Deficiency of mitochondrial aldehyde dehydrogenase increases type 2 diabetes risk in males via autophagy dysregulation

Skeletal muscle is the most insulin-sensitive, glucose-consuming organ. [...]we further tested whether ALDH2 deficiency influenced skeletal muscle insulin sensitivity. Many reports have suggested that over activation of skeletal muscle autophagy, a cell renewal and catabolic process, exacerbates insulin resistance in diabetes, and ALDH2 has been considered to be deeply involved in its regulation. [...]we evaluated the levels of autophagic end product, p62, as an autophagic marker as well as the expression and phosphorylation levels of the components of the Akt/AMPK/mTOR signaling pathway to illustrate the molecular mechanisms of ALDH2 deficiency in the development of diabetes. [...]the prevalence of diabetes was lower and much more comparable among the female patients of all three ALDH2 genotype groups. [...]these findings suggest that ALDH2 mutation may contribute to diabetes risk in the Chinese population, particularly in males. Furthermore, the ultimate goal of diabetes treatment has changed from simple glycemic control to simultaneous cardiovascular protection, and the use of sodium-glucose cotransporter-2 (SGLT-2), dipeptidyl peptidase 4 (DPP4) inhibitors, or glucagon-like peptide-1 (GLP-1) analogs strongly represents this shift. [...]ALDH2 supplementation or activation represents a potential therapeutic target for the treatment of diabetes, because of its extensive cardioprotective role beyond insulin sensitivity regulation.