Prohormone processing products as mechanistic indicators of islet cell dysfunction during the natural history of type 1 diabetes

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Battelle Memorial Institute's Pacific Northwest National Laboratory a $1.92 million Project Grant (R01DK147558) on August 11, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847).

The recipient will identify and validate intermediate products of islet prohormone processing as blood-based mechanistic markers of islet cell dysfunction across the natural history of Type 1 diabetes. Work includes four main components: discovering prohormone processing products within pancreatic islet tissue using advanced proteomics; developing a high-throughput, multiplexed mass spectrometry-based assay for simultaneous monitoring of these products in blood circulation; examining the markers' potential as mechanistic indicators of islet cell dysfunction in alpha cells, beta cells, and delta cells; and exploring their predictive value for Type 1 diabetes progression. The research targets improved understanding of disease trajectory and assessment of treatment efficacy through minimally invasive blood-based markers.

The award obligates $1,920,030 and runs from August 11, 2026, through August 10, 2028, with work performed in Richland, Washington.

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disorder that is characterized by the targeted destruction of the insulin-producing β-cells in the pancreas. Emerging evidence suggests that T1D pathogenesis involves progressive islet cell dysfunction, including not only β-cells, but also α-cells and δ-cells. As a result, the development of minimally invasive blood-based mechanistic markers that can evaluate α-cell and β-cell (DYS)functions in vivo is critical for understanding the disease trajectory and assessing treatment efficacy. The overall objective here is to identify and verify the intermediate products of islet prohormone processing as novel markers of islet cell dysfunction (including α- and β-cells) circulating in the blood throughout the progression of T1D. This goal is built upon emerging data on altered prohormone processing during different stages of T1D and the unique tissue-specific characteristics of islet prohormones, making them ideal for serving as cell-type-specific markers in circulation. We hypothesize that intermediate prohormone processing products display distinct and dynamic patterns in circulation during T1D progression and can serve as mechanistic indicators of islet cell dysfunction. To test this, our overall strategy consists of four main components: 1) identifying prohormone processing products within pancreatic islet tissue using advanced proteomics; 2) developing an innovative, high- throughput, multiplexed mass spectrometry-based assay for enabling simultaneous monitoring of these products in blood circulation; 3) examining the potential of these markers as mechanistic indicators for islet cell dysfunction; 4) exploring their potential predictive values for T1D progression. Specifically, aim 1 will focus on the discovery of in situ islet prohormone processing products from human islet tissue specimen and investigating the underlying mechanisms of altered prohormone processing using advanced top-down and bottom-up proteomics. The development of a highly multiplexed LC-MS assay using parallel reaction monitoring (PRM) will also be an important part of this aim. Aim 2 will utilize cross-sectional and longitudinal clinical samples following clinical onset from various trials to evaluate how these prohormone products changes over time and their potentials as markers of islet cell dysfunction by applying the novel multiplexed LC-MS assay developed in aim 1. Aim 3 will define the relationship of intermediate prohormone products with clinical T1D progression through longitudinal samples collected during the diabetes prevention trial (DPT-1). Impact statement: this project is expected to significantly deepen our understanding of islet cell dysfunction in T1D by identifying and verifying intermediate prohormone products as novel islet-specific mechanistic markers. These markers offer promising clinical applications, including monitoring disease progression, assessing treatment efficacy, and optimizing trial designs by improving patient stratification. Moreover, the development and deployment of a highly multiplexed LC-MS assay for prohormone products will provide a powerful tool for future translational research by enabling monitoring of islet cell functionality in individuals during the T1D progression.