Myocardial ischemia reperfusion in diabetes: mechanism of injury and its drug treatment

Abstract

Diabetes with myocardial ischemia-reperfusion injury(MIRI) represents a common complication of diabetes mellitus (DM), and cardiovascular disease remains the leading cause of death in DM patients. Consequently, preventing cardiovascular disease in individuals with diabetes continues to pose a significant challenge. Hyperglycemia-induced elevation of reactive oxygen species (ROS), activation of ferroptosis, and impairment of cardioprotective pathways collectively increase diabetic patients’ susceptibility to myocardial ischemia. MIRI, characterized by oxygen deprivation followed by restoration of blood flow, causes irreversible tissue damage. The pathophysiological mechanisms underlying MIRI in diabetes involve ferroptosis, oxidative stress, inflammation, intracellular calcium overload, and endoplasmic reticulum stress. These mechanisms interact synergistically to directly or indirectly aggravate myocardial damage. This review aims to achieve two objectives: first, to summarize the underlying pathogenic mechanisms of MIRI in DM; second, to outline the pharmacological effects and molecular targets of therapeutic agents for diabetic MIRI.

Introduction

Diabetes mellitus (DM) is a metabolic disorder caused by hyperglycemia and insufficient endogenous insulin secretion or impaired insulin utilization [1]. In 2021, 521 million people had diabetes, a figure projected to exceed 1.3 billion by 2050 [2]. Recently, epidemiological studies confirm that cardiovascular diseases are the most prevalent complications of diabetes and the leading cause of death in diabetic patients [3]. The incidence of cardiovascular disease among diabetic patients is approximately four times higher than in non-diabetic individuals [4]. Among various cardiovascular diseases, MIRI stands out as a significant concern. Temporary cessation of arterial blood supply followed by reperfusion leads to tissue damage [5]. Clinical evidence indicates that diabetic patients experience poorer outcomes after MIRI compared to non-diabetic patients [6].

In diabetic patients, hyperglycemia, insulin resistance, and excess fatty acids increase oxidative stress, disrupt protein kinase C signaling, and elevate advanced glycation end products, leading to vascular inflammation, vasoconstriction, and thrombosis that exacerbate exacerbating myocardial injury during ischemia and reperfusion [7, 8]. Furthermore, elevated glucose levels increase myocardial infarction size during MIRI and enhance Reactive oxygen species (ROS) production both in vivo and in vitro [9, 10]. Insulin resistance also exacerbates inflammation and endothelial dysfunction, further impairing cardiac function and increasing MIRI susceptibility [11]. Insulin resistance exacerbates inflammation and endothelial dysfunction, intensifies myocardial dysfunction, and heightens susceptibility to MIRI [12]. Clinical studies indicate that DM increases susceptibility to MIRI [13], and intensified DM management can reduce the risk of major macrovascular and microvascular events by ≥ 10%. Therefore, in-depth exploration of the susceptibility to MIRI in diabetic myocardium and its underlying pathomechanisms may provide crucial guidance for the early prevention and treatment of MIRI in diabetic cardiomyopathy.

Mechanism of action

Extensive clinical research indicates that diabetic hearts exhibit heightened sensitivity to ischemia-reperfusion injury (IRI), and the cardioprotective effects of ischemic preconditioning and pharmacological preconditioning are diminished in diabetic conditions. Consequently, diabetic patients face a higher probability of acute events, and the potential for reducing infarct size through cardioprotective interventions may be limited [14]. Mechanisms underlying the increased susceptibility to MIRI in diabetes include Ferroptosis, oxidative stress, inflammation, intracellular calcium overload, endoplasmic reticulum stress [15–17]. These mechanisms not only play distinct yet critical roles individually but also exhibit interrelated interactions.

