From Human to Mouse and Back Again: Genetic and Genomic Ta(i)les of Islet Dysfunction in Type 2 Diabetes

Type 2 diabetes (T2D) is a complex genetic disease with substantial environmental inputs leading to glucose homeostasis defects. Insulin production is central to proper glucose control, and islet cell dysfunction and death lie at the nexus of T2D genetics and pathophysiology. Comprehensive identification of genes and pathways contributing to these processes is essential for mechanistic understanding and therapeutic targeting. Here, we summarize the latest human and mouse T2D genetic and genomic studies and assess how these parallel variant-to-function efforts and associated data contribute convergent or complementary insights and new opportunities to dissect T2D islet (dys)function. We distill mechanistic and phenotypic studies of candidate T2D effector genes into prevailing themes by which these T2D risk genes likely contribute to islet dysfunction. We assess how recent molecular and metabolic studies in genetically diverse mice (i.e., Collabo-rative Cross, Diversity Outbred) help to nominate new putative T2D effector genes and processes for future exploration and provide examples where these studies illuminate potential limitations of studies using inbred mice. Finally, we discuss opportunities to address knowledge gaps and modeling challenges to translate T2D genetic associations into molecular and pathophysiologic understanding.