@article{6479a6c445454e13a381422ceacedc69,
title = "Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model",
abstract = "Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50-100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic beta-cell function was improved, and insulitis and pancreatic CD45.1(+) cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8(+) T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-gamma production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate beta-cell effects, NOD-derived MIN6N8 beta-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2D(b) than H-2K(b) under all conditions. Moreover, more 10-12 mer peptides were isolated from H-2D(b) after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts beta-cell function.",
keywords = "advanced glycation end products, alagebrium chloride, cross-link breaker, immunopeptidome, NOD mouse, autoimmune diabetes, type 1 diabetes, GLYCATION END-PRODUCTS, BETA-CELL DYSFUNCTION, T-CELLS, INSULIN-SECRETION, DENDRITIC CELLS, LYMPH-NODES, TYPE-1, RAGE, EXPRESSION, RECEPTOR",
author = "Borg, {Danielle J.} and Pouya Faridi and Giam, {Kai Lin} and Peta Reeves and Fotheringham, {Amelia K.} and McCarthy, {Domenica A.} and Sherman Leung and Ward, {Micheal S.} and Harcourt, {Brooke E.} and Rochelle Ayala and Scheijen, {Jean L.} and David Briskey and Dudek, {Nadine L.} and Schalkwijk, {Casper G.} and Raymond Steptoe and Purcell, {Anthony W.} and Forbes, {Josephine M.}",
note = "Funding Information: Acknowledgments: The MIN6N8 cell line used for in vitro experiments were kindly provided by Prof. Jun-ichi Miyazaki, Osaka University. The TCRα and TCRβ founder lines used to generate the G9C8 mice were kind gifts from Susan F. Wong, Cardiff University. We would like to acknowledge the staff at the UQ Biological Research Facility, Crystal Chang of the Histology Facility and Sandrine Roy and Ali Ju of the Microscopy Facility, located in the Translational Research Institute. We would like to acknowledge the provision of instrumentation, training, and technical support by the Monash Biomedical Proteomics Facility. Computational resources for omic analysis were supported by the R@CMon/Monash Node of the NeCTAR Research Cloud, an initiative of the Australian Government{\textquoteright}s Super Science Scheme and the Education Investment Fund. We would like to extend our sincere thanks to Dr Ristan Greer for statistical advice. Funding Information: This was funded by the National Health and Medical Research Council of Australia (NHMRC; 1023664, 1165490, 1084283, 1043315 J.M.F., R.S., A.W.P.), the Victorian Government In-frastructure Program, and the Mater Foundation. Authors were specifically supported by: MaterThe MIN6N8 cell line used for in vitro experiments were kindly provided by Prof. Jun-ichi Miyazaki, Osaka University. The TCR? and TCR? founder lines used to generate the G9C8 mice were kind gifts from Susan F. Wong, Cardiff University. We would like to acknowledge the staff at the UQ Biological Research Facility, Crystal Chang of the Histology Facility and Sandrine Roy and Ali Ju of the Microscopy Facility, located in the Translational Research Institute. We would like to acknowledge the provision of instrumentation, training, and technical support by the Monash Biomedical Proteomics Facility. Computational resources for omic analysis were supported by the R@CMon/Monash Node of the NeCTAR Research Cloud, an initiative of the Australian Gov-ernment?s Super Science Scheme and the Education Investment Fund. We would like to extend our sincere thanks to Dr Ristan Greer for statistical advice. Conflicts of Interest: The funders had no role in the design of the study; in the collection, analyses, Foundation (D.J.B.), Victorian Department of Health and Human Services acting through the Victorian Cancer Agency (P.F.), Australian Postgraduate Award Scholarship (P.R., A.K.F.), NHMRC Project Grant (1023664; D.M., J.M.F.), UQ/JDRF Postgraduate Scholarship (S.L.), JDRF Postdoctoral Fellowship (M.S.W.), NHMRC Peter Doherty Fellowship (B.E.H.), NHMRC Project Grant (1165490, 1084283; K.L.G., R.A.), NHMRC Principal Research Fellowship (1137739; A.W.P.), ARC Fellowship (FT110100372; R.S.) and NHMRC Senior Research Fellowship (1004503, 1102935; J.M.F.). Funding Information: Funding: This was funded by the National Health and Medical Research Council of Australia (NHMRC; 1023664, 1165490, 1084283, 1043315 J.M.F., R.S., A.W.P.), the Victorian Government Infrastructure Program, and the Mater Foundation. Authors were specifically supported by: Mater Foundation (D.J.B.), Victorian Department of Health and Human Services acting through the Victorian Cancer Agency (P.F.), Australian Postgraduate Award Scholarship (P.R., A.K.F.), NHMRC Project Grant (1023664; D.M., J.M.F.), UQ/JDRF Postgraduate Scholarship (S.L.), JDRF Postdoctoral Fellowship (M.S.W.), NHMRC Peter Doherty Fellowship (B.E.H.), NHMRC Project Grant (1165490, 1084283; K.L.G., R.A.), NHMRC Principal Research Fellowship (1137739; A.W.P.), ARC Fellowship (FT110100372; R.S.) and NHMRC Senior Research Fellowship (1004503, 1102935; J.M.F.). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = jul,
doi = "10.3390/metabo11070426",
language = "English",
volume = "11",
journal = "Metabolites",
issn = "2218-1989",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "7",
}