Advertisement

Biological Trace Element Research

, Volume 189, Issue 1, pp 201–208 | Cite as

Zinc Chelator Inhibits Zinc-Induced Islet Amyloid Polypeptide Deposition and Apoptosis in INS-1 Cells

  • He Tian
  • Zhan-You WangEmail author
Article

Abstract

Amyloid deposition and beta cell apoptosis are characteristic pathological features of type 2 diabetes mellitus (DM). Islet amyloid polypeptide (IAPP) is the most abundant component of amyloid deposition. Monomeric IAPP does not form amyloid deposition, but the fibrous IAPP may aggregate and form amyloid deposits. Previous studies have shown that zinc is closely related to IAPP deposition through crosslink with monomeric IAPP into fibrous aggregates. In this study, we aimed to investigate whether chelating zinc could inhibit zinc-induced amyloid deposits and apoptosis of islet beta cell. N, N, N′, N′-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) is a specific chelator of zinc, with membrane permeability. It could effectively reduce the concentration of intracellular zinc. So, we used TPEN to treat hIAPP-transfected INS-1 cells. By MTT assay, the concentration (1 μM) and incubation time (12 h) of TPEN without affecting cell viability were determined. The results showed that TPEN reduced zinc-induced IAPP deposition in the culture system. Furthermore, we analyzed the effect of zinc and TPEN on the apoptosis and insulin level. The results showed that TPEN could reverse zinc-induced INS-1 cell apoptosis and insulin secretion. And the anti-apoptosis effects of TPEN is related to extracellular regulated protein kinases (ERK)/c-jun N-terminal kinase (JNK) signaling pathway. The present data indicated that chelating zinc could inhibit zinc-induced amyloid deposition and beta cell apoptosis. Thus, maintaining zinc homeostasis in islet beta cell might become a useful strategy for DM therapy.

