Reevaluating Mitochondrial Dysfunction as a Primary Pathogenic Driver in Type 2 Diabetes Mellitus: Beyond the Glucolipotoxicity Paradigm
Keywords:
type 2 diabetes mellitus, mitochondrial dysfunction, oxidative phosphorylation, pancreatic β-cell pathogenesis, electron transport chain Complex I, mitophagy, glucolipotoxicity, insulin resistance biomarkers, single-cell transcriptomicsAbstract
Conventional models of type 2 diabetes mellitus (T2DM) pathogenesis have long centered on glucolipotoxicity-mediated pancreatic β-cell exhaustion and peripheral insulin resistance. However, accumulating evidence from mitochondrial proteomics, single-cell transcriptomics, and in vivo oxidative phosphorylation flux analyses challenges this reductionist framework. This review critically interrogates whether mitochondrial dysfunction constitutes a primary upstream lesion rather than a secondary metabolic consequence. We systematically evaluated data from 47 longitudinal cohort studies (n = 218,400 participants) alongside mechanistic murine and human islet models. Our findings indicate that electron transport chain Complex I haploinsufficiency and impaired mitophagy-mediated quality control precede detectable hyperglycemia by 3–7 years. These observations necessitate a fundamental reconceptualization of early T2DM diagnostics, therapeutic target prioritization, and the clinical timeline of intervention for at-risk populations.
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