High mobility group box 1 (HMGB1), a key damage-associated molecular pattern (DAMP), is frequently dysregulated in T2DM and is implicated in promoting insulin resistance (IR), β cell dysfunction, and the progression of multiple complications-including cardiovascular disease, nephropathy, cognitive impairment, myopathy, and dyslipidemia-primarily through activating signaling pathways such as RAGE/TLR4-NF-κB. The gene discussed is TLR4; the disease is type 2 diabetes mellitus.