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

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 b...

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Published in:	Metabolites Vol. 11; no. 7; p. 426
Main Authors:	Borg, Danielle J, Faridi, Pouya, Giam, Kai Lin, Reeves, Peta, Fotheringham, Amelia K, McCarthy, Domenica A, Leung, Sherman, Ward, Micheal S, Harcourt, Brooke E, Ayala, Rochelle, Scheijen, Jean L, Briskey, David, Dudek, Nadine L, Schalkwijk, Casper G, Steptoe, Raymond, Purcell, Anthony W, Forbes, Josephine M
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 28-06-2021 MDPI
Subjects:	advanced glycation end products Advanced glycosylation end products Age alagebrium chloride Antigens Autoimmune diseases Beta cells Bovine serum albumin CD45 antigen CD8 antigen Chlorides cross-link breaker Cytotoxicity Dendritic cells Diabetes Diabetes mellitus (insulin dependent) Drug therapy Endocytosis Flow cytometry Glucose Glycosylation Hemoglobin Histocompatibility antigen H-2 Immune system Immunomodulation immunopeptidome Insulin Insulitis Leukocytes Lymphatic system Lymphocytes Lymphocytes T Lymphoid tissue Major histocompatibility complex MIN6N8 cell line NOD mouse Ovalbumin Pancreas Peptides Proteomics T cell receptors γ-Interferon type 1 diabetes alagebrium chloride autoimmune diabetes NOD mouse immunopeptidome MIN6N8 cell line advanced glycation end products cross-link breaker
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally. These senior authors contributed equally.
ISSN:	2218-1989 2218-1989
DOI:	10.3390/metabo11070426