Circulating β-Hydroxybutyrate in Glycemic Progression and Diabetic Cardiomyopathy: Adaptive Signal or Maladaptive Substrate?

Circulating ketone bodies (KBs), particularly β-hydroxybutyrate (β-HB), have emerged as metabolites with dual roles as both oxidative fuels and metabolic signaling molecules. Beyond serving as an alternative energy substrate, β-HB regulates diverse pathways involved in oxidative stress, inflammation, and mitochondrial function. However, the clinical implications of circulating KBs remain uncertain. This review summarizes current evidence regarding the potential role of KBs in glycemic progression and diabetic cardiomyopathy (DCM). Epidemiologic and experimental studies report conflicting associations between KB levels and the progression to hyperglycemia or type 2 diabetes, with some findings suggesting that elevated KB levels may reflect a metabolically favorable phenotype or a compensatory mechanism, whereas others indicate links to worsening glycemia. Similarly, studies in DCM have produced divergent results, with β-HB reported to improve mitochondrial function and cardiac performance in some models while contributing to metabolic inflexibility and adverse cardiac remodeling in others. We discuss potential mechanisms underlying these discrepancies and propose that the metabolic effects of β-HB are context-dependent, influenced by factors such as circulating concentration, the mode of ketosis induction, and the underlying metabolic or disease stage. Understanding these contextual determinants may help clarify whether β-HB represents an adaptive metabolic signal or a maladaptive substrate shift in cardiometabolic disease.