Extracellular release of high mobility group box1 protein from necrotic beta-cells in the pathogenesis of type 1 diabetes mellitus

Nonobese diabetic (NOD) mice, an animal model of human type 1 diabetes mellitus (T1DM), exhibit impaired phagocytosis of apoptotic cells. In addition to phagocytosis, degradation of apoptotic cells determines the level of dead cells in tissues. Therefore, the work examined the kinetics of apoptotic cell degradation in vitro. The work revealed that macrophages from NOD mice digested internalised apoptotic thymocytes at a reduced rate compared to macrophages from control mice. How defective clearance leads to the development of T1DM is unclear. Necrosis is associated with inflammation, and high mobility group box 1 protein (HMGB1) released from necrotic cells induce inflammation. The relationship between beta-cell death and HMGB1 release was investigated. The results showed that HMGB1 was released from necrotic beta-cells in a dose-dependent manner. If impaired, clearance of apoptotic beta-cells results in an increased population of necrotic beta-cells. HMGB1 release could initiate or exacerbate an inflammatory response in NOD mice.