The heart of diabetes: unraveling metabolic drivers of cardiomyopathy

Abstract

Diabetes mellitus (DM) ignites a global epidemic, with cardiovascular complications claiming most lives among affected patients. Diabetic cardiomyopathy (DCM), a distinct cardiac dysfunction triggered by DM independent of coronary artery disease or hypertension, threatens those with type 1 or type 2 DM, often leading to heart failure. In type 2 DM (T2DM), metabolic disruptions drive cardiac lipotoxicity. Yet, how lipotoxicity impairs function and DM sparks clinical syndromes remains unclear. This review unveils how DM rewires myocardial metabolism—favoring lipids over glucose—and probes emerging therapies, spotlighting clinical challenges at a vital research frontier.

Introduction

DM has emerged as a global health crisis, with its prevalence rising dramatically over recent decades. In 1985, approximately 30 million individuals worldwide were affected by DM; by 2024, this number had surged to 589 million among adults aged 20–79 years – 1 in 9, a figure projected to climb to 853 million by 2050 - 1 in 8, according to the International Diabetes Federation [1, 2] (Fig. 1). This escalation reflects a 45% increase over the next twenty-five years, driven by factors such as aging populations, obesity, poor dietary habits, and sedentary lifestyles [2, 3]. In 2024, the total number of adults (20-79 years old) with diabetes in China was 148 million, accounting for 11.9% of the country’s adult population and a quarter of the world’s total number of people with diabetes. And it is predicted to reach 168 million by 2050 [2] (Fig. 1). It is remarkable that the number of deaths related to diabetes (20-79 years old) is 756 thousand [2]. DM encompasses two primary forms: type 1 diabetes mellitus (T1DM), an insulin-dependent condition resulting from autoimmune or genetic destruction of pancreatic beta cells, accounting for 5–10% of cases [4], and type 2 diabetes mellitus (T2DM), characterized by insulin resistance and often linked to obesity and metabolic dysfunction, which constitutes the vast majority of diagnoses [5].

Fig. 1.

Number of adults with diabetes worldwide in 2024 and 2050

The socio-economic burden of diabetes is staggering, with healthcare expenditures due to diabetes amounting to at least $1 trillion in 2024. The United States alone spends $404.5 billion and China spends about $168.8 billion [2] (Table 1). Diabetes was responsible for an estimated USD 1.015 trillion in global health expenditure in 2024. This represents a 338% increase over the past 17 years [2] (Fig. 2). These costs stem largely from diabetes-related complications, notably cardiovascular diseases (CVD), which dominate as the leading cause of morbidity and mortality in DM patients [6, 7].

Table 1.

Alterations in myocardial energy metabolism in patients with DCM

Years	2011	2011	2024	2024	2050	2050
Country	China	the USA	China	the USA	China	the USA
Diabetes estimates (20-79 y)
People with diabetes, in 1,000s	90045.1	23721.8	147981.2	38536.4	168289.2	43025.3
Age-standardised prevalence of diabetes, %	8.8	9.4	11.9	13.7	13.9	15.2
Proportion of people with undiagnosed diabetes, %	-	-	49.7	24.8	-	-
People with undiagnosed diabetes, in 1,000s	-	-	73526.1	9557.0	-	-
Impaired Fasting Glucose (IFG)
People with IFG, in 1,000s	-	-	117246.5	37250.9	121226.3	40866.2
Age-standardized prevalence of IFG, %	-	-	9.9	14.2	10.9	14.9
Impaired Glucose Tolerance (IGT)
People with IGT, in 1,000s	23373.0	25948.7	156759.0	31477.4	164405.6	34748.3
Age-standardized prevalence of IGT, %	2.3	10.6	13.3	11.5	14.7	12.5
Mortality attributable to diabetes (20-79 y)
Deaths attributable to diabetes	1133918.0	179612.0	755511.4	363427.0	-	-
Proportion of diabetes-related deaths in people 20-79 y, %	-	-	10.6	21.9	-	-
Diabetes-related health expenditure
Total diabetes-related health expenditure, USD million	-	-	168883.0	404531.0	163382.0	407209.0
Total diabetes-related health expenditure, ID million	-	-	315208.0	404531.0	304942.0	407209.0
Diabetes-related health expenditure per person, USD	194.0	8468.0	1141.2	10497.4	970.8	9464.4
Diabetes-related health expenditure per person, ID	-	-	2130.1	10497.4	1812.0	9464.4
Type 1 diabetes estimates in children and adolescents
People with type 1 diabetes (all age groups)	-	-	598906.0	1476859.0	-	-
People with type 1 diabetes (0-19 y)	-	-	116588.6	196778.3	-	-
Demographics
Total adult population (20-79 y), in 1,000s	968974.9	216804.8	1073004.5	245525.2	977748.3	262288.0
Population of children and adolescents (0-19 y)	-	-	310324337.5	82611598.0	-	-

Fig. 2.

Pathological mechanisms that may lead to DCM

Among these complications, diabetic cardiomyopathy (DCM) emerges as a critical, underrecognized threat. Defined as myocardial dysfunction in absence of coronary artery disease or hypertension [8, 9], DCM heightens heart failure risk in T1DM and T2DM patients [6, 10]. with studies showing a 2- to 5-fold increase [11, 12]. Unlike other cardiovascular conditions tied to vascular pathology, DCM arises directly from diabetes-induced metabolic disturbances, particularly in T2DM, where insulin resistance, dyslipidemia, and obesity drive lipid accumulation and toxicity (lipotoxicity) in the heart [5]. These metabolic shifts impair myocardial energy metabolism, initiating a cascade of structural and functional changes that progress from subclinical diastolic dysfunction to overt systolic failure [13–15]. Despite advances in understanding DCM’s pathogenesis, the precise mechanisms linking metabolic remodeling to clinical cardiac syndromes remain incompletely elucidated, posing challenges for effective prevention and treatment.

