Beta Cell Impairment in T1D: Insights from Glucose Metabolism in Human Pancreas Slices
Contact PI: Edward Phelps, PhD, University of Florida (R01 DK147991)
Clayton Mathews PhD, Co-Investigator, University of Florida
Craig Vander Kooi, PhD, Co-Investigator, University of Florida
Start Date: May 1, 2026
Abstract
The proposed studies will address a major gap in our understanding of T1D, namely, to the mechanisms of β cell failure from a metabolic as well as an immunological perspective. We have proposed this specific project because of a sincere belief that it has high potential to reveal significant, novel, and translatable information regarding β cell dysfunction that will be of therapeutic benefit for individuals with both established T1D as well as persons with pre-diabetes. The goal is to identify components of the glucose sensing and insulin secretory machinery pathways that are altered during the natural history of disease progression in type 1 diabetes (T1D), and to characterize the metabolic and immunological signals responsible for the functional loss in β cell activity that are specifically associated with this disease.
This goal will be achieved by performing two lines of experimentation. Specific Aim 1 will determine the specific nature of dysfunctional bioenergetics of β cells in early stages of T1D. Using live human pancreas tissue slices from nPOD, we will employ multi-modal measurements of islet functionality. We will map molecular changes in β cell glucose metabolism to steps in T1D etiology using MALDI imaging (spatial metabolomics) and Akoya PhenoCycler (spatial proteomics). Aim 2 will determine the relationship between immune dysregulation and β cell dysfunction. Using live human pancreas tissue slices from nPOD and mouse models of T1D, we will assess the relationship between islet function and local immune microenvironment using novels tools such as fixable calcium indicators. Our team will leverage combined expertise to synergize the understanding of islet dysfunction in T1D. Phelps has expertise in islet imaging and physiology, Mathews specializes in β cell metabolism and T1D immunology, and Vander Kooi is an expert in spatial metabolomics. Together, we will provide a comprehensive analysis of the metabolic and immunologic mechanisms underlying β cell dysfunction in T1D.
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