![\"\"](\"img\/Insulin-Amylin.png\" "\\"Insulin-Amylin\\"")
The cellular environment of \u03b2-cell granules is unique in its high concentrations of Zn2+, insulin and proinsulin c-peptide in addition to IAPP. C-peptide is the co-product of insulin synthesis, which connects insulin A- and B-chains in the precursor proinsulin and is co-secreted with insulin in equal molar. A high concentration of Zn2+, maintained by a \u03b2-cell specific zinc transporter \u2013 ZnT8, is believed to be important for the efficient storage of insulin: zinc coordinates the formation of insulin hexamers, which form crystals in the dense core of \u03b2-cell granules. ). We hypothesize<\/strong> that intermolecular interactions with insulin, zinc and c-peptide are important for the native inhibition of IAPP aggregation inside \u03b2-cell granules. Using state-of-the-art<\/em> discrete molecular dynamics (DMD) simulations, we showed that both insulin monomers and dimers could bind IAPP monomer and inhibit IAPP self-association by competing with same amyloidogenic regions, subsequently preventing aggregation. <\/span>Therefore, comparing to high zinc concentrations where insulin is insoluble in the crystal form, zinc-deficiency due to loss-of-function mutations of ZnT8 shifts insulin oligomer\/crystallization equilibrium toward soluble monomers and dimers, which can efficiently inhibit IAPP aggregation and reduce T2D risk. Currently, we are trying to understand the effects of other granule molecules, including zinc, c-peptide, and their complex, on IAPP aggregation.<\/p>\n![\"\"](\"img\/polyphenols.png\" "\\"Insulin-Amylin\\"")
We are also actively exploring other approaches to inhibit IAPP aggregation. There are many reports about natural-occurring polyphenols, including resveratrol from grape, curcumin from turmeric, EGCG from green tea, and so on, which have inhibitory effects on IAPP aggregation. The advantage of these natural-occurring polyphenols is their low toxicity and the fact that they can be administrated for a long period of time. Understanding their mechanism is important for designing de novo anti-amyloid drugs to treat T2D. Additionally, nanomedicinal approach is also an attractive approach to serve as not only drug carriers but also as anti-amyloid agents themselves. Therefore, we are also looking for anti-amyloid nanoparticles and trying to identify their physicochemical determinants for optimal drug loading and amyloid inhibiting functions.<\/p>\n
31. Z. Zhang, G. Huang, S. Gupta, E. Sargent, H. Tang, F. Ding, \u201cDeterminants for Sub-stoichiometric Inhibition of IAPP and A-Beta Amyloid Aggregations by Bri2 BRICHOS\u201d, ACS Chemical Neuroscience, 16(6): 1150\u20131160 (2025) doi:10.1021\/acschemneuro.4c00839<\/p>\n
30. Z. Song, H. Tang, A. Gatch, Y. Sun and Feng Ding, \u201cIslet Amyloid Polypeptide Fibril Catalyzes Amyloid-\u03b2 Aggregation by Promoting Fibril Nucleation Rather than Direct Axial Growth\u201d, International Journal of Biological Macromolecules (Elsevier), 279(1): 135137 (2024) doi: 10.1016\/j.ijbiomac.2024.135137<\/p>\n
29. X. Fan, X. Zhang, J. Yan, H. Xu, W. Zhao, F. Ding*, F. Huang*, Y. Sun*, \u201cComputational Investigation of Co-Aggregation and Cross-Seeding between A\u03b2 and hIAPP Underpinning the Crosstalk in Alzheimer\u2019s Disease and Type-2 Diabetes\u201d, J. Chem. Inf. Model., 64(13): 5303\u20135316 (2024) doi:10.1021\/acs.jcim.4c00859<\/p>\n
28. G. Huang, H. Tang, Y. Liu, C. Zhang, P. C. Ke, Y. Sun, F. Ding, \u201cDirect Observation of Seeded Conformational Conversion of hIAPP In Silico Reveals the Mechanisms for Morphological Dependence and Asymmetry of Fibril Growth\u201d, Journal of Chemical Information and Modeling, (63)18: 5863\u20135873 (2023) doi: 10.1021\/acs.jcim.3c00898<\/p>\n
