Targeting mitochondrial dysfunction for the treatment of diabetic complications: Pharmacological interventions through natural products

Abstract

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.

Plants Secondary Metabolites as Blood Glucose-Lowering Molecules

“…It comprises insulin secretion and insulin action. It activates NF-κB and JNK, IRS degradation, suppresses GLUT-4 expression and translocation, activates inflammatory responses [ 36 , 37 ]. Plant secondary metabolites can stimulate mitochondrial metabolism and/or decrease mitochondrial dysfunction through targeting sirtuin 1 activators (SIRT1) and PPAR α [ 37 ].…”

“…Mitochondria is a major source of free radicals. However, overproduction of free radicals causes mitochondrial dysfunction [ 37 , 38 ].…”

Ethyl ferulate, a lipophilic phenylpropanoid, prevents diabetes‐associated renal injury in rats by amelioration of hyperglycemia‐induced oxidative stress via activation of nuclear factor erythroid 2‐related factor 2

“…Chronic hyperglycemia leads to the activation of various pathways cumulating in development of oxidative stress which has been identified as a key player in the pathogenesis of diabetic complications (Brownlee, 2005;Kaikini et al, 2017). Renal oxidative stress was measured in tissue homogenates by measuring the level of major intracellular antioxidant namely GSH, and antioxidant enzymes namely superoxide dismutase and catalase.…”

Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

“…Besides the bioenergetics function mitochondria have a key function in cell signaling, cell proliferation/death, aging, involvement in disease, metabolic events, maintaining cytosolic Ca 2+ homeostasis, and reactive oxygen species (ROS) synthesis (156). ROS synthesis are key players for the onset of pathways in the initiation of mitochondrial dysfunction resulting in the pathogenesis of the atrophy and diminished efficacy of skeletal muscle (157) and eventually into diabetic impairments and insulin resistance (158). One of the functions of DMPK is that it exhibits a mitochondrial-related protective role against apoptosis through oxidative stress.…”