Using Extracellular Vesicles to Define Brain Insulin Resistance in Type-2-diabetes & Alzheimer's

Abstract Brain insulin resistance is often described as a pathological mechanism linking type-2-diabetes (T2D) and Alzheimer’s disease (AD). In this proposal, we will combine our novel approach for isolating and characterizing extracellular vesicles (EVs) with traditional peripheral insulin resistance measures, ISF measures of free metabolites and proteins, and brain specific measures of metabolic flux in two different mouse models of peripheral insulin resistance that mimic aspects of type 2 diabetes (T2D) and Alzheimer’s disease (AD). This approach will provide a powerful, comprehensive view of brain insulin resistance. The goal of this pilot grant is 3 fold: First, to generate data for a larger, R01 application in 2024 (PAR-22-093/NOT-AG-21-053). Second, as a new University of Kentucky faculty member interested in brain metabolism and CNS disease, build a relationship with the CNS-MET COBRE where my lab’s expertise with in vivo tools (e.g. in vivo microdialysis, biosensors, EEG/EMG, etc.) can serve as a compliment to ongoing COBRE research initiatives, like the metabolomics core. And lastly, translate our preclinical findings to build an EV-based brain insulin signature for use in the plasma or CSF of human subjects with prediabetes or presymptomatic AD.