Research ArticleMetabolism

SerpinB13 antibodies promote β cell development and resistance to type 1 diabetes

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Science Translational Medicine  07 Apr 2021:
Vol. 13, Issue 588, eabf1587
DOI: 10.1126/scitranslmed.abf1587

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Dismantling a barrier to β cell development

Autoantibodies to the protease inhibitor serpinB13 have previously been linked to delayed onset of type 1 diabetes (T1D) in humans. Now, Kryvalap et al. show using mouse pancreatic explant cultures that the protease inhibitor serpinB13 regulates the Notch signaling involved in pancreatic development. Mouse models of T1D exposed to anti-serpinB13 antibody during development showed increased numbers of pancreatic progenitor cells along with ameliorated pancreatic islet cell development. This study suggests that serpinB13 could potentially be a therapeutic target in children with T1D.

Abstract

Pancreatic endocrine cell development is dependent on the rescue of the neurogenin3 (Ngn3) transcription factor from repression by Notch. The signals that prevent Notch signaling, thereby allowing the formation of pancreatic endocrine cells, remain unclear. We show that inhibiting serpinB13, a cathepsin L (CatL) protease inhibitor expressed in the pancreatic epithelium, caused in vitro and in vivo cleavage of the extracellular domain of Notch1. This was followed by a twofold increase in the Ngn3+ progenitor cell population and enhanced conversion of these cells to express insulin. Conversely, both recombinant serpinB13 protein and CatL deficiency down-regulated pancreatic Ngn3+ cell output. Mouse embryonic exposure to inhibitory anti-serpinB13 antibody resulted in increased islet cell mass and improved outcomes in streptozotocin-induced diabetes at 8 weeks of age. Moreover, anti-serpinB13 autoantibodies stimulated Ngn3+ endocrine progenitor formation in the pancreas and were associated with delayed progression to type 1 diabetes (T1D) in children. These data demonstrate long-term impact of serpinB13 activity on islet biology and suggest that promoting protease activity by blocking this serpin may have prophylactic potential in T1D.

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