Autophagy-nutrient sensing pathways in diabetic complications

The incidence of diabetes has been increasing in recent decades which is affecting the population of both, developed and developing countries. Diabetes is associated with micro and macrovascular complications which predominantly result from hyperglycemia and disrupted metabolic pathways. Persistent hyperglycemia leads to increased reactive oxygen species (ROS) generation, formation of misfolded and abnormal proteins, and disruption of normal cellular functioning. The inability to maintain metabolic homeostasis under excessive energy and nutrient input, which induces insulin resistance, is a crucial feature during the transition from obesity to diabetes. According to various study reports, redox alterations, intracellular stress and chronic inflammation responses have all been linked to dysregulated energy metabolism and insulin resistance. Autophagy has been considered a cleansing mechanism to prevent these anomalies and restore cellular homeostasis. However, disrupted autophagy has been linked to the pathogenesis of metabolic disorders such as obesity and diabetes. Recent studies have reported that the regulation of autophagy has a beneficial role against these conditions. When there is plenty of food, nutrient-sensing pathways activate anabolism and storage, but the shortage of food activates homeostatic mechanisms like autophagy, which mobilises internal stockpiles. These nutrient-sensing pathways are well conserved in eukaryotes and are involved in the regulation of autophagy which includes SIRT1, mTOR and AMPK. The current review focuses on the role of SIRT1, mTOR and AMPK in regulating autophagy and suggests autophagy along with these nutrient-sensing pathways as potential therapeutic targets in reducing the progression of various diabetic complications.