Disrupted lipid metabolism is an early event in diabetic heart functional abnormalities (33). McGavock et al. discovered myocardial lipid deposition in diabetic patients with normal heart function, implying that metabolic disturbances occur prior to the development of left ventricular dysfunction (33). Diabetic heart lipid metabolism is impacted due to changes in the expression of transporters involved in FA uptake (34), alterations in the PPAR signaling pathway during FA oxidation (35), accumulation of lipotoxicity, and activation of the MAPK signaling pathway (36). Lipid metabolism alterations in type 2 diabetes mellitus (T2DM) have been widely reported, and notably, lipid accumulation in type 1 diabetes mellitus (T1DM) has also been reported by relevant studies (37–39).

Heart FAs are composed of non-esterified FAs that combine with plasma albumin in the bloodstream and esterified FAs in the form of lipoprotein (40). In cardiomyocytes, 70%–90% of cytosolic FA is translocated into mitochondria for β-oxidation, which results in the production of ATP, while the remaining fraction is esterified to triglycerides (TAGs) (11). As the primary metabolic substrate, long-chain FAs (LCFAs) are esterified to fatty acyl-CoAs, which are then converted to acylcarnitines by carnitine palmitoyltransferase-1 (CPT1). Carnitine acylcarnitine translocase then transports acylcarnitines across the inner mitochondrial membrane to convert them into carnitines (41). Finally, mitochondrial FA undergoes β-Oxidation to produce acetyl CoA, which is further metabolized into the tricarboxylic acid cycle to produce ATP (41).

In diabetic hearts, lipid oxidation is increased while glucose oxidation is decreased (9). Members of the Sirtuins family overexpression can assist the heart's glucose oxidation efficiency (73). Glycolipid metabolism can be improved by activating AMPK signaling pathway, which promotes glucose uptake and oxidation (74).

Glucose is aerobically oxidized, producing pyruvate, which enters the mitochondria for oxidative decarboxylation. Acetyl CoA and NADH produced by β-oxidation reduce glucose oxidation through activating pyruvate dehydrogenase kinase (PDK) and inhibiting the phosphorylation of the pyruvate dehydrogenase (PDH) enzyme complex (12). This relationship between FA and glucose metabolism is called the glucose-FA cycle or Randle cycle (12, 41).

AGEs and the occurrence and progression of DCM are closely related phenomena (3, 4). AGEs accumulation is often observed in DCM disease models (91). Reducing the levels of AGEs and Receptor for AGEs (RAGE) is beneficial for structural and functional abnormalities improvement in diabetic heart (91).

AGEs are found in tissues, cells, and blood. They are the collective term for a class of stable end products formed after the free amino groups of substances such as proteins, amino acids, lipids, or nucleic acids undergo a series of reactions involving condensation, rearrangement, cleavage, and oxidative modification with the carbonyl groups of reducing sugars (6, 92).

Blood glucose levels and AGEs levels in the body are closely correlated. Persistently elevated blood sugar levels promote the glycosylation reaction between proteins and glucose, which leads to the production of AGEs in insulin deficient or insulin resistant diabetes (6).

Binding of AGEs to their receptors (RAGEs) activates multiple intracellular signaling pathways. For instance, AGEs can activate nuclear factor kappa A-β (NF-κB) (25) and protein kinase C (PKC) (93, 94) signaling, which can result in the production of reactive oxygen species (ROS), inflammatory responses, and cardiac dysfunction. AGEs induced by high glucose (HG) directly bind to MD2 to form the AGEs-MD2-TLR4 complex, which starts the proinflammatory pathway, leading to inflammatory diabetic cardiomyopathy (26). Fruthermore, AGEs have the ability to alter protein structure, promote collagen cross-linking, and accelerate atherosclerosis development. The activation of AGE/RAGE signaling pathway stimulates the activaion of fibroblast and promotes fibroblast differentiation into myofibroblast, which increases extracellular matrix accumulation and accelerates pathological remodeling of diabetes heart (95).

