Integrated Imaging and Genetic Approaches to Elucidating Islet Heterogeneity in Health and Diabetes

Caroline Ward, BA - Final Dissertation Defense - HUGEN PhD Candidate Department of Human Genetics Doctoral Candidate, Caroline Ward, BA, will defend the following dissertation on “Integrated Imaging and Genetic Approaches to Elucidating Islet Heterogeneity in Health and Diabetes” COMMITTEE CHAIR: Zachary Z. Freyberg, MD, PhD Committee Members: Beth L. Roman, PhDQuasar S. Padiath, PhD, MBBSMichael J. Jurczak, PhD ABSTRACT: The pancreatic islet is a heterogeneous micro-organ whose cellular composition and signaling vary across cell types, anatomical location, sex, and disease state. This dissertation develops complementary strategies to resolve that heterogeneity, first in human type 1 diabetes (T1D) and then in a mouse model of β-cell dopamine signaling. In the first study, an AI-guided whole-slide imaging pipeline coupled to a hierarchical Bayesian and mixed-effects statistical framework was applied to immunohistochemically stained pancreata from 106 non-diabetic and T1D donors, quantifying all four endocrine cell types across more than two million islets. T1D produced a coordinated remodeling of islet composition: profound β-cell loss was accompanied by reciprocal α-cell expansion, whereas δ- and PP-cells were largely resilient. These changes were regionally concentrated, most pronounced in the pancreatic head, and were modulated by sex, age, and disease duration, with pseudotime analysis resolving distinct trajectories of compositional change across disease progression. The second study examined the contributions of β-cell dopamine D2 receptor (D2R) signaling to glycemic control using a tamoxifen-inducible, β-cell-specific D2R conditional knockout (cKO) mouse model. Loss of β-cell D2R produced sex-dependent metabolic phenotypes: females showed blunted glucose-stimulated insulin secretion and diet-dependent glucose intolerance, whereas males showed enhanced glycemic control and islet secretion. Multiplex RNAscope revealed