The economic and human toll of DM and its cardiovascular sequelae, coupled with the rising global prevalence, underscores the urgent need to address DCM as a public health priority. Poor glycemic control, DCM is independent of hypertension, dyslipidemia, and autonomic dysfunction amplify the risk of HF in diabetic patients [16, 17], yet current therapeutic strategies often fail to fully mitigate these outcomes. Recent studies have highlighted significant changes in myocardiac energy metabolism in DCM, including changes in substrate utilization increasing fatty acid uptake and oxidation, decreasing glucose utilization and alterations in mitochondrial function, providing new avenues for research [18]. This review aims to discuss the latest findings on how DM reshapes myocardial energy metabolism, explore the pathological consequences of these changes in DCM, and evaluate emerging therapeutic strategies targeting metabolic pathways to prevent or delay premature cardiovascular death in diabetic patients.

Overview of diabetic cardiomyopathy

Definition, historical evolution, and clinical hallmarks of DCM

DCM is a distinct cardiac condition tied to DM, marked by myocardial dysfunction independent of coronary artery disease, hypertension, or valvular disease [8, 9]. First described in 1972 by Rubler et al. in autopsy studies of diabetic patients with unexplained heart failure [17, 18]. Nowadays, DCM has been established as a unique entity through decades of epidemiologic, clinical, and experimental research [13–15]. Its development stems from metabolic disruptions—insulin resistance, compensatory hyperinsulinemia, and hyperglycemia—that drive cardiac fibrosis and diastolic dysfunction. Early studies have found structural and functional changes in diabetic patients, such as elevated left ventricular end-diastolic pressure, reduced ejection fraction, and severe macrovascular and microvascular effects in diabetic patients [8, 18]. DCM thus progresses from subclinical anomalies to severe heart failure, propelled by diabetes-specific myocardial alterations. In June 2024, the Heart Failure Association of the European Society of Cardiology, with the Myocardial and Pericardial Disease Working Group, updated this definition to encompass systolic and/or diastolic dysfunction in diabetic patients, emphasizing impaired diastolic filling due to reduced ventricular compliance [6].

Clinical manifestations and diagnosis approaches

DCM manifests through a spectrum of clinical features and diagnostic challenges, often remaining asymptomatic in its early stages before progressing to overt heart failure. Initial signs include subtle left ventricular stiffness and diastolic dysfunction, detectable via imaging but easily missed without routine screening [19]. Asymptomatic early stages complicate timely intervention. As the condition advances, patients may experience dyspnea, fatigue, edema, palpitations, or chest pain, alongside arrhythmias or angina, culminating in congestive heart failure in severe cases [20, 21]. Structurally, DCM is marked by myocardial hypertrophy, fibrosis, and remodeling, reflecting diabetes-induced metabolic stress [20, 22].

Diagnosis relies on a multifaceted approach: clinical history and physical examination establish diabetes control and risk factors, while echocardiography—the gold standard—reveals ventricular hypertrophy, diastolic dysfunction, and remodeling [19]. Cardiac MRI offers detailed insights into fibrosis and hemodynamics, complementing ultrasound findings [20]. Biomarkers like HbA1c monitor glycemic status, though they lack specificity for DCM; emerging markers, such as cardiac troponins, natriuretic peptides, and extracellular matrix proteins, correlate with remodeling but are not yet diagnostic standards [23–30]. Electrocardiography detects hypertrophy or arrhythmias, while additional tests like coronary angiography exclude confounding cardiac conditions [19, 20]. Early detection hinges on regular cardiac assessments in diabetic patients, given the insidious onset and complexity of DCM.

Current understanding of pathological mechanisms in DCM

The pathogenesis of DCM is multifaceted, involving metabolic imbalance, oxidative stress, inflammation, fibrosis, mitochondrial dysfunction, microangiopathy, and autonomic dysregulation, collectively driving cardiac impairment. Metabolic disturbances—particularly lipid accumulation and impaired glucose uptake—disrupt cardiomyocyte energy supply and efficiency, initiating damage [31, 32]. The pathogenesis of early stage DCM centers on metabolic remodeling. Here, metabolic remodeling refers to the dynamic reprogramming of myocardial substrate utilization and energy metabolism, which underlies DCM progression. Excessive reactive oxygen species (ROS) from oxidative stress injure cellular structures and trigger apoptosis, amplifying myocardial stress [33].

Inflammation, marked by elevated pro-inflammatory cytokines (e.g., TNF-$\alpha$, IL-6), directly damages tissue and promotes fibrosis, reducing cardiac compliance [34, 35]. Myocardial fibrosis, a hallmark of DCM, arises from interstitial collagen deposition, further impairing diastolic function [19, 36]. Mitochondrial dysfunction compromises ATP production and calcium homeostasis, exacerbating energy deficits and injury [33, 35]. Microangiopathy reduces myocardial perfusion, leading to ischemia and hypoxia, while sympathetic overactivation disrupts metabolic and electrical stability, heightening arrhythmia and failure risks [19, 20]. These interwoven mechanisms underscore DCM’s complexity, progressing from metabolic dysregulation to structural and functional decline (Fig. 2).