Ferroptosis

Ferroptosis is a form of programmed cell death that depends on the accumulation of iron and lipid peroxides [18]. It is implicated in various diseases, such as malignant tumors, neurodegenerative diseases, and MIRI [19, 20]. Several studies have now confirmed the presence of ferritinopathy in cardiomyocytes within diabetic animal models [21]. Research indicates cardiac tissue is prone to accumulating free iron [22], and iron overload represents a significant contributor to cardiomyocyte injury [23]. As a ferritin storage protein, ferritin promotes iron-mediated Fenton reactions by reducing excess intracellular free iron concentrations and lipid ROS, leading to oxidative damage and cardiac dysfunction associated with IRI [25]. Li et al. discovered iron deposition and excessive ROS generation during diabetic myocardial injury, with ferroptosis participating in diabetic with MIRI via the endoplasmic reticulum stress pathway [26]. Inhibiting glutamine degradation is a key step in ferroptosis, which mitigates MIRI [24]. These studies indicate that ferroptosis plays a critical role in MIRI [27].

High glucose (HG) conditions can increase ROS production, subsequently elevating the generation of lipid peroxidation products such as Malondialdehyde. This, coupled with increased Fe²⁺ levels and reduced glutathione (GSH) and GPX4 levels, collectively contributes to the induction of ferroptosis [28]. Studies have revealed that HG intake also leads to heightened ROS production, exacerbating oxidative stress, increasing Glutathione Disulfide (GSSG) generation, and decreasing GSH content [29]. This may result in mitochondrial abnormalities, such as reduced mitochondrial volume and increased membrane structural density. GPX4, a key regulator of ferroptosis, exhibits significantly reduced protein levels under HG conditions. The decrease in GPX4 leads to enhanced lipid ROS formation, increased lipid peroxidation, and ultimately cellular ferroptosis [28]. Ferritin-inhibitor-1 (FII-1), a potent selective inhibitor of ferritinase, prevents membrane lipid damage through redox mechanisms, thereby inhibiting cell death [30]. In vivo and in vitro results indicate that FII-1 reduces Acyl-CoA Synthetase Long Chain Family Member 4（ACSL4）and Nuclear Receptor Coactivator 4（NCOA4）expression and mitigates myocardial injury severity.

Fig. 1.

Mechanisms of Ferroptosis: Iron ions promote lipid ROS production via cellular iron transport pathways, while GSH-dependent GPX4 clears lipid peroxides. When this balance is disrupted, accumulated lipid ROS trigger ferroptosis

Oxidative stress

Generation of ROS in diabetic myocardium

Elevated levels of oxidative stress in diabetic patients primarily result from an imbalance between the production of ROS and their clearance by the endogenous antioxidant defense system [31]. In diabetic conditions, hyperglycemia, metabolic disorders, increased oxidative stress, and mitochondrial dysfunction may elevate ROS production and accumulation, leading to DeoxyriboNucleic Acid (DNA) and protein damage and impairing cardiomyocyte function. Studies reveal that adding ferroptosis inhibitors reduces cell death in hyperglycemic environments, suggesting the potential therapeutic significance of targeting this pathway. Overall, the ferroptosis process and its associated proteins are closely linked to disorders of glucose and lipid metabolism. However, research on the relative role of ferroptosis in diabetic MIRI remains scarce and inconclusive [32–34]. Hyperglycemia, as the core metabolic abnormality in diabetes, promotes ROS production through multiple pathways. First, advanced glycation end products (AGEs) induced by hyperglycemia bind to their receptor, receptor for advanced glycosylation end products (RAGE), activating downstream signaling pathways, such as nuclear factor kappa-B(NF-κB) and Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase, which leads to sustained ROS release [35, 36]. Second, under insulin resistance, the efficiency of the mitochondrial electron transport chain decreases, further exacerbating ROS production. Additionally, impaired function of antioxidant enzyme systems in diabetic myocardium—such as reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity—weakens intracellular ROS scavenging capacity, creating a vicious cycle [37, 38]. Studies indicate that in diabetic mouse models, myocardial ROS levels are significantly elevated and positively correlated with myocardial cell apoptosis and fibrosis severity [39]. These findings suggest that hyperglycemia and insulin resistance not only constitute the primary pathological basis of diabetes but also serve as significant drivers of excessive intracellular ROS accumulation in cardiomyocytes.

