Key result
NAD+ depletion-driven sirtuin impairment promotes mitochondrial dysfunction and metabolic uncoupling in diabetic heart failure.
Why the study?
Human studies linking sirtuins to metabolic remodeling in diabetic heart failure are largely associative, highlighting a substantial translational gap.
This narrative review positions the NAD+–sirtuin–PDH axis as a central mechanistic framework linking systemic metabolic disturbances in diabetes to glycolysis–oxidation uncoupling, mitochondrial dysfunction, and energetic failure in heart failure.
NAD+-sirtuin axis links diabetic metabolism to HF energetics; leaves open whether targeting improves outcomes.
Heart failure (HF) in the setting of diabetes represents a distinct cardiometabolic phenotype characterized by profound disturbances in myocardial glucose metabolism, mitochondrial function, and energetic efficiency. Growing evidence indicates that sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases, play a central role in coordinating glucose utilization, oxidative metabolism, and stress responses in the heart. Findings from genetically modified animal models and cardiomyocyte studies demonstrate that sirtuin impairment, often driven by NAD+ depletion and redox imbalance, further suppresses metabolic activity and promotes metabolic inflexibility, whereas restoration of NAD+ availability or sirtuin activity improves mitochondrial efficiency and metabolic coordination. Human studies, including analyses of myocardial tissue and circulating biomarkers, provide supportive but largely associative evidence, highlighting a substantial translational gap. In this review, we synthesize experimental and clinical data linking sirtuin signaling to the metabolic remodeling observed in diabetic HF, with particular emphasis on glycolysis–oxidation uncoupling, pyruvate dehydrogenase regulation, and mitochondrial dysfunction. We critically discuss context-dependent effects, apparent contradictions, and current limitations of the field, emphasizing differences between diabetic and non-diabetic HF, as well as phenotype- and stage-specific considerations. Finally, we explore therapeutic implications and outstanding questions, positioning the NAD+–sirtuin axis as a unifying mechanistic framework that links systemic metabolic disease to cardiac energetic failure and underscores the potential for metabolism-informed, precision strategies in diabetic HF.
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Krekora et al. (2026) conducted a review in Diabetic heart failure and cardiometabolic disease. NAD+–sirtuin signaling modulation was evaluated. Sirtuin impairment driven by NAD+ depletion promotes glycolysis-oxidation uncoupling and mitochondrial dysfunction in diabetic heart failure.
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