Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model
Danielle J. Borg,
Pouya Faridi,
Kai Lin Giam,
Peta Reeves,
Amelia K. Fotheringham,
Domenica A. McCarthy,
Sherman Leung,
Micheal S. Ward,
Brooke E. Harcourt,
Rochelle Ayala,
Jean L. Scheijen,
David Briskey,
Nadine L. Dudek,
Casper G. Schalkwijk,
Raymond Steptoe,
Anthony W. Purcell,
Josephine M. Forbes
Affiliations
Danielle J. Borg
Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
Pouya Faridi
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Kai Lin Giam
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Peta Reeves
Tolerance and Autoimmunity Group, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia
Amelia K. Fotheringham
Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
Domenica A. McCarthy
Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
Sherman Leung
Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
Micheal S. Ward
Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
Brooke E. Harcourt
Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
Rochelle Ayala
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Jean L. Scheijen
Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, 6211 Maastricht, The Netherlands
David Briskey
School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD 4067, Australia
Nadine L. Dudek
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Casper G. Schalkwijk
Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, 6211 Maastricht, The Netherlands
Raymond Steptoe
Tolerance and Autoimmunity Group, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia
Anthony W. Purcell
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Josephine M. Forbes
Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
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 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-γ 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 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.
