Emerging Insights into the Relationship Between Amino Acid Metabolism and Diabetic Cardiomyopathy

Abstract

Diabetes mellitus (DM) is a complex global pandemic that frequently leads to multiple complications. Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with type 1 and 2 diabetes and is fundamentally characterized by abnormalities in myocardial structure and function. Metabolic disorders occupy a leading role in the pathogenesis of DCM, manifesting as disrupted substrate metabolism, dysregulated signaling pathways, and energy imbalance. Given the limited benefits of conventional therapeutic strategies targeting glucolipid metabolism, increasing research efforts have focused on amino acid metabolism. Amino acids are involved in the synthesis of nitrogen-containing compounds and serve as an energy source under specific conditions. Moreover, emerging studies demonstrate that metabolic disturbances of specific amino acids-such as branched-chain amino acids (BCAAs), glutamine, and arginine-exacerbate mitochondrial dysfunction and oxidative stress, thereby promoting myocardial fibrosis and cardiomyocyte injury. Therefore, this review aims to summarize the general characteristics and regulatory pathways of amino acid metabolism, as well as the specific mechanisms by which metabolic alterations of amino acids contribute to the pathogenesis and progression of diabetic cardiomyopathy, with the hope of advancing more effective translational therapeutic approaches.

Keywords: amino acid metabolism; aromatic amino acid; branched-chain amino acid; diabetic cardiomyopathy.

Figure 1

Pathways of amino acid metabolism. Most amino acids undergo catabolic processes in the liver, primarily through deamination to form α-keto acids and ammonia (NH3/NH4⁺). The resulting α-keto acids are oxidized in the mitochondria for energy production, converted into glucose and fatty acids, or resynthesized into NEAAs. Ammonia is predominantly detoxified via the ornithine cycle to form urea and ultimately excreted by the kidneys. Moreover, certain amino acids can be decarboxylated to yield carbon dioxide and amines. The arrows in the figure represent either the transport of substances or the course of biochemical processes.

Figure 2

Regulation of amino acid metabolic enzymes. Enzymes involved in amino acid metabolism are regulated by a variety of factors. Bioactive compounds in food, such as quercetin and organic acids, can inhibit or activate the activity of different digestive enzymes. Cofactor dysfunction may lead to impaired enzyme activity and disease pathogenesis. In addition, the transcription of enzymes is regulated by factors such as diet, the gut microbiota, hormone levels, and transcription factors. + and − represent the activation and inhibition of digestive enzyme activity, respectively.

Figure 3

Branched-Chain Amino Acids Metabolism in DCM. Under physiological conditions, BCAAs undergo catabolism via a series of enzymatic reactions in the mitochondria of skeletal muscle, myocardium, and hepatic tissues. In diabetes, the interplay of impaired glucose/lipid metabolism, vagal dysfunction, and gut microbiota disruption alters the status of substrates and enzymes within the myocardial BCAA metabolic pathway, which contributes to the pathogenesis of DCM. Mechanistically, autophagy dysregulation, oxidative stress, and inflammatory responses collectively drive myocardial hypertrophy and fibrosis, ultimately manifesting as impaired cardiac function. An upward arrow indicates an increase in a substance or the promotion of a biological process, while a downward arrow indicates a decrease in a substance or the inhibition of a biological process.