Acrolein induces mitochondrial dysfunction and insulin resistance in muscle and adipose tissues in vitro and in vivo.

Type 2 diabetes mellitus (DM) is a common chronic condition characterized by persistent hyperglycemia and is associated with insulin resistance (IR) in critical glucose-consuming tissues, including skeletal muscle and adipose tissue. Oxidative stress and mitochondrial dysfunction are known to play key roles in IR. Acrolein is a reactive aldehyde found in the diet and environment that is generated as a fatty acid product through the glucose autooxidation process under hyperglycemic conditions. Our previous studies have shown that acrolein impairs insulin sensitivity in normal and diabetic mice, and this effect can be reversed by scavenging acrolein. This study demonstrated that acrolein increased oxidative stress and inhibited mitochondrial respiration in differentiated C2C12 myotubes and differentiated 3T3-L1 adipocytes. As a result, insulin signaling pathways were inhibited, leading to reduced glucose uptake. Treatment with acrolein scavengers, N-acetylcysteine, or carnosine ameliorated mitochondrial dysfunction and inhibited insulin signaling. Additionally, an increase in acrolein expression correlated with mitochondrial dysfunction in the muscle and adipose tissues of diabetic mice. These findings suggest that acrolein-induced mitochondrial dysfunction contributes to IR, and scavenging acrolein is a potential therapeutic approach for treating IR.