Human soluble receptor for advanced glycation end products therapy delays autoimmune diabetes in the non-obese diabetic mouse — ASN Events
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Human soluble receptor for advanced glycation end products therapy delays autoimmune diabetes in the non-obese diabetic mouse (#161)

Sherman Leung 1 2 , Danielle Borg 1 , Domenica McCarthy 1 , Aowen Zhuang 1 , Amelia Fotheringham 1 , Giovanna Di Trapani 2 , Per-Henrik Groop 3 , Mikael Knip 3 , Josephine Forbes 1 4
  1. Mater Research Institute - The University of Queensland, Woolloongabba, QLD, Australia
  2. School of Natural Sciences, Griffith University, Nathan, QLD, Australia
  3. University of Helsinki, Helsinki, Finland
  4. Mater Clinical School, The University of Queensland, Brisbane, QLD, Australia

Type 1 diabetes (T1D) is rising in incidence and this has been attributed to environmental changes that increase the levels of circulating advanced glycation end products (AGEs). AGEs bind to their receptor, receptor for AGEs (RAGE). Both circulating AGE levels and RAGE expression are altered in children prior to T1D diagnosis. This study aimed to deliver recombinant human soluble RAGE (sRAGE), a decoy RAGE isoform, to reduce RAGE signalling prediabetes in the non-obese diabetic (NOD) mouse.

Female NOD mice were randomised and intraperitoneally injected twice daily with recombinant human sRAGE (25 µg) or vehicle (PBS) from days 50-64 of life. Mice were followed until 0 (n=6), 2 (n=14) or 22 weeks (n=15) post-treatment.

Human sRAGE therapy protected mice from diabetes up to day 225 of life compared to mice given the vehicle (13% vs 53%; p=0.01). While the non-fasted blood glucose concentrations of vehicle mice progressively increased from day 50-225, sRAGE mice did not follow this trend (slope non-zero vs zero; p<0.0001). Furthermore, sRAGE treatment reduced fasted blood glucose levels at day 225 (6.5 vs 7.8 mmol/L; p=0.0007). At day 80, oral glucose tolerance tests revealed unchanged area under the glucose curves (899 vs 835 mmol/L.120min; p=0.19) but the area under the insulin curves demonstrated increased insulin secretion (37.1 vs 29.8 ng/mL.120min; p=0.02). Flow cytometry confirmed alterations in splenic leukocyte numbers at day 64 including an increase in CD11b+CD11c+CD8-RAGE+ dendritic cells (2.7-fold; p=0.008) as well as classical (F4/80+CD11c-Ly6C+; 2-fold; p=0.04) and non-classical macrophages (F4/80+CD11c-Ly6C-; 1.9-fold; p=0.02). Splenic T cell numbers were unchanged immediately following treatment but by day 225, sRAGE treated mice had reduced total CD8+ T cells (1.4-fold; p=0.04) and naïve CD8+ T cells (CD62L+CD44-; 1.6-fold; p=0.01).

These results demonstrate that human sRAGE therapy in NOD mice protects against autoimmune diabetes, improves glycaemic control and alters systemic antigen presenting cell and T cell numbers.