SerpinB1 Delays T1D Progression and Improves Glucose Homeostasis in NOD Mice

T1D occurs when the functional β-cell mass is reduced by an autoimmune cell-mediated attack. As recently reported, inducing β-cell proliferation during early life results in an almost complete resolution of T1D in rodents. SerpinB1 (sB1), a protease inhibitor, has been shown to promote β-cell proliferation by inhibiting pancreatic elastase, and to regulate specific pro-inflammatory cells, e.g., Th17 cells via blockade of cathepsin proteases. Previous studies have demonstrated beneficial effects of alpha-1-antitrypsin (AAT), another elastase inhibitor similar to sB1, in the progression of T1D in rodents and humans. Here, we tested the effects of sB1 in 1) delaying T1D onset, and 2) improving glucose homeostasis in female NOD mice, by inducing β-cell growth and suppressing autoimmunity. To examine the role of sB1 in T1D development (Study 1) we injected 4-week-old NOD mice daily with vehicle or recombinant mouse serpinb1a (rmsb1a) at different doses, intradermally for 28 weeks. Strikingly, the percentage of diabetes-free animals was higher in the rmsb1a groups compared to the non-injected group. Interestingly, islet infiltration scores were lower in rmsb1a mice compared to the vehicle-injected animals. In addition, β-cell proliferation levels were significantly higher in rmsb1a-treated mice compared to the vehicle group (~3-fold, P<0.05). Finally, rmsb1a treated mice displayed a higher proportion of CD4+FoxP3+ cells and a lower count of Th17 cells compared to the vehicle group. In Study 2, diabetic NOD female mice were injected daily with either vehicle, rmsb1a or rmsb1a+AAT, intradermally for 10 weeks. We observed that glycemic levels were lower in rmsb1a and rmsb1a+AAT treated animals compared to vehicle and CTRL mice. Taken together, the beneficial effects of rmsb1a in delaying the onset and preventing progression of T1D by expanding β-cell numbers and increasing immune cell tolerance, point to the protease inhibitor as a potential therapeutic to limit hyperglycemia in T1D patients. Disclosure G. Basile: None. H. Kim: None. L. Xiao: None. J. Hu: None. H. Wang: None. P. Pemberton: Employee; Self; Serplus Technology LLC, Stock/Shareholder; Self; Redd Pharmaceuticals. R. Kulkarni: None. Funding National Institutes of Health (R41DK115326, R01DK103215)