Abstract: Diabetes mellitus and its complications are serious epidemic diseases associated with metabolism and an important health and socioeconomic problem worldwide. Therefore, there is still a need to find new drug targets to reduce the occurrence and development of diabetes mellitus and related complications. Non-steroidal anti-inflammatory drug activator gene-1(NAG-1), also known as growth differentiation factor 15(GDF15), is a divergent member of the transforming growth factor-β(TGF-β) superfamily(hereinafter referred to as NAG-1/GDF15). NAG-1/GDF15 plays an important regulatory role in a variety of diseases, including cancer, cardiovascular diseases, obesity, and diabetes mellitus. This review briefly introduced the structure and expression regulation mechanism of NAG-1/GDF15, focused on the research progress and molecular mechanism of NAG-1/GDF15 in diabetes mellitus-related in vivo and in vitro studies, and summarized the research of anti-diabetic drug regulating NAG-1/GDF15. This review will provided a theoretical basis for the basic research of NAG-1/GDF15 in diabetes mellitus and related metabolic diseases and the development of anti-diabetic drugs regulating NAG-1/GDF15 from a broad aspect.