E.L. Saafi, G.J. Cooper, Induction of apoptosis by human amylin in RINm5F islet beta-cells is associated with enhanced expression of p53 and p21WAF1/CIP1. FEBS Lett. 455, 315–320 (1999)CrossRefPubMed
26.
P. Lovis, E. Roggli, D.R. Laybutt, S. Gattesco, J.Y. Yang, C. Widmann, A. Abderrahmani, R. Regazzi, Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction. Diabetes 57, 2728–2736 (2008)CrossRefPubMedPubMedCentral
27.
H. Yuan, X. Zhang, X. Huang, Y. Lu, W. Tang, Y. Man, S. Wang, J. Xi, J. Li, NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of beta-cells via JNK, p38 MAPK and p53 pathways. PLoS ONE 5, e15726 (2010)CrossRefPubMedPubMedCentral
28.
V.B. Cismasiu, J. Duque, E. Paskaleva, D. Califano, S. Ghanta, H.A. Young, D. Avram, BCL11B enhances TCR/CD28-triggered NF-kappaB activation through up-regulation of Cot kinase gene expression in T-lymphocytes. Biochem. J. 417, 457–466 (2009)CrossRefPubMedPubMedCentral
29.
Y. Lin, X. Tang, Y. Zhu, T. Shu, X. Han, Identification of PARP-1 as one of the transcription factors binding to the repressor element in the promoter region of COX-2. Arch. Biochem. Biophys. 505, 123–129 (2011)CrossRefPubMed
30.
S.D. Varma, P.S. Devamanoharan, A.H. Ali, Formation of advanced glycation end (AGE) products in diabetes: prevention by pyruvate and alpha-ketoglutarate. Mol. Cell. Biochem. 171, 23–28 (1997)CrossRefPubMed
31.
L.B. Lingelbach, A.E. Mitchell, R.B. Rucker, R.B. McDonald, Accumulation of advanced glycation end products in aging male Fischer 344 rats during long-term feeding of various dietary carbohydrates. J. Nutr. 130, 1247–1255 (2000)PubMed
32.
Z. Zhao, C. Zhao, X.H. Zhang, F. Zheng, W. Cai, H. Vlassara, Z.A. Ma, Advanced glycation end products inhibit glucose-stimulated insulin secretion through nitric oxide-dependent inhibition of cytochrome c oxidase and adenosine triphosphate synthesis. Endocrinology 150, 2569–2576 (2009)CrossRefPubMedPubMedCentral
33.
M.T. Coughlan, F.Y. Yap, D.C. Tong, S. Andrikopoulos, A. Gasser, V. Thallas-Bonke, D.E. Webster, J. Miyazaki, T.W. Kay, R.M. Slattery, D.M. Kaye, B.G. Drew, B.A. Kingwell, S. Fourlanos, P.H. Groop, L.C. Harrison, M. Knip, J.M. Forbes, Advanced glycation end products are direct modulators of beta-cell function. Diabetes 60, 2523–2532 (2011)CrossRefPubMedPubMedCentral
34.
Y. Zhu, A. Ma, H. Zhang, C. Li, PPARgamma activation attenuates glycated-serum induced pancreatic beta-cell dysfunction through enhancing Pdx1 and Mafa protein stability. PLoS ONE 8, e56386 (2013)CrossRefPubMedPubMedCentral
35.
Ge QM, Dong Y, Su Q. Effects of glucose and advanced glycation end products on oxidative stress in MIN6 cells. Cell Mol Biol (Noisy-le-grand). 2010; 56 Suppl: OL1231-8
36.
A.K. Mohamed, A. Bierhaus, S. Schiekofer, H. Tritschler, R. Ziegler, P.P. Nawroth, The role of oxidative stress and NF-kappaB activation in late diabetic complications. Biofactors 10, 157–167 (1999)CrossRefPubMed
37.
K.C. Lan, C.Y. Chiu, C.W. Kao, K.H. Huang, C.C. Wang, K.T. Huang, K.S. Tsai, M.L. Sheu, S.H. Liu, Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-kappaB-activated cyclooxygenase-2/prostaglandin E2 up-regulation. PLoS ONE 10, e0124418 (2015)CrossRefPubMedPubMedCentral
38.
39.
C. Arous, P.G. Ferreira, E.T. Dermitzakis, P.A. Halban, Short term exposure of beta cells to low concentrations of interleukin-1beta improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression. J. Biol. Chem. 290, 6653–6669 (2015)CrossRefPubMedPubMedCentral
40.
M. Cnop, N. Welsh, J.C. Jonas, A. Jorns, S. Lenzen, D.L. Eizirik, Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2), S97–S107 (2005)CrossRefPubMed
41.
M.Y. Donath, J. Storling, K. Maedler, T. Mandrup-Poulsen, Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J. Mol. Med. 81, 455–470 (2003)CrossRefPubMed
42.
I. Rakatzi, H. Mueller, O. Ritzeler, N. Tennagels, J. Eckel, Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1. Diabetologia 47, 249–258 (2004)CrossRefPubMed
43.
