Identifying natural factors of the progression to type 1 diabetes (T1D) provides a unique opportunity to develop novel preventative strategies for this disease. Our laboratory has identified serpin B13 proteinase inhibitor as a potential player, activity of which is involved in modifying the timing of T1D development. In this study we examined whether blocking of serpin B13 with a monoclonal antibody (mAb) in early life causes any changes in pancreatic islet development that may explain beneficial impact of this activity later in life. First, our animal studies showed that blocking of serpin B13 during mid-pregnancy caused robust increase in the number of Ngn3+ progenitor cells at day E16.5 and accelerated conversion of these cells to beta cells. Similar changes were observed in embryonic pancreatic buds in vitro. On the other hand, the serpin B13 protein significantly downregulated the output of Ngn3+ cells in these in vitro cultures. Importantly, at 2 to 3 months after birth, the offspring of serpin B13 mAb-treated mothers demonstrated increased islet cell mass and responded to the diabetes-inducing agent, streptozotocin, with markedly improved glucose tolerance and renal function, compared with control animals. Second, our screening of 280 children, previously enrolled in a DPT-1 clinical trial, for serpin B13 autoantibody (AA) revealed an inverse correlation of this AA with risk level for T1D, as well as a positive association with longer diabetes-free interval. These data demonstrate the significant, long-term impact of serpin B13 activity on islet biology and suggest that blocking this serpin has the potential to partially prevent, or at least slow down, the development of T1D both in the mouse and human.
Y. Kryvalap: None. M.L. Jiang: None. N. Kryvalap: None. K.A. Mueller: None. J. Czyzyk: None.