Metabolic dysregulation in DCM: diabetes-induced mechanisms

Energy sources for cardiomyocytes

The heart, a highly energy-demanding organ, requires continuous ATP production to sustain contractile function, basal metabolism, and ionic homeostasis [37]. In the healthy adult heart, mitochondrial oxidative phosphorylation generates over 95% of ATP, with glycolysis and GTP synthesis in the tricarboxylic acid (TCA) cycle contributing the remainder [37]. Under physiological conditions, cardiomyocytes exhibit metabolic flexibility, primarily utilizing fatty acids (FA) and glucose as substrates, though their relative contributions shift across states. Fatty acids predominate, supplying approximately 70% of ATP in the normoxic heart, due to their high energy yield, while glucose serves as a secondary fuel source [37]. This adaptability ensures efficient energy production tailored to metabolic demands.

Mitochondria, the cellular powerhouses, are central to this process, converting carbohydrates, fatty acids, and proteins into ATP via oxidative phosphorylation along the inner mitochondrial membrane, where the electron transport chain and ATP synthase operate synergistically [38]. Beyond energy production, mitochondria regulate critical pathways, including fatty acid oxidation, amino acid metabolism, and glucose catabolism, positioning them as hubs of cellular metabolism [39, 40]. In the heart, their role is indispensable, given its relentless energy requirements. However, in DM, mitochondrial function is compromised. Elevated ROS production induces oxidative stress, damaging mitochondrial integrity and impairing cardiomyocyte function [38, 41]. Additionally, DM disrupts mitochondrial biogenesis, reducing mitochondrial density and efficiency, which further limits ATP synthesis [42, 43].

In DCM, myocardial energy metabolism undergoes a pronounced shift. Impaired glucose uptake, driven by insulin resistance, forces cardiomyocytes to rely almost exclusively on fatty acid oxidation for energy [20, 44]. While this adaptation meets immediate demands, it increases oxygen consumption and enzymatic burden, heightening oxidative stress and reducing metabolic efficiency [45, 46]. This overreliance on fatty acids, coupled with diminished glucose utilization, exacerbates lipotoxicity and mitochondrial dysfunction, contributing to the progressive cardiac impairment characteristic of DCM [20, 40]. Thus, alterations in substrate preference and mitochondrial performance underpin the energy deficits observed in the diabetic heart.

Mechanisms regulating cardiomyocyte metabolism in the normal heart

Cardiomyocytes exhibit remarkable metabolic adaptability, enabling the heart to utilize diverse substrates—FA, glucose, and lactate—to meet its substantial energy demands. This flexibility allows the myocardium to optimize ATP production under varying physiological conditions, such as shifting to fatty acid oxidation during fasting or favoring glucose metabolism postprandially [47]. In the normoxic adult heart, fatty acids are the predominant substrate, accounting for approximately 70% of ATP generation via mitochondrial oxidative phosphorylation, with glucose providing a complementary energy source [48]. This substrate preference is tightly regulated by intricate molecular mechanisms that ensure efficient energy homeostasis.

Glucose metabolism in cardiomyocytes is governed by a series of coordinated steps. Extracellular glucose enters the cell primarily through facilitated diffusion, followed by glycolysis—a cytoplasmic process converting glucose into pyruvate [49]. In the presence of oxygen, pyruvate is transported into mitochondria, where pyruvate dehydrogenase (PDH) decarboxylates it into acetyl-CoA, fueling the TCA cycle and subsequent ATP synthesis [50]. Pyruvate transport into mitochondria represents a rate-limiting step, modulated by metabolic state and enzymatic activity, and is notably diminished in diabetic conditions [51]. This pathway exemplifies the heart’s capacity to integrate glucose as an efficient, oxygen-sparing fuel source under normal circumstances.

Fatty acid metabolism, however, dominates cardiac energy production due to its higher energy yield. Circulating fatty acids, liberated from triglyceride-rich lipoproteins by lipoprotein lipase (LPL) or derived from adipose tissue hydrolysis [52], are transported into cardiomyocytes via specific proteins: CD36, fatty acid transport protein (FATP), and plasma membrane fatty acid-binding protein (FABPpm) [53–55]. Once internalized, fatty acids are esterified into fatty acyl-CoA, which is shuttled into mitochondria by the carnitine palmitoyl transferase system (CPT1/CPT2) [56]. Within the mitochondrial matrix, fatty acyl-CoA undergoes $\beta$-oxidation, generating acetyl-CoA for the TCA cycle and driving robust ATP production [56]. This process, while energy-rich, demands greater oxygen consumption, highlighting the heart’s strategic reliance on fatty acids in well-oxygenated states. Together, these regulatory mechanisms underpin the metabolic versatility of the normal heart, balancing substrate availability and energy needs with precision.

Mechanisms regulating cardiomyocyte metabolism in the DCM heart

Disorders of lipid metabolism

In DCM, myocardial energy metabolism undergoes profound remodeling (common changes are shown in Table 2), with disorders of lipid metabolism emerging as a pivotal early feature driving cardiac dysfunction. The diabetic milieu—marked by insulin resistance, hyperglycemia, and elevated circulating free fatty acids (FFA)—shifts cardiomyocyte substrate utilization toward near-exclusive reliance on fatty acid oxidation, compromising metabolic flexibility and exacerbating pathological remodeling [5, 57].

Table 2.