K. Maedler, P. Sergeev, F. Ris, J. Oberholzer, H.I. Joller-Jemelka, G.A. Spinas, N. Kaiser, P.A. Halban, M.Y. Donath, Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002)CrossRefPubMedPubMedCentral
44.
I. Kharroubi, L. Ladriere, A.K. Cardozo, Z. Dogusan, M. Cnop, D.L. Eizirik, Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145, 5087–5096 (2004)CrossRefPubMed
45.
J. Buteau, W. El-Assaad, C.J. Rhodes, L. Rosenberg, E. Joly, M. Prentki, Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 47, 806–815 (2004)CrossRefPubMed
46.
F. Xin, L. Jiang, X. Liu, C. Geng, W. Wang, L. Zhong, G. Yang, M. Chen, Bisphenol A induces oxidative stress-associated DNA damage in INS-1 cells. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 769, 29–33 (2014)CrossRefPubMed
47.
S. Tornovsky-Babeay, D. Dadon, O. Ziv, E. Tzipilevich, T. Kadosh, R. Schyr-Ben Haroush, A. Hija, M. Stolovich-Rain, J. Furth-Lavi, Z. Granot, S. Porat, L.H. Philipson, K.C. Herold, T.R. Bhatti, C. Stanley, F.M. Ashcroft, P. In’t Veld, A. Saada, M.A. Magnuson, B. Glaser, Y. Dor, Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in beta cells. Cell Metab. 19, 109–121 (2014)CrossRefPubMed
48.
D.A. Cunha, M. Igoillo-Esteve, E.N. Gurzov, C.M. Germano, N. Naamane, I. Marhfour, M. Fukaya, J.M. Vanderwinden, C. Gysemans, C. Mathieu, L. Marselli, P. Marchetti, H.P. Harding, D. Ron, D.L. Eizirik, M. Cnop, Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human beta-cell apoptosis. Diabetes 61, 2763–2775 (2012)CrossRefPubMedPubMedCentral
49.
O.D. Maddocks, C.R. Berkers, S.M. Mason, L. Zheng, K. Blyth, E. Gottlieb, K.H. Vousden, Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013)CrossRefPubMed
50.
C. Evans-Molina, R.D. Robbins, T. Kono, S.A. Tersey, G.L. Vestermark, C.S. Nunemaker, J.C. Garmey, T.G. Deering, S.R. Keller, B. Maier, R.G. Mirmira, Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure. Mol. Cell. Biol. 29, 2053–2067 (2009)CrossRefPubMedPubMedCentral
51.
K.K. Brown, B.R. Henke, S.G. Blanchard, J.E. Cobb, R. Mook, I. Kaldor, S.A. Kliewer, J.M. Lehmann, J.M. Lenhard, W.W. Harrington, P.J. Novak, W. Faison, J.G. Binz, M.A. Hashim, W.O. Oliver, H.R. Brown, D.J. Parks, K.D. Plunket, W.Q. Tong, J.A. Menius, K. Adkison, S.A. Noble, T.M. Willson, A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes 48, 1415–1424 (1999)CrossRefPubMed
52.
J.S. Wu, T.N. Lin, K.K. Wu, Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. J. Cell. Physiol. 220, 58–71 (2009)CrossRefPubMed
53.
Y. Ren, C. Sun, Y. Sun, H. Tan, Y. Wu, B. Cui, Z. Wu, PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation. Vascul. Pharmacol. 51, 169–174 (2009)CrossRefPubMed
54.
J.C. Strum, R. Shehee, D. Virley, J. Richardson, M. Mattie, P. Selley, S. Ghosh, C. Nock, A. Saunders, A. Roses, Rosiglitazone induces mitochondrial biogenesis in mouse brain. J. Alzheimers Dis. 11, 45–51 (2007)PubMed
Metadata
Title
Inhibition of tumor suppressor p53 preserves glycation-serum induced pancreatic beta-cell demise
Authors
Y. Li
T. Zhang
Q. Huang
Y. Sun
X. Chang
H. Zhang
Y. Zhu
X. Han
Publication date
01-11-2016
Publisher
Springer US
Published in
Endocrine / Issue 2/2016
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-016-0979-5

Other articles of this Issue 2/2016

Endocrine 2/2016 Go to the issue

Original Article

Late-night salivary cortisol may be valuable for assessing treatment response in patients with Cushing’s disease: 12-month, Phase III pasireotide study

Original Article

Serial post-surgical stimulated and unstimulated highly sensitive thyroglobulin measurements in low- and intermediate-risk papillary thyroid carcinoma patients not receiving radioactive iodine

Original Article

In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway

Original Article

Type 1 familial partial lipodystrophy: understanding the Köbberling syndrome

Original Article

SF-1 deficiency causes lipid accumulation in Leydig cells via suppression of STAR and CYP11A1

Editorial

Is the hypothalamic–pituitary–adrenal axis disrupted in type 2 diabetes mellitus?

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits