Mitochondrial dysfunction-driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic syndrome characterized by chronic hyperglycemia, progressive pancreatic β-cell malfunction, and peripheral insulin resistance. There is growing evidence suggesting that mitochondrial dysfunction and apoptosis play a critical role in the development and advancement of T2DM. Mitochondria are essential for cellular energy metabolism and redox homeostasis. It is the metabolic stress and apoptotic cell death in insulin-producing β-cells and insulin-sensitive tissues induced by mitochondrial dysfunction caused by excessive reactive oxygen species (ROS) production, imbalanced mitochondrial dynamics, impaired mitophagy, mitochondrial fission-fusion imbalance, and defective biogenesis. This review summarizes the molecular pathways by which mitochondrial dysfunction triggers inflammatory responses, such as activation of NLRP3 inflammasomes, cytokine release, and mitochondria-mediated intrinsic apoptotic signaling. We describe the role of these pathways in insulin resistance and in the emergence of diabetic complications like neuropathy, nephropathy, myopathy, and hepatopathy. New treatment approaches aimed at mitochondrial integrity and apoptotic signaling are promising. These are AMPK/PGC-1α pathway activators, mitochondria-targeted antioxidants (MitoQ, SS-31), and mitophagy and ferroptosis modulators. But poor tissue specificity, poor bioavailability, and patient-to-patient variability are limitations in clinical translation. Lastly, the review highlights the possibilities of personalized medicine strategies that incorporate the use of mitochondrial profiling to maximize therapeutic outcomes. Collectively, available evidence suggests that therapeutic strategies restoring mitochondrial quality control in β-cells may offer greater disease-modifying potential than glucose-centric interventions alone.