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Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model. | LitMetric

AI Article Synopsis

  • The study investigates how advanced glycation end products (AGEs) affect type 1 diabetes (T1D) development and tests if alagebrium chloride (ALT) treatment before diabetes onset can prevent the disease in mice.
  • Results show that while ALT did not lower circulating AGEs or halt T1D progression, it did enhance pancreatic β-cell function and reduce signs of inflammation in the pancreas.
  • Proteomic analysis revealed that ALT treatment led to specific changes in cellular processes but did not alter key immune responses, indicating that the protection observed was likely due to direct effects on β-cells rather than immune system modulation.

Article 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 (NOD) 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 NOD mice and NOD 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-2D than H-2K under all conditions. Moreover, more 10-12 mer peptides were isolated from H-2D 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305727PMC
http://dx.doi.org/10.3390/metabo11070426DOI Listing

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