27. N. Benhamou Goldfajn, H. Tang, F. Ding, \u201cSub-Stoichiometric Inhibition of Insulin against IAPP Aggregation is Attenuated by the Incompletely Processed N-Terminus of proIAPP\u201d, ACS Chemical Neuroscience, 13(13): 2006\u20132016 (2022) doi:10.1021\/acschemneuro.2c00231<\/p>\n
26. H. Tang, Y. Sun, F. Ding, \u201cThe Hydrophobic\/Hydrophilic Ratio of Amphiphilic Helix Mimetics Determines the Effects on Islet Amyloid Polypeptide Aggregation\u201d, Journal of Chemical Information and Modeling, 62(7): 1760\u20131770 (2022) doi:10.1021\/acs.jcim.1c01566<\/p>\n
25. N. Andrikopoulos, Z. Song, X. Wan, A. Douek, I. Javed, C. Fu, X. Changkui, Y. Xing, F. Xin, Y. Li, A. Kakinen, K. Koppel, R. Qiao, A. Whittaker, J. Kaslin, T. Davis*, Y. Song*, F. Ding*, P.C. Ke*, \u201cInhibition of Amyloid Aggregation and Toxicity with Janus Iron Oxide Nanoparticles\u201d, Chem. Mater., 33, 16, 6484\u20136500 (2021) doi: 10.1021\/acs.chemmater.1c01947<\/p>\n
24. Chen P, Ding F, Cai R, Javed I, Yang W, Zhang Z, Li Y, Davis TP, Ke PC, Chen C., \u201cAmyloidosis Inhibition, a New Frontier of the Protein Corona\u201d, Nano Today, 35:100937 (2020) doi: 10.1016\/j.nantod.2020.100937<\/p>\n
23. Koppel K, Tang H, Javed I, Parsa M, Mortimer M, Davis TP, Lin S, Chaffee AL, Ding F and Ke P, \u201cElevated Amyloidoses of Human IAPP and Amyloid Beta by Lipopolysaccharide and Their Mitigation by Carbon Quantum Dots\u201d, Nanoscale, in press (2020)<\/p>\n
22. A Nandakumar, Y Xing, R Aranha, A Faridi, A Kakinen, I Javed, K Koppel, E Pilkington, A Purcell, T Davis, P Faridi, F Ding, PC Ke, \u201cHuman Plasma Protein Corona of A\u03b2 Amyloid and Its Impact on IAPP Cross-Seeding\u201d, Biomacromolecules, 21, 988-998 (2020) DOI: 10.1021\/acs.biomac.9b01650<\/p>\n
21. A Faridi, Y Sun, M Mortimer, RR Aranha, A Nandakumar, Y Li, I Javed, A Kakinen, Q Fan, AW Purcell, TP Davis,* F Ding,* P Faridi,* and P Ke*, \u201cGraphene quantum dots rescue protein dysregulation of pancreatic \u03b2-cells exposed to human islet amyloid polypeptide\u201d, Nano Research, in press (2019)<\/p>\n
20. A Kakinen, Y Xing, NDH Arachchi, I Javed, L Feng, A Faridi, AM Douek, Y Sun, J Kaslin, TP Davis*, MJ Higgins*, F Ding*, and P Ke*, \u201cSingle-molecular hetero-amyloidosis of human islet amyloid polypeptide\u201d, Nano Lett, in press, (2019) Just Accepted<\/p>\n
19. P. C. Ke, E. H. Pilkington, Y. Sun, I. Javed, A. Kakinen, G. Peng, F. Ding, . P. Davisa, \u201cMitigation of Amyloidosis with Nanomaterials\u201d, Advanced Materials, in press, (2019)<\/p>\n
18. Y. Sun, A. Kakinen, Y. Xing, P. Faridi, A. Nandakumar, A.W. Purcell, T.P. Davis, P. Ke, and F. Ding, \u201cAmyloid self-assembly of hIAPP8-20 via the accumulation of helical oligomers, -helix to \u03b2-sheet transition, and formation of \u03b2-barrel intermediates\u201d, Small, in press, (2019)<\/p>\n
17. Y. Sun, A. Kakinen, Y. Xing, E.H. Pilkington, T.P. Davis, P. Ke, & F. Ding, \u201cNucleation of \u03b2-rich Oligomers and \u03b2-barrels in the Early Aggregation of Human Islet Amyloid Polypeptide\u201d, BBA-Molecular Basis of Disease, 1865 (2), 434-444, DOI: 10.1016\/j.bbadis.2018.11.021 <\/a> (2019)<\/p>\n 16. M. Wang, Y. Sun, X. Cao, G. Peng, I. Javed, A. Kakinen, T.P. Davis, S. Lin, J. Liu, F. Ding, and P. Ke, \u201cGraphene Quantum Dots against Human IAPP Aggregation and Toxicity in Vivo\u201d, Nanoscale 10, 19995, DOI: 10.1039\/C8NR07180B <\/a> (2018)<\/p>\n 15. A. Faridi,Y. Sun, Y. Okazaki, G. Peng, J. Gao, A. Kakinen, P. Faridi, M. Zhao, I. Javed, A.W. Purcell, T.P. Davis, S. Lin, R. Oda, F. Ding, P. Ke, \u201cMitigating Human IAPP Amyloidogenesis in Vivo with Chiral Silica Nanoribbons\u201d, Small, 14, 1802825, DOI: 10.1002\/smll.201802825 <\/a>(2018)<\/p>\n 14. Pilkington E.P., Gustafsson O.J.R., Xing Y., Hernandez-Fernaud J., Zampronio