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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Article number426
Number of pages21
Issue number7
Publication statusPublished - Jul 2021


  • advanced glycation end products
  • alagebrium chloride
  • cross-link breaker
  • immunopeptidome
  • NOD mouse
  • autoimmune diabetes
  • type 1 diabetes
  • TYPE-1
  • RAGE

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