HMGB1: a key molecule linking chronic inflammation to complications in type 2 diabetes mellitus and a target for exercise intervention

TL;DR

This paper explores how HMGB1, a molecule linked to inflammation, contributes to type 2 diabetes and its complications, and how exercise can help by targeting this pathway.

Contribution

The paper systematically reviews HMGB1's role in T2DM and proposes exercise as a non-pharmacological intervention to target HMGB1-driven inflammation.

Findings

HMGB1 is dysregulated in T2DM and contributes to insulin resistance and complications via RAGE/TLR4−NF−κB pathways.

Exercise mitigates HMGB1-driven pathology by downregulating HMGB1 and reducing inflammation.

Exercise improves glycemic control, autophagy, and reduces oxidative stress, indirectly targeting HMGB1 effects.

Abstract

The pathological process of type 2 diabetes mellitus (T2DM) is closely associated with chronic low−grade inflammation. 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. Exercise, a cornerstone non−pharmacological intervention, effectively mitigates HMGB1−driven pathology through multifaceted mechanisms. These include direct downregulation of HMGB1 expression and suppression of its downstream inflammatory pathways, as well as indirect effects via improved glycemic control, enhancing autophagy, and reduced oxidative stress. This review aims to systematically examine the evidence for the role of HMGB1 in T2DM pathogenesis and its complications, and to evaluate exercise as a potential strategy to target this inflammatory pathway, thereby providing a theoretical framework for future therapeutic approaches.

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