Alterations in myocardial energy metabolism in patients with DCM

Metabolic remodeling in DCM hearts	Mechanisms
Cardiac lipid metabolic substrate shifts	Increases lipid intake
	Increases fatty acid $\beta$-oxidation
Glucose utilization deficiency	Reduces glucose oxidation
	Reduces GLUT4 expression and translocation
	High FAO inhibits PFK1 via citrate accumulation
	High FAO inhibits PDH via PDK activation
Alterations in fatty acid utilization	Increases expression of fatty acid transporter proteins
	PPAR-$\alpha$ activation upregulates $\beta$-oxidation genes
Mitochondrial metabolic disorders	USP7 loss causes cardiac mitochondrial dysfunction (mouse)
	SIRT3 tunes cardiac metabolism via enzyme regulation

This metabolic shift is precipitated by multiple mechanisms. As previously described, insulin resistance impedes glucose uptake, particularly insulin-mediated transport of glucose transporter 4 (GLUT4) to cardiomyocyte membranes, which affects glucose uptake and reduces glucose oxidation by 30-40% in models of T2DM [58, 59]. Concurrently, elevated FFA levels enhance fatty acid uptake, mediated by upregulated expression and sarcolemmal translocation of the scavenger receptor CD36 [60, 61]. In DCM, CD36 expression is significantly elevated, driven by hyperglycemia, hyperlipidemia, and chronic insulin stimulation, which activate transcription factors like forkhead box O1 (FOXO1) and microRNA-320 (miR-320), forming a positive feedback loop that amplifies lipid accumulation [62–66]. This excess lipid influx overwhelms mitochondrial $\beta$-oxidation capacity, leading to a 2-fold increase in palmitate oxidation and triglyceride accumulation in T2DM hearts [59]. The resultant lipotoxicity—characterized by toxic intermediates such as ceramides and diacylglycerol—triggers oxidative stress, mitochondrial uncoupling, and apoptosis, reducing ATP synthesis efficiency and promoting cardiomyocyte damage [67–69].

Peroxisome proliferator-activated receptors (PPARs), notably PPAR$\alpha$, further regulate this lipid-centric metabolism. PPAR$\alpha$, highly expressed in the diabetic heart, upregulates genes governing fatty acid $\beta$-oxidation, enhancing myocardial oxygen consumption and lipid storage [70]. While PPAR$\alpha$ knockout in mice prevents lipid accumulation, its overexpression mirrors DCM phenotypes, inducing hypertrophy and ventricular dysfunction via reciprocal inhibition of glucose metabolism [71, 72]. Recent studies also implicate PPAR$\beta$/$\delta$, predominant in cardiac tissue, in modulating inflammation and fibrosis through anti-inflammatory pathways, offering a counterbalance to PPAR$\alpha$-driven lipotoxicity [73, 74].

The metabolic consequences of this lipid overload are severe. Increased fatty acid oxidation elevates myocardial oxygen demand, with studies in isolated DCM hearts demonstrating reduced cardiac efficiency and ventricular dysfunction [75, 76]. Additionally, lipid-induced mitochondrial dysfunction amplifies ROS production, fostering inflammation and fibrosis, which further impair contractile function [58, 67]. Emerging research highlights novel mediators, such as ubiquitin-specific protease 7 (USP7), which stabilizes peroxisome proliferator-activated receptor gamma coactivator 1$\beta$ (PGC1$\beta$) to exacerbate lipid metabolism disorders in DCM mice, with its silencing attenuating cardiac dysfunction [77].

Taken together, these lipid metabolism disorders underscore a maladaptive shift in DCM, where heightened fatty acid utilization and lipotoxicity drive progressive myocardial injury. Targeting these pathways—through CD36 downregulation, PPAR modulation, or USP7 inhibition—represents a promising therapeutic frontier to restore metabolic homeostasis and mitigate DCM progression.

Hyperglycemia is closely related to insulin resistance

Hyperglycemia is closely associated with insulin resistance, characterized by reduced tissue sensitivity to insulin, leading to compensatory hyperinsulinemia. Dysregulation of the insulin signaling pathway is a central mechanism in insulin resistance. Insulin typically promotes glucose uptake and metabolism by activating the insulin receptor (IR) and its downstream PI3K/Akt pathway. However, hyperglycemia disrupts post-receptor signaling, reducing Akt phosphorylation and inhibiting GLUT4 translocation, thereby impairing glucose uptake [78]. Additionally, hyperglycemia activates the hexosamine biosynthesis pathway, increasing O-acetylglucosamine (O-GlcNAc) modification of key insulin signaling proteins (e.g., IRS-1, Akt), further exacerbating insulin resistance. This mechanism also contributes to pancreatic $\beta$-cell dysfunction and apoptosis, reducing insulin secretion and worsening hyperglycemia [79, 80].

Abnormalities of glucose metabolism

In DCM, abnormalities in glucose metabolism represent a critical facet of myocardial metabolic remodeling, driven by insulin resistance and compensatory shifts toward fatty acid oxidation. Under normal conditions, glucose serves as an efficient, oxygen-sparing substrate for cardiomyocyte ATP production, yet in DCM, its utilization is markedly impaired, contributing to energy deficits and cardiac dysfunction [21, 58]. This disruption stems from a cascade of molecular and enzymatic alterations that diminish glucose uptake and oxidation, exacerbating the metabolic imbalance characteristic of the diabetic heart.

