Elevated branched-chain α-keto acids exacerbate macrophage oxidative stress and chronic inflammatory damage in type 2 diabetes mellitus

Chronic inflammation is a primary reason for type 2 diabetes mellitus (T2DM) and its complications, while disordered branched-chain amino acids (BCAA) metabolism is found in T2DM, but the link between BCAA catabolic defects and inflammation in T2DM remains elusive and needs to be investigated. The changes in BCAA catabolism, inflammation, organ damage, redox status, and mitochondrial function in db/db mice with treatments of BCAA-overload or BCAA catabolism activator were analyzed in vivo. The changes in BCAA catabolic metabolism, as well as the direct effects of BCAAs/branched-chain alpha-keto acids (BCKAs) on cytokine release and redox status were also analyzed in primary macrophages in vitro. Inactivation of branched-chain ɑ-ketoacid dehydrogenase (BCKDH) complex was found in multiple organs (liver, muscle and kidney) of db/db mice. Long-term high BCAA supplementation further increased BCKA levels, inflammation, tissue fibrosis (liver and kidney), and macrophage hyper-activation in db/db mice, while enhancing BCAA catabolism with pharmacological activator reduced these adverse effects in db/db mice. In vitro, the BCAA catabolism was unchanged in primary macrophages of db/db mice, and elevated BCKAs but not BCAAs promoted the cytokine production in primary macrophages. Moreover, BCKA stimulation was associated with increased mitochondrial oxidative stress and redox imbalance in macrophages and diabetic organs. Impaired BCAA catabolism is strongly associated with chronic inflammation and tissue damage in T2DM, and this effect is at least partly due to the BCKAs-induced macrophage oxidative stress. This study highlights that targeting BCAA catabolism is a potential strategy to attenuate T2DM and its complications.