The Dichotomic and Timely Regulation of SerpinB13 Plays a Role in Beta-Cell Neogenesis and Pancreatic Islet Expansion

There has been recent emphasis on the potential role of a functional crosstalk between the exocrine and endocrine pancreas in the development of type 1 diabetes (T1D). Our interest in this was sparked by our observations that, (i) serpinB13, a protease inhibitor of cathepsin L, is expressed in mouse pancreatic ductal cells, and (ii) an antibody response to serpinB13 is associated with better clinical outcomes in mice and humans with T1D. The exact pattern of serpinB13 expression in the human pancreas has, to date, not been examined. Similarly, the exact role of serpinB13 in beta-cell biology and diabetes remains unclear. We aimed to determine the distribution of serpinB13 expression using immunochemistry on pancreatic sections obtained from nPOD. In addition, we developed a mouse serpinB13 genetic knockout model to examine the role of this serpin in regulating pancreatic islet morphology. Visiopharm software was used for an unbiased quantitative image analysis of islet size and cellularity. We found that in healthy humans, serpinB13 expression was confined to the pancreatic ducts, mimicking the pattern we observed previously in rodents. Studies of serpinB13 genetic deficiency revealed that early inhibition of serpinB13 increased the small pancreatic islet population while with time this trend reversed, and a drop in the number of pancreatic islets was observed. Our results demonstrate that serpinB13 is expressed in the exocrine epithelial compartment of the human pancreas. In addition, quite unexpectedly, serpinB13 appears to play a dual role in regulating pancreatic islet mass. More specifically, we postulate that serpinB13 initially hampers the development of additional insulin-producing cells, but with time it promotes expansion of the already formed beta cells. Thus, we propose an approach that first impedes serpinB13, followed by later administration of this serpin, which may lead to an increase in beta-cell mass and improved resistance to T1D. Disclosure Y.Kryvalap: None. S.Z.Meng: None. R.Habte: None. J.Czyzyk: None.