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Methylmalonate Overload Despite Glycemic Control Drives Diabetic Heart Damage
Shanjie Wang1,2, Miao Yan1,2, Yiying Zhang3
1Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, China (S.W., M.Y., Y.W., J.G., Z.C., X. Liu, Z.L., R.L., G.M., P.W., Y.H., Y.L., Zeng Wang, X. Luo, H.C., Zhuozhong Wang, S.Y., S.F., B.Y.).
Circulation Research
|July 29, 2026
Summary
Methylmalonic acid (MMA) accumulation, not linked to cobalamin (Cbl) deficiency, drives heart damage in diabetes. Metformin mitigates this by enhancing MMA clearance and mitochondrial function, challenging current treatment guidelines.
Area of Science:
- Cardiology
- Metabolic Diseases
- Biochemistry
Background:
- Diabetic heart failure remains a significant problem despite glycemic control.
- Metabolic remodeling contributes to diabetic cardiomyopathy, but mechanisms are poorly understood.
- Methylmalonic acid (MMA) elevation is paradoxically linked to cardiovascular mortality in diabetics with normal cobalamin (Cbl) levels.
Purpose of the Study:
- Investigate the mechanisms of contradictory MMA accumulation in the diabetic heart.
- Determine the translational significance of MMA dysmetabolism in diabetic cardiovascular complications.
- Clarify the roles of Cbl and metformin in MMA metabolism and heart health in diabetes.
Main Methods:
- Analysis of serum Cbl, MMA, and cardiac biomarkers in a large human cohort (12,751 participants).
- Characterization of methylmalonyl-CoA mutase (Mmut) expression in human diabetic hearts.
- Utilized cardiomyocyte-specific Mmut knockout/overexpressing mice, 13C-isotope tracing, RNA sequencing, and immunoprecipitation to elucidate molecular mechanisms.
Main Results:
- Elevated serum MMA correlated with subclinical heart damage and adverse outcomes in diabetics, independent of Cbl deficiency.
- Decreased cardiac Mmut expression and MMA overload were observed in diabetic humans and mice.
- MMA dysmetabolism preceded cardiac dysfunction, and branched-chain amino acid restriction alleviated MMA accumulation and heart damage.
- Cbl supplementation was ineffective, while metformin mitigated MMA-induced heart damage via AMPK activation and enhanced Mmut-Cbl cooperation.
Conclusions:
- Diabetes-related MMA dysmetabolism triggers subclinical heart damage resistant to glycemic control and Cbl supplementation.
- Findings challenge the clinical consensus on Cbl and metformin's impact on MMA levels in diabetic management.
- Identified isoleucine and valine as primary cardiac MMA sources and miR-499 as a regulator of Mmut expression.
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