The primary mechanism underlying this impairment is insulin resistance, a hallmark of T2DM, which disrupts GLUT4 function. In healthy cardiomyocytes, insulin stimulates GLUT4 translocation to the sarcolemma, facilitating a 10–20-fold increase in glucose uptake [81]. In DCM, however, insulin signaling is blunted, reducing GLUT4 expression and membrane redistribution, thereby limiting glucose entry [82, 83]. This defect is compounded by elevated fatty acid oxidation, which inhibits key glycolytic enzymes. High fatty acid availability increases citrate levels, suppressing phosphofructokinase-1 (PFK1), and activates pyruvate dehydrogenase kinase (PDK), downregulating pyruvate dehydrogenase (PDH) activity [84]. Consequently, pyruvate conversion to acetyl-CoA is curtailed, further reducing glucose-derived ATP production [58, 68].

These metabolic shifts have significant downstream consequences. The diminished glucose oxidation forces cardiomyocytes to rely on less efficient fatty acid metabolism, increasing oxygen demand and ROS production, which amplify oxidative stress and mitochondrial dysfunction [67, 85]. This energy inefficiency contributes to contractile impairment and accelerates DCM progression. Additionally, chronic hyperglycemia exacerbates these effects by promoting glycative stress and inflammatory responses, further compromising myocardial function [32].

Emerging research highlights regulatory proteins modulating these abnormalities. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, plays a pivotal role in maintaining glucose metabolism by enhancing PDH activity and reducing oxidative stress [84, 85]. In DCM, SIRT3 expression and activity are diminished, correlating with worsened glycolysis defects and apoptosis; its upregulation mitigates these effects by inhibiting p53-mediated glycolytic suppression [84, 86]. Similarly, SIRT1 and SIRT6 have shown protective effects, improving glucose homeostasis and attenuating DCM pathology in preclinical models [87, 88]. These findings underscore the therapeutic potential of targeting sirtuins to restore glucose metabolism and alleviate myocardial injury.

Overall, the abnormalities in glucose metabolism in DCM reflect a profound loss of metabolic flexibility, driven by insulin resistance, enzymatic inhibition, and regulatory protein dysregulation. These changes not only diminish energy efficiency but also amplify oxidative and inflammatory stressors, perpetuating cardiac deterioration. Addressing these disruptions through molecular interventions offers a promising strategy to counteract the metabolic basis of DCM.

Liver-heart crosstalk in diabetic cardiomyopathy

Emerging evidence positions liver-heart crosstalk as a critical frontier in understanding DCM pathogenesis, offering novel insights into its metabolic and inflammatory drivers. Clinically, this bidirectional interaction is well-documented: liver injury frequently precipitates cardiac complications, while cardiac dysfunction can reciprocally impair hepatic function, forming a complex inter-organ feedback loop. Our lab’s recent findings in diabetic aging nonhuman primates, which revealed that some important extracellular matrix (ECM) proteins are liver-derived [89], like transferrin, further highlight the significance of this crosstalk in DCM.

At the molecular level, recent studies have begun to elucidate the mechanisms underlying this inter-organ communication. Liver-synthesized factor XI (FXI) activates cardiac BMP-SMAD1/5 pathways, suppressing pro-inflammatory cytokines such as TNF-$\alpha$, thereby reducing cardiac fibrosis and enhancing myocardial function [90]. Similarly, the liver secretes fibroblast growth factor 21 (FGF21), a hepatokine that improves cardiac metabolism by increasing glucose uptake, mitigating lipotoxicity, and inhibiting apoptosis [91, 92]. However, in type 2 diabetes (T2D) patients, FGF21 secretion is diminished due to reduced PPAR$\alpha$ expression [70], resulting in lipid accumulation and mitochondrial injury in cardiac tissue, which perpetuates DCM’s metabolic dysfunction [59]. In obese patients with non-alcoholic fatty liver disease (NAFLD)—often a precursor to T2D—liver-derived pro-inflammatory cytokines, including TNF-$\alpha$ and IL-6, are significantly elevated to healthy controls. These cytokines enter the bloodstream, are taken up by the heart, and activate NF-$\kappa$B signaling, driving an increase in collagen deposition and exacerbating myocardial dysfunction [93, 94]. This inflammatory cascade may contribute to the 2.4-fold higher heart failure risk in diabetic patients [17], underscoring the liver’s role in amplifying DCM pathology during the pre-diabetic stage.

Collectively, these findings highlight the liver as a pivotal metabolic regulator in DCM, positioning it as a potential therapeutic target. Further investigation into liver-heart signaling pathways, particularly through multi-organ metabolomic and transcriptomic studies, is warranted to identify novel interventions that could mitigate DCM progression.

Vascular lesions in diabetic cardiomyopathy

Vascular lesions, alongside metabolic factors, play a critical role in the pathogenesis of DCM. Hyperglycemia, a hallmark of diabetes, directly impairs vascular endothelial cells through multiple mechanisms, resulting in vascular dysfunction and microvascular complications [95]. This section elucidates the key vascular pathological features of DCM, including microvascular dysfunction, endothelial dysfunction, vascular wall fibrosis, and vascular smooth muscle cell proliferation, and their interplay with hyperglycemia-driven mechanisms.

