Targeting Mitochondrial Dysfunction for the Treatment of Diabetic Complications: Pharmacological Interventions through Natural Products

Diabetes mellitus is a chronic hyperglycemic condition with deleterious effects on microcirculation, resulting in diabetic complications. Chronic hyperglycemia induces the generation of reactive oxygen species (ROS), which are the key pathological triggers in the development of diabetic complications. ROS are responsible for the activation of various pathways involved in the genesis of diabetic complications, mitochondrial dysfunction, as well as insulin resistance. The review describes normal mitochondrial physiology and abnormal alterations, which occur in response to hyperglycemia. Mitochondrial biogenesis is a highly regulated process mediated by several transcription factors, wherein mitochondrial fusion and fission occur in harmony in a normal healthy cell. However, this harmony is disrupted in hyperglycemic condition indicated by alteration in functions of essential transcription factors. Hyperglycemia‑induced mitochondrial dysfunction plays a key role in diabetic complications, pancreatic β‑cell dysfunction, as well as skeletal muscle insulin resistance as demonstrated by various in vitro, preclinical, and clinical studies. The review focuses on the various factors involved in mitochondrial biogenesis and maintenance of healthy mitochondrial function. Several phytoconstituents act through these pathways, either directly by stimulating biogenesis or indirectly by inhibiting or preventing dysfunction, and produce a beneficial effect on overall mitochondrial function. These phytoconstituents have enormous potential in amelioration of diabetic complications by restoring normal mitochondrial physiology and need detailed evaluation by preclinical and clinical studies. Such phytoconstituents can be included as nutraceuticals or adjuvant therapy to the mainstream treatment of diabetes.