Drug-Induced Insulin Sensitivity Impairments: Potential Involvement of Disturbed Mitochondrial Dynamics and Mitophagy Pathways

The pathogenesis of insulin resistance is influenced by environmental factors, genetic predispositions, and several medications. Various drugs used to manage multiple ailments have been shown to induce insulin resistance, which could lead to Type II Diabetes mellitus (T2DM). Central to drug-induced insulin resistance is mitochondrial dysfunction. Amongst disturbed pathways in drug-induced mitochondrial toxicity is mitophagy, a process that removes dysfunctional mitochondria through the lysosomal pathways to maintain mitochondrial quality. A balance must always be maintained between mitochondrial dynamics and mitophagy, as any alterations may contribute to the pathogenesis of metabolic diseases such as diabetes mellitus. If damaged mitochondria are not removed, their accumulation leads to increased production of reactive oxygen species (ROS) and release of calcium and cytochrome C, which leads to apoptosis. This review paper focuses on the implications of the mitophagy initiation pathways, such as Adenosine Monophosphate-activated Protein Kinase/Mammalian Target of Rapamycin (AMPK/mTOR), PTEN-induced kinase 1, and Parkin RBR E3 ubiquitin-protein ligase, PINK/Parkin, and the receptor-mediated pathways, such as FUN14 domain containing 1 (FUNDC1) and Bcl-2 interacting protein 3 (BNIP3/NIX), as a crucial link between drug-induced mitochondrial dysfunction and insulin sensitivity impairment. It also focuses on the implications of mitochondrial dynamics in drug-induced insulin impairments. Pharmacological agents such as simvastatin, clarithromycin, olanzapine, and dexamethasone have been investigated and shown to induce insulin resistance in part through altered mitochondrial function. In this review paper, we further illuminate disturbances in mitophagy and mitochondrial dynamics that could also be pivotal in insulin resistance development as a result of exposure to these drugs. Mitophagy and mitochondrial dynamics remain understudied. Exploring the implications of mitophagy pathways and mitochondrial dynamics on drug-induced insulin resistance could lead to the development of new approaches that can be used to mitigate insulin resistance associated with different classes of pharmacological modalities.