Systems to identify the cell type-specific and molecular functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently investigating and discovering T2D risk gene functions relevant to human cells are needed. We will describe the merging of fruit fly genetics and physiology with human islet biology to address this fundamental gap in diabetes research. Based on our ability to measure insulin production and secretion in Drosophila, we identified fly orthologs of T2D risk genes that are regulators of insulin output. With human islets, we performed loss- and gain-of-function studies using lenti-viral gene delivery systems and identified cognate human T2D risk genes that regulate human beta cell function, including BCL11A, SIX3 and PRC1. High-throughput genetic and physiological systems described today could be useful for identifying cell-specific T2D risk gene functions, including unsuspected regulators of human beta cell function like BCL11A and PRC1, and should improve genome-scale investigations of genetic mechanisms underlying T2D risk.