TY - JOUR
T1 - Short duration alagebrium chloride therapy prediabetes does not inhibit progression to autoimmune diabetes in an experimental model
AU - Borg, Danielle J.
AU - Faridi, Pouya
AU - Giam, Kai Lin
AU - Reeves, Peta
AU - Fotheringham, Amelia K.
AU - McCarthy, Domenica A.
AU - Leung, Sherman
AU - Ward, Micheal S.
AU - Harcourt, Brooke E.
AU - Ayala, Rochelle
AU - Scheijen, Jean L.
AU - Briskey, David
AU - Dudek, Nadine L.
AU - Schalkwijk, Casper G.
AU - Steptoe, Raymond
AU - Purcell, Anthony W.
AU - Forbes, Josephine M.
N1 - 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’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:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7
Y1 - 2021/7
N2 - 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 β-cell function was im-proved, 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-γ production by leuko-cytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-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-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db 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 β-cell function.
AB - 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 β-cell function was im-proved, 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-γ production by leuko-cytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-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-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db 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 β-cell function.
KW - Advanced glycation end products
KW - Alagebrium chloride
KW - Autoimmune diabetes
KW - Cross-link breaker
KW - Immunopep-tidome
KW - MIN6N8 cell line
KW - NOD mouse
KW - Type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85109382490&partnerID=8YFLogxK
U2 - 10.3390/metabo11070426
DO - 10.3390/metabo11070426
M3 - Article
C2 - 34203471
AN - SCOPUS:85109382490
SN - 2218-1989
VL - 11
JO - Metabolites
JF - Metabolites
IS - 7
M1 - 426
ER -
