Evaluation of the pharmacological cathepsin S inhibitor LY3000328 on autoimmune diabetes in mice

There is an emerging role for the lysosomal protease cathepsin S (CTSS) in the pathogenesis of type 1 diabetes (T1D). This is supported by key findings, including that circulating levels of CTSS are increased in individuals with T1D, and that genetic ablation of Ctss in non-obese diabetic (NOD) mice - a well-established model of autoimmune diabetes - reduces both insulitis and diabetes incidence. In this study, we evaluated the impact of the pharmacological Ctss inhibitor LY3000328 on diabetes development in NOD mice. Female NOD mice were fed a standard diet with or without LY3000328 (10 mg/kg/day) from three weeks of age. The effect of treatment on diabetes incidence, insulitis, glucose tolerance, and circulating inflammatory markers was assessed. Furthermore, the spatial insulin and Ctss protein expressions were investigated in pancreatic islets from pre-diabetic and diabetic NOD mice fed diet with or without LY3000328. Finally, cathepsin B and L protein levels were quantified in both spleen and pancreas lysates. Compared to NOD mice on control diet, NOD mice on the LY3000328 diet had accelerated diabetes incidence, impaired glucose tolerance, and tended to have more insulitis. Moreover, 13-week-old NOD mice from the LY3000328 group had a reduced insulin-positive area within the islets, an increased Ctss-positive area within the islet infiltrate, and elevated pancreatic cathepsin B and L levels. Our study shows that LY3000328 accelerates diabetes development in NOD mice. The data highlight the multifaceted involvement of Ctss in T1D pathogenesis and emphasize the complexity of targeting Ctss as a therapeutic strategy.