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
Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia.
Pregnancy and Development, Mater Research Institute, The University of Queensland, South Brisbane, QLD 4101, Australia.
Metabolites. 2021 Jun 28;11(7):426. doi: 10.3390/metabo11070426.
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.
晚期糖基化终末产物（AGEs）促成1型糖尿病（T1D）发病机制的具体机制尚不清楚。由于用氯氨酮（ALT）进行终身药物治疗可减缓实验性T1D的进展，我们推测在糖尿病前期进行急性ALT治疗可能有效。然而，在雌性非肥胖糖尿病（NOD）小鼠中，在糖尿病前期（第50 - 100天）给予ALT并不能预防实验性T1D。ALT并未降低循环中的AGEs或其前体。尽管如此，胰腺β细胞功能得到改善，胰岛炎和胰腺CD45.1细胞浸润减少。淋巴组织未受影响。在输注致敏的GC98 CD8 T细胞受体转基因T细胞之前进行ALT预处理，可降低血糖浓度并延缓糖尿病发生，提示ALT对胰岛有作用而非免疫调节作用。事实上，ALT并未降低卵清蛋白预免疫的NOD小鼠白细胞产生的干扰素-γ，且给予致糖尿病的ALT处理的NOD脾细胞的NOD受体并未预防T1D。为阐明β细胞效应，使用免疫肽组学检测了NOD来源的MIN6N8β细胞主要组织相容性复合体（MHC）I类a表面抗原。总体而言，在各种治疗过程中未观察到免疫肽组的重大变化，所有肽均表现出等位基因特异性共有结合基序。正如预期的那样，在所有条件下，与H - 2K相比，更长的MHC I类a肽与H - 2D结合。此外，与牛血清白蛋白（BSA）或AGE - BSA + ALT处理相比，在AGE修饰的牛血清白蛋白（AGE - BSA）处理后，从H - 2D中分离出更多的10 - 12聚体肽。MIN6N8细胞的蛋白质组学显示，与BSA处理相比，AGE - BSA处理使与分解代谢、免疫系统、细胞周期和突触前内吞作用相关的过程富集。这些数据表明，在糖尿病前期给予短期ALT干预并不能阻止实验性T1D，但会短暂影响β细胞功能。