Keywords

Islet amyloid polypeptide Zinc Zinc chelator Apoptosis Diabetes mellitus 

Notes

Funding information

This study was supported by National Program on Key Basic Research Project (973 Program) (2012CB722405).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Sasahara K (2018) Membrane-mediated amyloid deposition of human islet amyloid polypeptide. Biophys Rev 10:453–462CrossRefGoogle Scholar
  2. 2.
    Mao Y, Yu L, Mao M, Ma C, Qu L (2018) Design and study of lipopeptide inhibitors on preventing aggregation of human islet amyloid polypeptide residues 11-20. J Pept Sci 24Google Scholar
  3. 3.
    Zhang XX, Pan YH, Huang YM, Zhao HL (2016) Neuroendocrine hormone amylin in diabetes. World J Diabetes 7:189–197CrossRefGoogle Scholar
  4. 4.
    Sanke T, Hanabusa T, Nakano Y, Oki C, Okai K, Nishimura S, Kondo M, Nanjo K (1991) Plasma islet amyloid polypeptide (amylin) levels and their responses to oral glucose in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 34:129–132CrossRefGoogle Scholar
  5. 5.
    Cao P, Marek P, Noor H, Patsalo V, Tu LH, Wang H, Abedini A, Raleigh DP (2013) Islet amyloid: from fundamental biophysics to mechanisms of cytotoxicity. FEBS Lett 587:1106–1118CrossRefGoogle Scholar
  6. 6.
    Ahmad E, Ahmad A, Singh S, Arshad M, Khan AH, Khan RH (2011) A mechanistic approach for slet amyloid polypeptide aggregation to develop anti-amyloidogenic agents for type-2 diabetes. Biochimie 93:793–805CrossRefGoogle Scholar
  7. 7.
    Gurlo T, Rivera JF, Butler AE, Cory M, Hoang J, Costes S, Butler PC (2016) CHOP contributes to, but is not the only mediator of, IAPP induced beta-cell apoptosis. Mol Endocrinol 30:446–454CrossRefGoogle Scholar
  8. 8.
    Brender JR, Hartman K, Reid KR, Kennedy RT, Ramamoorthy A (2008) A single mutation in the nonamyloidogenic region of islet amyloid polypeptide greatly reduces toxicity. Biochemistry 47:12680–12688CrossRefGoogle Scholar
  9. 9.
    Nanga RP, Brender JR, Xu J, Hartman K, Subramanian V, Ramamoorthy A (2009) Three-dimensional structure and orientation of rat islet amyloid polypeptide protein in a membrane environment by solution NMR spectroscopy. J Am Chem Soc 131:8252–8261CrossRefGoogle Scholar
  10. 10.
    Brender JR, Krishnamoorthy J, Messina GM, Deb A, Vivekanandan S, La Rosa C, Penner-Hahn JE, Ramamoorthy A (2013) Zinc stabilization of prefibrillar oligomers of human islet amyloid polypeptide. Chem Commun (Camb) 49:3339–3341CrossRefGoogle Scholar
  11. 11.
    Pithadia AS, Bhunia A, Sribalan R, Padmini V, Fierke CA, Ramamoorthy A (2016) Influence of a curcumin derivative on hIAPP aggregation in the absence and presence of lipid membranes. Chem Commun (Camb) 52:942–945CrossRefGoogle Scholar
  12. 12.
    Brender JR, Salamekh S, Ramamoorthy A (2012) Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective. Acc Chem Res 45:454–462CrossRefGoogle Scholar
  13. 13.
    Brender JR, Krishnamoorthy J, Sciacca MF, Vivekanandan S, D'Urso L, Chen J, La Rosa C, Ramamoorthy A (2015) Probing the sources of the apparent irreproducibility of amyloid formation: drastic changes in kinetics and a switch in mechanism due to micellelike oligomer formation at critical concentrations of IAPP. J Phys Chem B 119:2886–2896CrossRefGoogle Scholar
  14. 14.
    Norouzi S, Adulcikas J, Sohal SS, Myers S (2017) Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease. J Biomed Sci 24:87CrossRefGoogle Scholar
  15. 15.
    Li LB, Wang ZY (2016) Disruption of brain zinc homeostasis promotes the pathophysiological progress of Alzheimer’s disease. Histol Histopathol 31:623–627Google Scholar
  16. 16.
    Wang T, Wang CY, Shan ZY, Teng WP, Wang ZY (2012) Clioquinol reduces zinc accumulation in neuritic plaques and inhibits the amyloidogenic pathway in AbetaPP/PS1 transgenic mouse brain. J Alzheimers Dis 29:549–559CrossRefGoogle Scholar
  17. 17.
    Myers SA (2015) Zinc transporters and zinc signaling: new insights into their role in type 2 diabetes. Int J Endocrinol 2015:167503CrossRefGoogle Scholar
  18. 18.
    Wineman-Fisher V, Miller Y (2017) Insight into a new binding site of zinc ions in fibrillar amylin. ACS Chem Neurosci 8:2078–2087CrossRefGoogle Scholar
  19. 19.
    Nedumpully-Govindan P, Ding F (2015) Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration. Sci Rep 5:8240CrossRefGoogle Scholar
  20. 20.
    Hay DL (2017) Amylin. Headache 57(Suppl 2):89–96CrossRefGoogle Scholar
  21. 21.
    Erthal LC, Marques AF, Almeida FC, Melo GL, Carvalho CM, Palmieri LC, Cabral KM, Fontes GN, Lima LM (2016) Regulation of the assembly and amyloid aggregation of murine amylin by zinc. Biophys Chem 218:58–70CrossRefGoogle Scholar
  22. 22.
    Zhang S, Liu H, Chuang CL, Li X, Au M, Zhang L, Phillips AR, Scott DW, Cooper GJ (2014) The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet beta cells. FASEB 28(12):5083–5096CrossRefGoogle Scholar
  23. 23.
    Rodriguez Camargo DC, Tripsianes K, Buday K, Franko A, Gobl C, Hartlmuller C, Sarkar R, Aichler M, Mettenleiter G, Schulz M, Boddrich A, Erck C, Martens H, Walch AK, Madl T, Wanker EE, Conrad M, de Angelis MH, Reif B (2017) The redox environment triggers conformational changes and aggregation of hIAPP in type II diabetes. Sci Rep 7:44041CrossRefGoogle Scholar
  24. 24.
    Johnson KH, O'Brien TD, Betsholtz C, Westermark P (1989) Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 321:513–518CrossRefGoogle Scholar
  25. 25.
    Nedumpully-Govindan P, Yang Y, Andorfer R, Cao W, Ding F (2015) Promotion or inhibition of islet amyloid polypeptide aggregation by zinc coordination depends on its relative concentration. Biochemistry 54:7335–7344CrossRefGoogle Scholar
  26. 26.
    Brender JR, Hartman K, Nanga RP, Popovych N, de la Salud Bea R, Vivekanandan S, Marsh EN, Ramamoorthy A (2010) Role of zinc in human islet amyloid polypeptide aggregation. J Am Chem Soc 132:8973–8983CrossRefGoogle Scholar
  27. 27.
    Salamekh S, Brender JR, Hyung SJ, Nanga RP, Vivekanandan S, Ruotolo BT, Ramamoorthy A (2011) A two-site mechanism for the inhibition of IAPP amyloidogenesis by zinc. J Mol Biol 410:294–306CrossRefGoogle Scholar
  28. 28.
    Beck MW, Derrick JS, Suh JM, Kim M, Korshavn KJ, Kerr RA, Cho WJ, Larsen SD, Ruotolo BT, Ramamoorthy A, Lim MH (2017) Minor structural variations of small molecules tune regulatory activities toward pathological factors in Alzheimer’s disease. ChemMedChem 12:1828–1838CrossRefGoogle Scholar
  29. 29.
    Lee S, Zheng X, Krishnamoorthy J, Savelieff MG, Park HM, Brender JR, Kim JH, Derrick JS, Kochi A, Lee HJ, Kim C, Ramamoorthy A, Bowers MT, Lim MH (2014) Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer’s disease. J Am Chem Soc 136:299–310CrossRefGoogle Scholar
  30. 30.
    Rungby J (2010) Zinc, zinc transporters and diabetes. Diabetologia 53:1549–1551CrossRefGoogle Scholar
  31. 31.
    Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter GA, Wheeler MB (2010) Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53:1656–1668CrossRefGoogle Scholar
  32. 32.
    Nygaard SB, Larsen A, Knuhtsen A, Rungby J, Smidt K (2014) Effects of zinc supplementation and zinc chelation on in vitro beta-cell function in INS-1E cells. BMC Res Notes 7:84CrossRefGoogle Scholar
  33. 33.
    Subramanian SL, Hull RL, Zraika S, Aston-Mourney K, Udayasankar J, Kahn SE (2012) cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets. Diabetologia 55:166–174CrossRefGoogle Scholar
  34. 34.
    Zhao T, Bai J, Zou Q, Chen F, Xie Y (2017) Insulin in combination with cisplatin induces the apoptosis of ovarian cancer cells via p53 and JNK activation. Mol Med Rep 16:9095–9101CrossRefGoogle Scholar
  35. 35.
    Guan FY, Gu J, Li W, Zhang M, Ji Y, Li J, Chen L, Hatch GM (2014) Compound K protects pancreatic islet cells against apoptosis through inhibition of the AMPK/JNK pathway in type 2 diabetic mice and in MIN6 beta-cells. Life Sci 107:42–49CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of educationChina Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Histology and EmbryologyJinzhou Medical UniversityJinzhouPeople’s Republic of China

Personalised recommendations