Genome-wide association studies (GWAS) have generated a large database of disease associated variants. However, systematic studies on the role of genetic factors are rare due to the lack of a robust, time- and cost-efficient platform. Using isogenic hPSC-based pancreatic beta-like cells, we established a high throughput platform to systematically evaluate GWAS-identified diabetes associated genes, such as KCNJ11, KCNQ1, CDKAL1, GLIS3, GATA4/GATA6, in beta cell generation, function and survival both in vitro and in vivo. By collaborating with Environmental Protection Agency (EPA), we performed the first high throughput screen on the ToxCast library using hPSC-derived beta cells and identified propargite that causes beta cell specific cell death. In response to the COVID-19 pandemic, we applied hPSC-derived beta cells to study SARS-CoV-2 infection. Thus, we use isogenic hESC-derived pancreatic cells/organoids to study the role of genetic and environmental factors in diabetes progression, which will facility understanding the genetic network controlling pancreatic beta cell defects and perform drug screening.