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.