Future treatments for the chronic diabetic complications may include blocking the AGEs-RAGE system (96). Recent studies have shown that vitamin D reduces NF-κB activity, which decreases RAGE expression (97). Calcitriol has the potential to treat RAGE-mediated cardiovascular complications, because it down-regulates RAGE expression through the proteolysis of RAGE in HL-1 cardiomyocytes, mediated by disintegrin and metalloproteinase 10 (ADAM10) (97). In the DCM disease model, inhibition of protein kinase R (PKR) was found to improve diabetes-induced fibrosis by down-regulating AGEs and ERK 1/2 (98).

The accumulation of O-linked N-acetylglucosamine (O-GlcNAc), a post-translational modification of proteins, in the heart predisposes to glucotoxicity, inducing insulin resistance (4, 99). Diabetic cardiomyopathy can be improved by HBP hyperactive suppression (100, 101).

The primary branch of the glycolysis pathway is HBP. This pathway metabolizes 2%–5% of the glucose (99). O-GlcNAcylation is a dynamic and reversible modification that primarily occurs in the cytoplasm and nucleus, in contrast to advanced glycosylation and other forms of glycosylation in the endoplasmic reticulum and Golgi apparatus (102).

When glucose enters the cell, it is phosphorylated to glucose-6-phosphate and metabolized to fructose-6-phosphate, which feeds into the glucose oxidative metabolism, glycolysis, and gluconeogenesis pathways (7). The first reaction is the rate-limiting conversion of fructose-6-phosphate to glucosamine-6-phosphate by l-glutamine-fructose-6-phosphate amidotransferase (GFAT) with conversion of glucosamine to glutamine. The second reaction involves the use of acetyl CoA as a substrate to convert glucosamine-6-phosphate to n-acetylamino-6-phosphate by glucosamine-6-phosphate acetyltransferase. After that, phosphoglucomutase converts n-acetylglucosamine-6-phosphate to n-acetylglucosamine-1-phosphate. Finally, pyrophosphorylase catalyzes the conjugation of N-acetylglucosamine to uridine nucleotides, resulting in uridine diphosphate N-acetylglucosamine UDP GlcNAc, which acts as the monosaccharide donor for o-glcnacylation. O-GlcNAc transferase (OGT) links O-GlcNAc to protein serine and threonine residues during this process. Conversely, β-n-acetylglucosaminidase (OGA) removes O-GlcNAc (102).

Under physiological conditions, transient activation of O-GlcNAc signals acts as a cellular protective mechanism (103). However, growing evidence suggests that long-term O-Glcnacylation protein elevation in diabetic animals’ hearts is associated with glucose toxicity (103, 104). Hyperglycemia induces glycogen synthase O-Glcnacylation, which reduces its activity and leads to insulin resistance. Increased HBP flux and O-Glcnacylation increased FA oxidation during glucosamine perfusion in hearts in vitro, implying that high O-GlcNAC levels cause both cardiac lipotoxicity and cardiac glycotoxicity (27).

Additionally, the activity of a set of proteins related to metabolic regulation, such as IRS1/2, Akt, AMPK, and GLUT4, decreases through O-GlcNAc modification. Demonstrating that O-GlcNAcylation may be a potential mechanism underlying the typical metabolic dysfunction of hearts (99).

Recent research has demonstrated that the hypoglycemic drug dapagliflozin, a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor, reduces cardiac HBP and improves diastolic dysfunction in lipodystrophic T2DM mouse models (101). In diabetic rats with significantly increased O-GlcNAcylation, thiamine may block the biosynthesis of hexosamine and prevent diabetes-induced cardiac fibrosis (100).

Lactic acid is also a vital energy substrate for the myocardium during exercise or myocardial stress (15). Lactic acid is produced by glucose through anaerobic glycolysis (105). The discovery of monocarboxylate transporters (MCTs) laid the foundation for the study of the transmembrane transport of lactate. The MCTs consist of 14 members, and MCTs 1–4 are responsible for transporting monocarboxylates (like L-lactate and pyruvate) and ketone bodies across the plasma membrane (106). Lactate dehydrogenase (LDH) can convert lactic acid into pyruvate in normoxic conditions, providing energy for the tricarboxylic acid cycle (TCA) to produce ATP (106).

Diabetes impairs glucose and lactate metabolism in the myocardium (15). Decreased lactate uptake is associated with an increased cytosolic NADH/NAD⁺ ratio in the diabetic state (28).

