Salicylate Prevents Virus-Induced Type 1 Diabetes in the BBDR Rat

Abstract

Epidemiologic and clinical evidence suggests that virus infection plays an important role in human type 1 diabetes pathogenesis. We used the virus-inducible BioBreeding Diabetes Resistant (BBDR) rat to investigate the ability of sodium salicylate, a non-steroidal anti-inflammatory drug (NSAID), to modulate development of type 1 diabetes. BBDR rats treated with Kilham rat virus (KRV) and polyinosinic:polycytidylic acid (pIC, a TLR3 agonist) develop diabetes at nearly 100% incidence by ~2 weeks. We found distinct temporal profiles of the proinflammatory serum cytokines, IL-1β, IL-6, IFN-γ, IL-12, and haptoglobin (an acute phase protein) in KRV+pIC treated rats. Significant elevations of IL-1β and IL-12, coupled with sustained elevations of haptoglobin, were specific to KRV+pIC and not found in rats co-treated with pIC and H1, a non-diabetogenic virus. Salicylate administered concurrently with KRV+pIC inhibited the elevations in IL-1β, IL-6, IFN-γ and haptoglobin almost completely, and reduced IL-12 levels significantly. Salicylate prevented diabetes in a dose-dependent manner, and diabetes-free animals had no evidence of insulitis. Our data support an important role for innate immunity in virus-induced type 1 diabetes pathogenesis. The ability of salicylate to prevent diabetes in this robust animal model demonstrates its potential use to prevent or attenuate human autoimmune diabetes.

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

“…Our analysis shows islets are composed of at least nine distinct cell types, including multiple β-cell subtypes, as well as it helped us detect a complex interplay between the different islet cells types that culminates in VEGF signaling by β-cells that drives vascularization through an ERK-dependent pathway in endothelial cells. It would be fascinating to extend these analyses to model organisms such as the NOD mouse or the BBDR where onset of T1D can be monitored (Bortell and Yang 2012;Yang et al 2013b). In these models, single-cell analysis would reveal not only changes in the exact composition of hormone-producing cells but also subtle differences within each group.…”

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

“…Interventions have also been possible to prevent KRV-induced diabetes in the BBDR rat [38,39]. These have helped to elucidate some mechanisms but the relevance to human disease is so far unknown.…”

Possible type 1 diabetes risk prediction: Using ultrasound imaging to assess pancreas inflammation in the inducible autoimmune diabetes BBDR model

“…In support of this, we previously found that pro-inflammatory IL-1β levels in sera of diabetes-induced rats were significantly increased at the same time point [24]. In humans, multiple pro-inflammatory cytokines, including IL-1β, were significantly higher in children positive for islet autoantibodies [25].…”

“…In support of this, in our previous studies, we compared the serum levels of inflammatory proteins in rats treated with pIC+KRV or pIC+H1 virus [24, 29]. Although H1 and KRV are both parvoviruses with 98% sequence identity, pIC+H1 treatment does not induce diabetes [30].…”