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Review Article Volume 13 Issue 1
Metabolic remodelling of the failing heart in diabetes: shifting substrates and emerging therapeutics
Anuj Maheshwari, Shivam Verma, Nishant Kanodia, Divya Singh, Narsingh Verma, Sajid Ansar, Sabiha Ansari, Alok Modi, Sanjay Singla, Shubhashree Patil, Shivangi Maheshwari, Amit Gupta, Rakesh Parikh, Anil Virmani, Singh NK, Surajeet Patra, Smita Singh, Jayant Panda, Anubha Varma Srivastava, Abhinav Verma, Raghunath Dantu, Vanshika Arora
Received: April 06, 2026 | Published: April 23, 2026
Citation: Maheshwar A, Verma S, Kanodia N, et al. Metabolic remodelling of the failing heart in diabetes: shifting substrates and emerging therapeutics. J Diabetes Metab Disord Control. 2026;13(1):44-48. DOI: 10.15406/jdmdc.2026.13.00312
Abstract
Heart failure (HF) remains a significant global health burden, with a disproportionately high prevalence and severity among individuals with diabetes mellitus (DM). Diabetic cardiomyopathy, a distinct clinical entity characterized by myocardial dysfunction in the absence of overt coronary artery disease or hypertension, underscores the critical contribution of metabolic dysregulation in disease pathogenesis. Under physiological conditions, the heart exhibits remarkable metabolic flexibility, efficiently switching between substrates—primarily fatty acids, glucose, lactate, ketone bodies, and amino acids—to meet its substantial energy demands via mitochondrial oxidative phosphorylation. This substrate utilization is finely regulated by hormonal signals, nutrient availability, and transcriptional control. However, in the failing heart, especially in the diabetic milieu, this flexibility is compromised. Key features of this maladaptive metabolic remodeling include mitochondrial dysfunction, impaired oxidative phosphorylation, and a shift toward inefficient glycolysis. Insulin resistance further impairs myocardial glucose uptake and promotes excessive fatty acid oxidation, leading to lipotoxicity and oxidative stress. Notably, recent studies have highlighted an increased reliance on ketone bodies as an alternative, oxygen-efficient energy source in diabetic heart failure. This review synthesizes current evidence on the pathophysiology of myocardial energy metabolism in diabetic HF and explores emerging therapeutic strategies aimed at restoring metabolic flexibility and enhancing cardiac efficiency.
Keywords: heart failure, diabetes mellitus, SGLT2 inhibitors, GLP-1 receptor agonists
©2026 Maheshwar, et al. This is an open access article distributed under the terms of the, which permits unrestricted use, distribution, and build upon your work non-commercially.