Oxidative stress exacerbates MIRI

During ischemia-reperfusion, myocardial cells rapidly generate large amounts of ROS. Excessive ROS attacks mitochondria, opening the mitochondrial permeability transition pore (mPTP). At this point, the mPTP permits the free passage of molecules smaller than 1.5 kDa, thereby increasing mitochondrial colloid osmotic pressure. This causes severe mitochondrial swelling, further impairing mitochondrial function. Damaged mitochondria are the primary source of ROS [40]. ROS can also be generated in the vascular wall via NADPH oxidase, xanthine oxidase, the mitochondrial electron transport chain, and uncoupled endothelial nitric oxide synthase (eNOS) [37]. In diabetic hearts, impaired mitochondrial respiratory capacity disrupts mitochondrial quality control, leading to increased accumulation of ROS [41, 42]. NADPH oxidase serves as the primary ROS donor in MIRI. Elevated ROS levels from fatty acid oxidation or NADPH oxidase in diabetes trigger myocardial cell death, inflammation, and fibrosis, thereby impairing cardiac structure and function [43]. Increased NADPH oxidase activity has also been observed in myocardial and vascular tissues of type 2 diabetic animal models [44]. In diabetic patients, both NADPH oxidase system activity and NADPH oxidase protein subunit levels are significantly elevated [33, 43]. Furthermore, ischemia, hypoxia, and nutrient deprivation lead to hypoxanthine accumulation, xanthine oxidase activation, and the induction of proinflammatory cytokines. During the reperfusion phase, significant increases in hypoxanthine/xanthine oxidase, mitochondrial, and nitric oxide synthase production are observed in endothelial cells, infiltrating neutrophils, and local tissue cells [45]. Finally, eNOS is an enzyme that produces nitric oxide (NO) in vascular endothelial cells. It plays a crucial role in maintaining cardiovascular health and is believed to prevent MIRI [46]. Research indicates that under diabetic pathophysiological conditions, eNOS undergoes decoupling, becoming a major source of increased ROS production in diabetes. Enhanced oxidative stress further exacerbates eNOS decoupling and endothelial dysfunction, leading to cardiovascular injury [47]. Under diabetic and ischemic conditions, excessive NO production, driven by the heightened activation of inducible eNOS, causes severe cardiomyocyte damage [48].

Inflammatory response

Diabetes enhances inflammatory response

Under diabetic conditions, inflammatory responses are significantly amplified during myocardial ischemia-reperfusion. Impaired insulin metabolic signaling and hyperglycemia can activate the NLR-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. The NLRP3 inflammasome stimulates myocardial dysfunction by activating IL-1β. Activated cathepsin-1 cleaves IL-1β and IL-18 precursors and promotes multiple proinflammatory pathways involving nuclear factor κB (NF-κB), chemokines, and ROS [49]. NF-κB enhances NLRP3 inflammasome assembly and activates cathepsin-1 [50]. Furthermore, hyperglycemia and hyperinsulinemia exacerbate inflammation by inducing endothelial dysfunction, promoting the release of damage-associated molecular patterns (DAMPs), and activating the Toll-like receptor 4 (TLR4) signaling pathway [51]. Moreover, elevated C-reactive protein (CRP) levels not only directly promote cytokine release but also exacerbate leukocyte adhesion and infiltration by inducing NF-κB and adhesion molecule expression, further impairing cardiomyocyte function [51]. Specific DAMP signaling in high-glucose environments promotes the formation of AGEs. These products significantly enhance NF-κB activity by binding to RAGE, Cluster of Differentiation 36 (CD36), and TLR4 receptors, thereby exacerbating inflammatory injury during myocardial ischemia-reperfusion in diabetes [52]. Long non-coding ribonucleic acid (lncRNAs) such as Myocardial Infarction Associated Transcript 1 (MIRT1) and Nuclear paraspeckle assembly transcript 1 (NEAT1) also participate in this process. The former mitigates inflammatory injury by inhibiting the NF-κB signaling pathway. At the same time, the latter exacerbates inflammation by targeting microRNA-27b (miR-27b)to regulate Recombinant Phosphatase and Tensin Homolog (PTEN)Induced Putative Kinase 1 (PINK1), indicating that RibonucleicAcid (RNA) molecules play crucial regulatory roles in diabetic MIRI [53].