Elevated fructose levels in the hearts of diabetic patients can be divided into extracellular and intracellular sources. Dietary intake is the main extracellular source of fructose, which enters the cardiomyocytes via the systemic circulation. The intracellular source is the polyol pathway, wherein glucose is reduced to sorbitol by aldose reductase and sorbitol is then oxidized to fructose by sorbitol dehydrogenase (SDH) (14).

It has been demonstrated that the proteins required for fructose transport, including GLUT5, GLUT11 and GLUT12, are expressed in the heart (13). The GLUT11 and GLUT12 have little impact on fructose transport in cardiomyocytes, while the glucose transporter GLUT5 is highly specific for fructose and has a low affinity for glucose transport (13).

The formation of fructose-derived AGEs is faster than that of AGEs derived from glucose. Persistent hyperglycemia activates polyol pathways, which cause T2DM to overproduce AGEs (107). Protocatechuic acid, a phenolic from the leaves of Polygonum cuspidatum, significantly suppressed AGEs levels in the serum of T2DM rats by inhibiting the activation of the polyol pathway through reducing the activities of aldose reductase and sorbitol dehydrogenase and increasing glyoxalase I activity (29).

Fructose exposure is associated with metabolic disorders, lipid accumulation, inflammation, and apoptosis (108, 109). Increased cellular fructose metabolism promotes the formation of O-Glcnacylation and AGEs, which are crucial for fructose-mediated cardiomyocyte signaling and dysfunction (13, 14).

In the field of diabetic cardiomyopathy research, the majority of research on metabolic substrates has focused on the changes in FA and glucose metabolism. However, amino acids and ketone bodies (KB) are also used as fuel by cardiomyocytes (17, 110). Branched amino acids (BCAA) and ketone bodies produce acetyl-CoA via branched-chain alpha-ketoate dehydrogenase (BCKD) and beta-hydroxybutyrate dehydrogenase (βDH), respectively, which supplies ATP to the heart (17).

Branched chain amino acids (BCAA) are composed of valine, leucine, and isoleucine (111). In the heart, the first step of BCAA metabolism is the transamination of BCAA into the corresponding branched-chain α-ketoic acid (BCKA) by mitochondrial branched-chain aminotransferase (BCATm). The second step involves oxidative decarboxylation of BCKA by mitochondrial branched-chain alpha-ketoate dehydrogenase (BCKDH). Finally, acetyl-CoA is generated for the TCA cycle (112).

Increased BCAA levels in the blood may be a diabetes risk factor (111). Targeting the gut microbiota to reduce the abnormalities of circulating branched chain amino acids may be a key strategy to improve heart function, according to Yang and his colleagues (112).

General control nonderepressible 2 (GCN2) is an evolutionarily conserved eukaryotic initiation factor 2α (eIF2α) Kinases, which serves as an amino acid sensor (113). When amino acid levels are insufficient, GCN2 can selectively stimulate amino acid biosynthetic gene expression, maintaining amino acid homeostasis (30, 113). GCN2 deficiency in mice improves streptozotocin (STZ) or high-fat diet (HFD) induced diabetic cardiac dysfunction by reducing lipotoxicity and reducing oxidative stress (30).

BCAA also has the function of regulating signaling pathways in the heart. Continuous mTOR signaling, particularly involving leucine, impairs insulin signaling via insulin receptor substrates (IRS) (16, 114). Additionally, impaired BCAA metabolism causes toxic BCAA metabolites accumulation (110). In myocardial fibroblasts, high expression of periosteal protein upregulates nucleosome assembly protein 1-like 2 (NAP1L2) to deacetylate enzymes related to BCAA catabolism, which promotes cardiac fibrosis in diabetic cardiomyopathy (31).

Diabetes can lead to an increase in circulating ketones bodies (KBs) (17, 115). Ketogenesis is the synthesis of KBs through consuming acetyl coenzyme A (acetyl-CoA) produced by lipolysis (116). The two main KBs, acetoacetate and β-hydroxybutyrate (βHB), are essential in maintaining bioenergy homeostasis in diabetic cardiomyopathy (116). It has been established that the expression of hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) is increased in T1DM hearts (32). In comparison with control rats, HMGCS2 protein expression was eight times higher in the hearts of diabetic rats (32). This suggests that the heart opposes “metabolic inflexibility” by transferring excess intramitochondrial Acetyl-CoA of FA oxidation to KBs, thereby releasing free CoA to balance the Acetyl-CoA/CoA ratio in favor of increased glucose oxidation via the pyruvate dehydrogenase complex. Enhanced ketogenesis is likely an adaptive mechanism of cardiac function in diabetic hearts (117).