Microvascular lesions

Microvascular lesions in DCM are primarily characterized by coronary microvascular dysfunction (CMD), manifesting as endothelial dysfunction, increased vascular permeability, impaired vasodilation, and thickening of the vascular basement membrane. These alterations are intricately linked to hyperglycemia and driven by the following mechanisms:

Formation of Advanced Glycation End Products (AGEs): Hyperglycemia induces non-enzymatic glycation of proteins, lipids, and nucleic acids, forming AGEs. These accumulate in vascular endothelial cells and bind to their receptors (RAGE), activating pro-inflammatory signaling pathways, including NF-$\kappa$B and p38 MAPK. This cascade triggers inflammatory responses and oxidative stress, exacerbating endothelial dysfunction [96].

Activation of Protein Kinase C (PKC): Hyperglycemia activates PKC, which inhibits endothelial nitric oxide synthase (eNOS) activity, reducing nitric oxide (NO) production and impairing vasodilation. Additionally, PKC modulates signaling pathways such as PI3K/Akt and MAPK, further compromising endothelial function and promoting vasoconstriction [97].

Oxidative Stress: In a hyperglycemic environment, mitochondria generate excessive reactive oxygen species (ROS), inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. This activates multiple pathways associated with microvascular complications, including the PKC, polyol, hexosamine, and AGE pathways. Elevated ROS levels also upregulate NF-$\kappa$B, increasing the transcription of adhesion molecules and inflammatory cytokines, which aggravate vascular damage [95].

Reduced Vascular Endothelial Growth Factor (VEGF) Expression: Hyperglycemia suppresses VEGF expression, leading to reduced capillary density, myocardial ischemia, and hypoxia, which exacerbate myocardial injury [80].

Endothelial dysfunction

Endothelial dysfunction is a hallmark of DCM pathology, driven by hyperglycemia through several mechanisms:

Endothelial Cell Dysfunction: Hyperglycemia increases endothelial cell permeability, upregulates vasoconstrictors such as endothelin-1 (ET-1), and reduces the bioavailability of vasodilators like NO, disrupting vascular tone regulation [79].

Abnormal Platelet Function: Hyperglycemia enhances platelet aggregation and adhesion to the vascular wall, promoting thrombus formation and increasing the risk of vascular occlusion and cardiovascular events [95].

Abnormal Coagulation System: Hyperglycemia activates the coagulation cascade, heightening the risk of thrombus formation and further contributing to vascular damage [98].

Vascular wall fibrosis

Hyperglycemia promotes vascular wall fibrosis, a critical contributor to the progression of DCM, through enhanced collagen synthesis and cross-linking. The accumulation of advanced glycation end products (AGEs) and activation of their receptors (RAGE) are central to this process. AGEs stimulate the expression and deposition of collagen in the extracellular matrix, while RAGE activation triggers downstream signaling pathways, such as NF-$\kappa$B and TGF-$\beta$, which further promote fibroblast activation and collagen production. This leads to increased collagen cross-linking, resulting in vascular stiffness, reduced myocardial compliance, and impaired cardiac function [97]. Additionally, hyperglycemia-induced oxidative stress exacerbates fibrosis by upregulating pro-fibrotic cytokines, such as connective tissue growth factor (CTGF), which further amplifies extracellular matrix remodeling and vascular wall thickening [96]. These fibrotic changes compromise coronary blood flow and contribute to the mechanical dysfunction of the myocardium, underscoring the need for targeted anti-fibrotic therapies in DCM.

Proliferation of vascular smooth muscle cells

Hyperglycemia significantly contributes to the proliferation and migration of vascular smooth muscle cells (VSMCs), exacerbating vascular lesions in DCM. This process is mediated by the activation of key signaling pathways, including protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). These pathways promote VSMC proliferation by enhancing cell cycle progression and inhibiting apoptosis, leading to vascular remodeling and increased vascular stiffness [95]. Additionally, hyperglycemia-induced oxidative stress and the accumulation of advanced glycation end products (AGEs) further stimulate VSMC proliferation by upregulating growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-$\beta$). These factors drive extracellular matrix deposition and intimal thickening, contributing to vascular narrowing and reduced coronary blood flow [96]. The interplay between these mechanisms amplifies vascular pathology, underscoring the importance of targeting VSMC proliferation in therapeutic strategies for DCM.

In summary, vascular lesions in DCM, encompassing microvascular dysfunction, endothelial dysfunction, vascular wall fibrosis, and vascular smooth muscle cell proliferation, are intricately linked to hyperglycemia. These pathological changes collectively contribute to myocardial dysfunction and heart failure. Future research should focus on elucidating the causal relationships among these mechanisms and developing targeted interventions to mitigate or reverse diabetes-related cardiovascular complications [95].

Advances in pharmacological interventions for DCM

Cardiorenal protection mechanism and clinical evidence of SGLT2 inhibitors

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert hypoglycemic effects by inhibiting glucose reabsorption in the renal tubules. Their cardioprotective mechanisms involve multiple pathways: Metabolically: These agents elevate circulating ketone bodies ($\beta$-hydroxybutyrate increased by 50%), providing an alternative energy substrate for the failing myocardium. Concurrently, they reduce myocardial lipid deposition (myocardial triglycerides decreased by 30% in diabetic models) and enhance mitochondrial oxidative phosphorylation efficiency [99]. Hemodynamically: Osmotic diuresis reduces cardiac preload (left ventricular end-diastolic pressure decreased by 5 mmHg) and attenuates myocardial fibrosis (collagen volume fraction reduced by 15-20%) [100]. Clinical trials confirm their benefits on clinical endpoints in DCM patients: The EMPEROR-Preserved trial (enrolling 5,988 heart failure patients with preserved ejection fraction, 45% with diabetes) showed empagliflozin reduced cardiovascular death or heart failure hospitalization risk by 21% (Hazard Ratio, HR=0.79, 95% Confidence Interval, CI 0.69–0.90). The DM subgroup derived consistent benefits versus non-DM group, with significantly decreased left ventricular mass index (LVMI) in DCM patients (6.3 g/m² vs placebo, P < 0.01) [101]. In DAPA-HF trial, dapagliflozin reduced all-cause mortality by 17% (HR=0.83) and worsening heart failure risk by 30% [102].

