PROJECT SUMMARY / ABSTRACT: Youth-onset type 2 diabetes (Y-T2D) is a rapidly growing epidemic in the US, with a severe phenotype and limited modifiable risk factors or effective therapies. Climate change, such as extreme heat, and water contamination by per- and polyfluoroalkyl substances (PFAS) are emerging risk factors for Y-T2D development and early diabetic kidney disease. Adolescents with obesity and pre-diabetes may be more susceptible to PFAS's detrimental effects on β-cell and kidney function due to their developing physiology and increased vulnerability to environmental stressors, including extreme heat. In response to NOT-HD-23-006, we propose an administrative supplement to R01 DK129211 for a first-of-its- kind transdisciplinary study to address knowledge gaps by examining the impact of PFAS exposure and heat waves on β-cell and kidney function during puberty in adolescents with obesity and pre-diabetes. We aim to investigate associations between individual PFAS and PFAS mixtures with β-cell and kidney injury during puberty, and examine whether heat waves modify the relationship between PFAS exposure and β-cell and kidney injury, hypothesizing that extreme heat intensifies this association. We will quantify PFAS in participants' plasma and residential water samples and determine heat wave exposure using data from the Colorado Climate Center and participants' residential history records. Our second aim is to integrate data on PFAS exposure and heat waves to understand pathways of β-cell and kidney injury, hypothesizing that PFAS exposure, heat waves, and multi-omic signatures associated with β-cell toxicity and kidney injury can predict subgroups of youth at risk of T2D onset and progression, and early kidney disease. We will measure proteomics and metabolomics in plasma and perform Latent Unknown Clustering Integrating multi-omics Data (LUCID) to integrate environmental factors with multi-omic features. These findings have the potential to revolutionize our understanding of environmental factors in Y-T2D, including the role of climate change-related weather events, such as extreme heat exposure, and inform precision medicine strategies for reducing modifiable PFAS exposure early in life, ultimately preventing β-cell and kidney damage and alleviating the burden of Y-T2D.