Diabetes affects 537 million people worldwide, a number that continues to rise rapidly each year. Approximately 90% of these cases are type 2 diabetes (T2D), a condition characterized by chronic hyperglycemia. Central to T2D pathophysiology are pancreatic islet cells, particularly beta cells, which secrete insulin to lower blood glucose, and alpha cells, which release glucagon to increase it. Given the heterogeneity of T2D across individuals and the significant differences between mouse and human islets, additional research is essential to uncover the pathophysiological changes in T2D patients and to enable more tailored therapeutic approaches. To address this need, the Human Pancreas Analysis Program (HPAP) continuously collects and profiles human islet cells from T2D patients and matched non-diabetic controls using a suite of advanced experimental assays. Leveraging HPAP data, this dissertation investigates the cellular heterogeneity and molecular profiles of human islets in both non-diabetic and T2D states. The dissertation begins with an overview of current knowledge on T2D pathophysiology, highlighting limitations in previous research and proposing HPAP data as a platform for a comprehensive analysis of human islets. Chapter 2 tackles the challenges of data integration inherent to large-scale consortium datasets like HPAP and, through a benchmarking study, identifies an optimal pipeline for integrating HPAP single-cell multimodal data. Chapter 3 applies this integration pipeline to HPAP data, uncovering previously unrecognized islet cell populations that likely represent a transitional state between alpha and beta cells—a process with potential therapeutic relevance. Chapter 4 examines the islet microenvironment using spatial proteomics, revealing an enrichment of macrophages and CD8+ T cells around the islets of T2D donors, suggesting a key role for the immune system in T2D progression. Finally, Chapter 5 outlines future directions for research. Overall, this dissertation provides an in-depth exploration of the cellular and molecular landscape of pancreatic islets in non-diabetic and T2D donors. The findings offer critical insights into human islet biology and T2D pathology, laying a foundation for future research and potential therapeutic strategies.