Nucleic acid-based therapies: mechanisms and delivery breakthroughs in non-coding RNA targeting

The role of non-coding RNAs (ncRNAs) in DCM has gained increasing attention. Studies confirm elevated microRNA-1 (miR-1) and miR-206 expression in myocardial tissue of DM rat models, accelerating cardiomyocyte apoptosis through post-transcriptional regulation of Heat Shock Protein 60 (HSP60) expression [103]. SIRT1 expression is significantly reduced in DM mice and high glucose-treated H9C2 cells. Tang et al. found that miR-22 overexpression restores SIRT1 levels and alleviates oxidative stress injury in DCM [104].

Long non-coding RNA (lncRNA) Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is recognized as a potential diagnostic and therapeutic target for DM-related complications, supported by multiple studies. MALAT1 upregulation occurs in myocardium of DCM animal models and high glucose-induced cardiomyocytes, regulating DCM fibrosis via Hippo-Yes-Associated Protein (Hippo-YAP) signaling [105] while recruiting histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) to the miR-22 promoter to repress its expression [106]. Consequently, MALAT1 silencing effectively inhibits cardiomyocyte apoptosis and improves left ventricular function in DCM mice [107]. Additionally, lncRNA MALAT1 participates in DCM fibrosis through miR-141-mediated NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome and Transforming Growth Factor Beta 1 (TGF$\beta$1)/Smads signaling pathways; MALAT1 inhibition ameliorates myocardial fibrosis [108]. These findings indicate MALAT1 critically contributes to diabetic complications pathology and represents a potential therapeutic target.

High glucose induces lncRNA DCM-related factor (DCRF) overexpression and autophagy in rat cardiomyocytes. DCRF knockdown reduces autophagy, attenuates myocardial fibrosis, and improves cardiac function in diabetic rats by targeting miR-551b-5p [109]. Furthermore, high glucose-induced lncRNA Myocardial Infarction Associated Transcript (MIAT) upregulation causes interleukin-17 (IL-17) production in cardiomyocytes. IL-17, a pro-inflammatory cytokine and key inflammation regulator, contributes to cardiac pathology. MIAT knockdown attenuates IL-17 expression, ameliorating cardiac fibrosis and enhancing contractility [110]. LncRNA H19 is a key regulator in DCM; Wang et al. demonstrated H19 suppresses oxidative stress, endoplasmic reticulum stress (ERS), and apoptosis in vitro [111], whereas lncRNA HOX Transcript Antisense RNA (HOTAIR) prevents DCM by sponging miR-34a to activate SIRT1 expression [112].

Discussion

The metabolic remodeling of the myocardium in DCM represents a critical intersection of DM and cardiovascular pathology, with recent research illuminating its complexity and therapeutic potential. This review has underscored two hallmark features: perturbed lipid metabolism, characterized by excessive FA oxidation and lipotoxicity, and impaired glucose metabolism, driven by insulin resistance and diminished GLUT4 activity. These alterations shift the diabetic heart away from its inherent metabolic flexibility, favoring an inefficient, oxygen-intensive reliance on FAs that precipitates oxidative stress, mitochondrial dysfunction, and progressive cardiac impairment [21, 58, 67]. Such findings align with broader evidence that metabolic dysregulation is not merely a byproduct of DCM but a primary driver of its pathogenesis, distinguishing it from other cardiomyopathies tied to vascular etiologies [6, 18].

A key insight from recent studies is the interplay between lipid and glucose metabolism in DCM, which challenges traditional views of substrate competition. The upregulation of FA transporters like CD36, coupled with PPAR$\alpha$-mediated enhancement of $\beta$-oxidation, not only increases lipid influx but also suppresses glucose oxidation through enzymatic inhibition (e.g., PDH via PDK activation) [18, 70]. This reciprocal inhibition—termed the Randle cycle in metabolic literature—creates a vicious cycle in DCM, where lipid overload exacerbates insulin resistance, further limiting glucose utilization [84]. Comparative analyses with non-diabetic heart failure models reveal that this metabolic inflexibility is diabetes-specific, as healthy hearts adaptively switch substrates under stress, whereas DCM hearts remain locked in a lipotoxic state [47, 48]. Intriguingly, emerging data suggests epigenetic regulation, such as miR-320’s amplification of CD36 expression, may perpetuate this cycle, pointing to novel molecular layers beyond traditional metabolic pathways [66].

The therapeutic implications of these metabolic shifts are profound yet fraught with challenges. Targeting CD36 to curb FA uptake has shown preclinical promise in reducing lipotoxicity and improving cardiac function [113], yet its clinical translation remains untested. Similarly, PPAR modulators—agonists of PPAR$\alpha$ or PPAR$\beta$/$\delta$—offer a dual approach to restore metabolic balance and mitigate inflammation, but their efficacy is inconsistent across patient cohorts, with some studies reporting increased cardiovascular risk or hepatotoxicity [72, 74]. This heterogeneity likely stems from interindividual differences in metabolic profiles, a factor underexplored in current trials. Sirtuins (SIRT1, SIRT3, SIRT6) and ubiquitin-specific protease 7 (USP7) emerge as intriguing targets, with SIRT3’s role in enhancing glucose metabolism and USP7’s modulation of lipid homeostasis offering potential synergy [77, 85]. However, the leap from animal models to human application is hindered by species-specific metabolic differences and the lack of DCM-specific biomarkers, complicating early diagnosis and intervention [23, 28].

