Diabetes and mitochondrial function: Role of hyperglycemia and oxidative stress Hyperglycemia is a major cause of diabetes and its complications. Four key mechanisms contribute to hyperglycemia-induced tissue damage: increased polyol pathway flux, increased advanced glycation end product (AGE) formation, activation of protein kinase C (PKC) isoforms, and increased hexosamine pathway flux. Hyperglycemia leads to increased superoxide production, which is linked to oxidative stress and damage. Diabetes is associated with increased free radicals and impaired antioxidant defenses, highlighting the role of reactive oxygen species (ROS) in diabetes progression. Mitochondrial dysfunction is also linked to type 2 diabetes, with mutations in mitochondrial DNA (mtDNA) and reduced mtDNA copy number contributing to its pathogenesis. The study of mtDNA's relationship to type 2 diabetes has revealed its influence on nuclear-encoded glucose transporters, glucose-stimulated insulin secretion, and uncoupling proteins (UCPs) in β-cell glucose toxicity. This review discusses mitochondrial factors in diabetes pathogenesis, the effects of hyperglycemia on mitochondrial function, and the possibility of transcriptional regulation in response to hyperglycemia. The main goal is to consider pathways involved in hyperglycemia-induced diabetic complications. The review highlights the role of oxidative stress, mitochondrial uncoupling proteins, and mitochondrial function in diabetes. It also discusses transcriptional regulatory circuits, β-cell insulin secretion, and new therapeutic targets. The conclusion emphasizes the importance of ROS in mediating metabolic defects in diabetes and the potential of targeting mitochondrial function for therapy.Diabetes and mitochondrial function: Role of hyperglycemia and oxidative stress Hyperglycemia is a major cause of diabetes and its complications. Four key mechanisms contribute to hyperglycemia-induced tissue damage: increased polyol pathway flux, increased advanced glycation end product (AGE) formation, activation of protein kinase C (PKC) isoforms, and increased hexosamine pathway flux. Hyperglycemia leads to increased superoxide production, which is linked to oxidative stress and damage. Diabetes is associated with increased free radicals and impaired antioxidant defenses, highlighting the role of reactive oxygen species (ROS) in diabetes progression. Mitochondrial dysfunction is also linked to type 2 diabetes, with mutations in mitochondrial DNA (mtDNA) and reduced mtDNA copy number contributing to its pathogenesis. The study of mtDNA's relationship to type 2 diabetes has revealed its influence on nuclear-encoded glucose transporters, glucose-stimulated insulin secretion, and uncoupling proteins (UCPs) in β-cell glucose toxicity. This review discusses mitochondrial factors in diabetes pathogenesis, the effects of hyperglycemia on mitochondrial function, and the possibility of transcriptional regulation in response to hyperglycemia. The main goal is to consider pathways involved in hyperglycemia-induced diabetic complications. The review highlights the role of oxidative stress, mitochondrial uncoupling proteins, and mitochondrial function in diabetes. It also discusses transcriptional regulatory circuits, β-cell insulin secretion, and new therapeutic targets. The conclusion emphasizes the importance of ROS in mediating metabolic defects in diabetes and the potential of targeting mitochondrial function for therapy.