Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes

Analysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes and consider the clinical impact of these findings. Lingering questions, including pathologic etiologies and consequences of altered prohormone expression and secretion in type 1 diabetes, and the natural history of circulating prohormone production in health and disease, are considered. Finally, key next steps required to move forward in this area are outlined, including longitudinal testing of relevant clinical populations, studies that probe the genetics of altered prohormone processing, the need for combined functional and histologic testing of human pancreatic tissues, continued interrogation of the intersection between prohormone processing and autoimmunity, and optimal approaches for analysis. Successful resolution of these questions may offer the potential to use altered prohormone processing as a biomarker to inform therapeutic strategies aimed at personalized intervention during the natural history of type 1 diabetes and as a pathogenic anchor for identification of potential disease-specific endotypes.

Automated summary

Analysis of data from clinical cohorts and human pancreatic tissue suggests that reduced prohormone processing is an early and persistent feature in type 1 diabetes. This article reviews the current knowledge on alterations in islet prohormone expression and processing in type 1 diabetes, discusses their clinical impact, and outlines key next steps for further research. Exploring prohormone processing as a potential biomarker for personalized intervention in the natural history of type 1 diabetes and as a pathogenic anchor for identifying disease-specific endotypes is important for future studies.