So far, TLR4 and RAGE have been extensively studied and proven to be specific HMGB1 receptors in a large number of studies.HMGB1 combined with RAGE or TLR4 can activate a variety of signaling pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway to mediate the occurrence of immune reactions such as autophagy (58), pyroptosis (59) and apoptosis (60) or the amplification of inflammation, thus playing a crucial role in diabetes, epilepsy, tumor and other diseases (3). This evidence concerns the gene TLR4 and diabetes mellitus.