In our study, we found that the TLR4, HMGB1, and NLRP3 levels were up regulated in Type 2 diabetic rat models with painful neuropathy and blocking of HMGB1 by natural inhibitor glycyrrhizin treatment decreased the expression of TLR4, HMGB1, and NLRP3, as well as ameliorated mechanical and thermal pain threshold. Here, HMGB1 is linked to type 2 diabetes mellitus.