Methylmalonate Overload Despite Glycemic Control Drives Diabetic Heart Damage

BACKGROUND: Despite optimal glycemic control, the heart failure burden remains substantial in diabetic patients. Metabolic remodeling is involved in this process, yet our current understanding is still in its infancy. Methylmalonic acid (MMA) is conventionally viewed as a marker of cobalamin (Cbl) deficiency. Paradoxically, MMA elevation-related cardiovascular mortality is more pronounced in diabetic patients with normal or high Cbl levels. This study investigated the mechanisms and translational significance of this contradictory MMA accumulation in the diabetic heart. METHODS: C-isotope tracing, RNA sequencing, immunoprecipitation, and biolayer interferometry. RESULTS: Elevated serum MMA was significantly associated with subclinical heart damage and adverse outcomes in diabetic adults, even in the absence of Cbl deficiency. Cardiac MMA overload and decreased protein expression of Mmut were observed in humans and mice with diabetes. Notably, MMA dysmetabolism preceded detectable cardiac dysfunction in diabetic mice and persisted even after glycemic normalization. Mechanistically, the hyperglycemic memory-associated molecule miR-499 binds to Mmut mRNA, suppressing its expression and driving MMA accumulation. Mmut deficiency amplified cardiac MMA overload and exacerbated disturbances in glycolipid metabolism and mitochondrial quality control, whereas adeno-associated virus-mediated Mmut overexpression attenuated cardiac MMA load and adverse remodeling in diabetic mice. Isotope tracing identified isoleucine and valine as the primary sources of cardiac MMA under diabetic conditions. Branched-chain amino acid-restricted diets alleviated diabetes-induced MMA accumulation and heart damage. Crucially, Cbl supplementation failed to alleviate MMA overload in diabetic mice, even at high doses or with activated forms. Strikingly, metformin, an established risk factor for Cbl deficiency, mitigated MMA-induced heart damage through dual mechanisms: activating AMPK (AMP-activated protein kinase)-dependent mitochondrial quality control to enhance tolerance to MMA, and directly promoting Mmut-Cbl cooperation to enhance MMA clearance. CONCLUSIONS: This study provides a foundation for understanding diabetes-related MMA dysmetabolism as a trigger for subclinical heart damage resistant to glycemic control and Cbl supplementation. Our findings challenge the prevailing clinical consensus regarding the impacts of Cbl and metformin use on MMA elevation in diabetic management.