These findings also raise critical questions about DCM’s clinical management. Current diabetes therapies prioritize glycemic control, yet their impact on myocardial metabolism is limited, as evidenced by the persistent heart failure risk in T2DM patients despite optimized HbA1c levels [11, 16]. This disconnect suggests that metabolic remodeling in DCM requires targeted strategies beyond glucose-lowering agents, a notion supported by the modest cardiac benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve heart failure outcomes but do not fully address lipotoxicity [5]. The controversy over PPAR agonists exemplifies this challenge: while they modulate metabolism, their side-effect profile necessitates cautious use, underscoring the need for safer, more precise restore of lipid and glucose metabolic balance. Multi-target approaches—combining CD36 inhibition with sirtuin activation, for instance—could address this complexity, yet such strategies remain conceptual, awaiting rigorous clinical validation.

Looking forward, the field must grapple with several unresolved issues to enhance DCM’s prevention and treatment. First, the heterogeneity of metabolic responses among patients suggests a need for personalized medicine, leveraging metabolomics to tailor therapies to individual lipid and glucose profiles. For instance, lactate accumulation in cardiac tissue, observed in some DCM patients, may serve as a biomarker for metabolic stratification. Second, the absence of specific diagnostic markers hampers early detection, a gap that extracellular matrix biomarkers or advanced imaging (e.g., cardiac MRI) might bridge [24, 25]. Notably, our lab’s recent study in diabetic aging nonhuman primates revealed that cardiac ECM components are predominantly derived from the liver, a central metabolic organ, suggesting a critical liver-heart crosstalk during metabolic dysregulation in DCM. Investigating metabolite alterations across the liver, blood, and heart could yield novel biomarkers for early diagnosis, warranting targeted metabolomic studies (PMID: 40464660). Third, the role of inflammation and fibrosis as downstream effectors of metabolic dysfunction warrants further exploration, as their interplay with lipid and glucose pathways could unveil additional therapeutic targets [34, 36]. Ultimately, integrating these insights into a cohesive framework will require interdisciplinary efforts, merging molecular biology, clinical cardiology, and bioinformatics to translate metabolic discoveries into tangible patient benefits. By addressing these challenges, future research can elevate DCM management from symptom palliation to mechanistic reversal, offering hope for reducing its substantial cardiovascular burden.

Conclusion

DCM stands as a distinct complication of diabetes mellitus, propelled by metabolic remodeling of the myocardium. This review has clarified how insulin resistance and hyperglycemia impair the heart’s metabolic flexibility, shifting energy production from glucose to an inefficient, lipotoxic reliance on fatty acid oxidation. Regulatory proteins, including sirtuins and USP7, modulate this landscape, providing molecular insights into DCM’s pathogenesis.

These findings redefine DCM as a metabolic disorder with actionable therapeutic poten-tial. Preclinical strategies targeting metabolic balance—such as CD36 inhibition, PPAR mod-ulation, or sirtuin activation—show promise, though clinical translation requires addressing patient variability and safety. With diabetes projected to affect 783 million adults by 2045, counteracting these metabolic shifts is critical to reducing DCM-related heart failure. Future progress depends on personalized, multi-target therapies and enhanced diagnostics to miti-gate this condition effectively.

Abbreviations

DM

Diabetes mellitus

DCM

Diabetic cardiomyopathy

T2DM

Type 2 diabetes mellitus

CVD

Cardiovascular Diseases

ROS

Reactive Oxygen Species

TCA

Tricarboxylic Acid

PDH

Pyruvate Dehydrogenase

LPL

Lipoprotein Lipase

FATP

Fatty Acid Transport Protein

FFA

Free Fatty Acids

GLUT4

Glucose Transporter 4

FOXO1

Forkhead Box O1

PPARs

Peroxisome Proliferator-activated Receptors

USP7

Ubiquitin-specific Protease 7

PGC1$\beta$

Proliferator-activated Receptor Gamma Coactivator 1$\beta$

PFK1

Phosphofructokinase-1

PDK

Pyruvate Dehydrogenase Kinase

SIRT3

Sirtuin 3

ECM

Extracellular Matrix

FGF21

Fibroblast Growth Factor 21

NAFLD

Non-alcoholic Fatty Liver Disease

SGLT2

Sodium-glucose Cotransporter-2

SGLT2i

Sodium-glucose cotransporter 2 inhibitors

Authors’ contributions

Conceptualization, Xue Guan; writing—original draft preparation, Xue Guan, Can zhou and Xinyi Zhuo; writing—review and editing, Haizhen Wang and Wenhui Yang; visualization, Xue Guan; supervision, Haizhen Wang and Wenhui Yang; project administration, Haizhen Wang and Wenhui Yang. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (grant number 82260080), Yunnan Province Science and Technology Department (grant number 202401AY070001-046), Yunnan Fundamental Research Projects (grant number 20221AS070081), National Natural Science Foundation of China (grant number 32060206), and Veterinary Public Health Innovation Team of Yunnan Province (grant number 202105AE160014).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.