Increased KBs use in T2DM may help improve cardiac energy efficiency (116). Ketone levels increase in patients with T2DM receiving SGLT-2 inhibitors, which may be associated with a reduced risk of heart failure mortality (118). The increased use of KBs in patients with heart failure or diabetes may be explained by the fact that ketone body breakdown requires less oxygen than FA oxidation to produce the same amount of ATP (119). In contrast with a control group receiving only AGE, Tao and his colleagues found that AGE plus KB treatment inhibited FA oxidation (120). However, KBs leads to DCM cardiac dysfunction and ventricular remodeling despite improvements in metabolic function (120). Therefore, there is still debate regarding how KBs utilization affects cardiac function in diabetes.

The pathological mechanism of diabetic cardiomyopathy is also related to the expression of non-coding RNA. MiRNA binds to the 3′ untranslated region (UTR) of messenger RNA (mRNA) molecule and regulates the expression of cardiac metabolism-related genes at the post-transcriptional level through mRNA translation inhibition or degradation (121). MiR-320 is highly expressed in diabetic cardiomyopathy mice and diabetic patients (18). It translocates to the nucleus and enhances the transcription of the FA metabolism-related gene CD36, which increases the uptake of free FA and induces myocardial lipotoxicity (18). Conversely, the expression of mir-200b-3p was decreased in DCM. Upregulation of mir-200b-3p inhibits CD36 and reduces cardiomyocyte apoptosis (19). Studies have shown that PGC-1β may be a target of miR-30c. MiR-30c reduces transcriptional activity of PPARα regulated by PGC-1β and suppresses the conversion of cardiac metabolism to FA induced by palmitate (21).

LncRNA is a specific transcript comprising over 200 nucleotides that are not translated into proteins. They bind to the miRNA through base pairing and block its regulatory function (122). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, also named NEAT2) is a long non-coding RNA with a miR-26a-binding region in the transcriptional sequence, which is significantly upregulated in cardiomyocytes treated with palmitic acid (123). The downregulation of MALAT-1 inhibits the TLR4/NF-κB signaling pathway by regulating HMGB1 expression, which may be the potential mechanism to relieve the inflammatory response and decrease myocardial lipotoxic injury (123).

At present, the research into metabolic disorders in diabetic cardiomyopathy is comprehensive and extensive. The changes in some signaling pathways and molecular targets have been relatively clear, but there are still some limitations that cannot be ignored.

To begin, the signal pathways underlying metabolic disorders in DCM crosstalk with one another, and the relevant molecular mechanisms are complex. For example, CD36 inhibits AMPK activation by forming a molecular complex with Lyn and LKB1 and then participates in the energy regulation process (124). PGC-1α not only regulates FA β-oxidation and excess myocardial lipid accumulation, but it also promotes the AMPK regulated expression of several key players in mitochondrial and glucose metabolism (55, 56).

Second, the multiple pathophysiological mechanisms involved in the development of DCM remain controversial. There is no agreement on whether changes in some signaling pathways and molecular targets (such as HBP and MG53) are beneficial or harmful in the process of disease progression has not yet reached a consensus. More experimental research and theoretical support are required.

In recent years, there has been an increase in the number of studies focusing on mitochondrial dysfunction. The balance between mitochondrial biogenesis and mitophagy is critical for maintaining cellular metabolism in the diabetic heart (125, 126). A comprehensive study of the mitochondrial quality control (MQC) system, which includes mitochondrial fission, fusion, and mitophagy, may shed new light on cardiometabolic disorders in DCM.

Besides, previous research by our group has shown that overexpression of the Hippo pathway effector YAP promotes cardiac remodeling and cardiac fibrosis, leading to cardiac dysfunction (127, 128). Additionally, it may also participate in the glycosylation process and affect diabetic cardiometabolism. However, more investigation into the relationship between these molecular and metabolic disorders in DCM is required. A greater understanding of diabetes and the complications associated with cardiovascular disease will result from an in-depth investigation of these signaling and pathological pathways in myocardial metabolic disorders.