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

Area of Science:

• Endocrinology
• Developmental Biology
• Protease Inhibitor Research

Background:

• Pancreatic endocrine cell formation relies on neurogenin3 (Ngn3) release from Notch pathway repression.
• The specific signals that modulate Notch signaling to permit endocrine cell development are not fully understood.

Purpose of the Study:

• To investigate the role of serpinB13, a cathepsin L (CatL) protease inhibitor, in regulating pancreatic endocrine cell development.
• To explore the potential of targeting serpinB13 for therapeutic interventions in diabetes.

Main Methods:

• In vitro and in vivo experiments involving inhibition of serpinB13 in pancreatic epithelial cells.
• Assessment of Notch1 cleavage, Ngn3+ progenitor cell populations, and insulin expression.
• Studies using recombinant serpinB13 protein and CatL-deficient models.
• In vivo administration of anti-serpinB13 antibodies in mouse models of diabetes and analysis of human autoantibodies.

Main Results:

• Inhibiting serpinB13 led to Notch1 extracellular domain cleavage, a twofold increase in Ngn3+ progenitor cells, and enhanced insulin expression.
• Recombinant serpinB13 and CatL deficiency reduced Ngn3+ cell output.
• Mouse embryonic exposure to anti-serpinB13 antibody increased islet cell mass and improved diabetes outcomes.
• Anti-serpinB13 autoantibodies in children were linked to increased Ngn3+ progenitor formation and delayed type 1 diabetes progression.

Conclusions:

• SerpinB13 activity significantly impacts islet biology and pancreatic endocrine cell development.
• Blocking serpinB13 promotes Ngn3+ progenitor formation and may serve as a prophylactic strategy for type 1 diabetes.
• Targeting protease activity by inhibiting serpinB13 holds potential for preventing or delaying type 1 diabetes.