C., Kakinen A., Faridi A., Ding F., Wilson P., Ke P.C. and Davis T.P., \u201cProfiling the Serum Protein Corona of Fibrillar Human Islet Amyloid Polypeptide\u201d, ACS Nano, in press (2018)<\/p>\n 13. A. Kakinen, J. Adamcik, B. Wang, X. Ge, R. Mezzenga, T.P. Davis, F. Ding, and P. Ke, \u201cNanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules\u201d, Nano Research, in press (2017)<\/p>\n 12. I. Javed, Y. Sun, J. Adamcik, B. Wang, A. Kakinen, E. Pilkington, F. Ding, R. Mezzenga, T. Davis, Thomas; P. Ke, \u201cCo-fibrillization of pathogenic and functional amyloid proteins with gold nanoparticles against amyloidogenesis\u201d, Biomacromolecules, in press (2017) DOI: 10.1021\/acs.biomac.7b01359<\/p>\n 11. Y. Xing, E. H. Pilkington, M. Wang, C. Nowell, A. Kakinen, Y. Sun, B. Wang, T. P. Davis, F. Ding and P. C. Ke, \u201cLysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide\u201d, Phys. Chem. Chem. Phys., in press, 2017, DOI: 10.1039\/C7CP06670H<\/a><\/p>\n 10. E. Pilkington, M. Lai, X. Ge, W. Stanley, B. Wang, M. Wang, A. Kakinen, M. Sani, M. Whittaker, E. Gurzov, F. Ding, J. Quinn, T. Davis, P. Ke, \u201cStar Polymers Reduce IAPP Toxicity via Accelerated Amyloid Aggregation\u201d, Biomacromolecules, in press (2017)<\/p>\n 9. Y. Sun, B. Wang, X. Ge and F. Ding, \u201cDistinct Oligomerization and Fibrillization Dynamics of Amyloid Core Sequences of Amyloid-beta and Islet Amyloid Polypeptide\u201d, PCCP, in press (2017)<\/p>\n 8. X. Ge, A. Kakinen, E.N. Gurzov, W. Yang, L. Pang, E.H. Pilkington, P. Govindan-Nedumpully, P. Chen, F. Separovic, T.P. Davis, P. C. Ke, and F. Ding, \u201cZinc-coordination and C-peptide complexation: a potential mechanism for the endogenous inhibition of IAPP aggregation\u201d, Chem. Comm., in press (2017) [link]<\/a><\/p>\n 7. P.C. Ke, M. Sani, F. Ding, A. Kakinen, I. Javed, F. Separovic, T. P. Davis, and R. Mezzenga, Implications of Peptide Assemblies in Amyloid Diseases, Chem. Soc. Rev., in press (2017)<\/p>\n 6. Pilkington E.H., Xing Y., Wang B., Kakinen A., Wang M., Davis T.P., Ding F., Ke P.C., \u201cEffects of Protein Corona on IAPP Amyloid Aggregation, Fibril Remodelling, and Cytotoxicity\u201d, Scientific Reports, in press (2017)<\/p>\n 5. E.N. Gurzov, B. Wang, E.H. Pilkington, P. Chen,A. Kakinen, W.J. Stanley, S.A. Litwak, E.G. Hanssen,T.P. Davis, F. Ding, and P.Chun Ke, \u201cInhibition of hIAPP Amyloid Aggregation and Pancreatic \u03b2-cell Toxicity by OH-terminated PAMAM Dendrimer\u201d, Small, in press (2016)<\/p>\n 4. P. Nedumpully-Govindan, E.N. Gurzov, P. Chen, E.H. Pilkington, W.J. Stanley, S.A. Litwak, T.P. Davis, P.C. Ke, and F. Ding, \u201cGraphene Oxide Inhibits hIAPP Amyloid Fibrillation and Toxicity in Insulin-Producing NIT-1 Cells\u201d, PCCP, 18:94-100 (2016) [download]<\/a><\/p>\n 3. P. Nedumpully-Govindan, A. Kakinen, E.H. Pilkington, T.P. Davis, P.C. Ke and F. Ding, \u201cStabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition\u201d, Scientific Reports, in press (2015)<\/p>\n 2. P. Nedumpully-Govindan, Y. Yang, R. Andorfer, W. Cao, and F. Ding, \u201cPromotion or Inhibition of IAPP Aggregation by Zinc Coordination Depends on Its Relative Concentration\u201d, Biochemistry, in press (2015)<\/p>\n 1. Nedumpully-Govindan P. and Ding F., \u201cInhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration\u201d, Scientific Reports 5, (2015)<\/p>\n","protected":false},"excerpt":{"rendered":" Accumulating evidence suggests that the aggregation of islet amyloid polypeptide (IAPP, a.k.a. amylin) is associated with \u03b2-cell death in type 2 diabetes (T2D). IAPP is co-secreted with insulin by pancreatic beta-cells, and also works together with insulin to control the serum glucose level. In vitro studies suggest that IAPP is one of the most amyloidogenic … <\/p>\n