Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Lowering glycation products in experimental autoimmune diabetes reduces islet inflammation through islet localised effects   (#138)

Danielle J Borg 1 , Micheal S Ward 1 , Domenica McCarthy 1 , Amelia K Fotheringham 1 , Linda A Gallo 1 , Brooke E Harcourt 1 , Lisa Tom 1 , Raymond Steptoe 2 , Josephine M Forbes 1
  1. Mater Research Institute- University of Queensland, Brisbane, Queensland, Australia
  2. Diamantina Institute- University of Queensland, Brisbane, Queensland, Australia

Advanced glycation end products (AGEs) are considered independent predictors of type 1 diabetes progression in islet autoantibody positive children. We aimed to study the immune effect of two AGE lowering therapies administered as short term treatments prediabetes. Randomised, fifty day old female NODShiLt mice (NOD; n=10/group) received (i) Vehicle only (ii) a diet 4-fold lower in AGE content or (iii) the drug, alagebrium chloride (ALT; 1mg/kg/day sc) from day 50 - 100 of life and were followed until diabetes diagnosis or day 200. For functional studies, NOD mice were treated from day 50 - 80 of life. NOD mice treated with ALT for 50 days, had a highly-significant reduction in diabetes incidence by day 200 compared to control mice (80% vs 20%, p=0.005). Conversely, mice fed a low AGE diet for 50 days and then returned to standard chow were not protected from diabetes compared to control (80% vs 60%, p=0.35) or continuous administration of the low AGE diet. After only 30 days of therapy (day 50-80), little variation was observed in CD4+, CD8+ or regulatory T cell, or antigen presenting cell numbers in pancreatic lymph nodes or spleen, however a significant reduction in insulitis was seen in mice treated with ALT or a low AGE diet compared to control mice (p<0.05; p<0.01, respectively). Immunofluorescence revealed reduced CD4+ T cell infiltration within pancreata after ALT therapy or a low AGE diet compared to controls (20 vs 80 vs 650 cells/nm2, respectively). Stimulated pancreatic leukocytes from ALT treated mice at day 80 showed markedly reduced levels of IL-2, IL-6, IFN-γ and TNF-α in comparison to the control (p=0.01). Despite this, splenocytes from ALT, but not low AGE diet treated mice, transferred diabetes to female NODscid recipients compared to untreated control cell transfer (69% vs 100% vs 62%, respectively). This suggests that AGE-lowering therapies may reduce diabetes incidence by modulating anti-islet immunity locally at the pancreatic islet or through direct immune-suppressive modulation.