Inflammatory response and myocardial Ischemia-Reperfusion injury

During myocardial ischemia, hypoxic cardiomyocytes release DAMPs, including high-mobility group box 1 (HMGB1) and heat shock proteins (HSPs). These molecules induce inflammation by activating the TLR4 signaling pathway [54]. When blood flow is restored, the reperfusion process introduces a large influx of immune cells, including neutrophils and macrophages, further amplifying the inflammatory response. These immune cells directly damage cardiomyocytes by releasing inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), and Interleukin-6 (IL-6) [55]. Furthermore, inflammatory cytokines activate the NF-κB signaling pathway, upregulating the expression of adhesion molecules like Intercellular Cell Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). This promotes the adhesion of immune cells to endothelial cells, thereby exacerbating myocardial injury [51]. Studies indicate that in diabetic mouse models, myocardial tissue exhibits significantly higher levels of inflammatory cytokine expression than in non-diabetic mice, and the severity of inflammation is positively correlated with myocardial infarction size [55]. Activation of the NLR-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a pivotal role in diabetes-associated IRI These findings indicate that the NLRP3 inflammasome exacerbates inflammation by regulating caspase-1 activation, thereby promoting the maturation and release of IL-1β and Interleukin-18 (IL-18). Inflammation plays a critical role in MIRI, and diabetes further intensifies this process.

Intracellular calcium overload

Changes in Na⁺-H⁺ exchangers in diabetic myocardium

In a stable internal environment, calcium influx and efflux maintain a dynamic equilibrium regulated by protein channels. The Na⁺-H⁺ exchanger (NHE) is a crucial ion channel that regulates intracellular pH and electrolyte balance in cardiomyocytes. Studies indicate that, under diabetic conditions, inhibition of NHE elevates intracellular pH in cardiomyocytes, thereby reducing the activity of the Na⁺-Ca2⁺ exchanger [56]. While this change partially alleviates calcium overload, it may also adversely affect myocardial contractile function. Furthermore, NHE inhibition disrupts intracellular electrolyte balance, particularly the distribution of Na⁺ and Ca²⁺, thereby altering the electrophysiological properties of cardiomyocytes [56]. Maintaining intracellular calcium homeostasis is critical for the normal function and growth of cardiomyocytes. Calcium overload in cardiomyocytes exacerbates ischemic injury, which occurs when the heart’s blood supply is compromised [57, 58].

Intracellular calcium overload in MIRI

Following prolonged hypoxia in cardiomyocytes, enhanced anaerobic metabolism may lead to H⁺ accumulation, resulting in the buildup of lactate, protons, and Nicotinamide Adenine Dinucleotide (NAD⁺) alongside decreased pH. This shift activates the NHE, elevating intracellular Na⁺ levels [59, 60]. Reduced contractility in diabetic cardiomyopathy correlates with alterations in intracellular calcium homeostasis at the cardiomyocyte level [61]. Strict regulation of intracellular calcium homeostasis is critical for maintaining normal cardiomyocyte function and growth; disruption of this homeostasis leads to endoplasmic reticulum stress (ERS), exacerbating ischemic damage to cardiomyocytes. During myocardial ischemia, reduced adenosine triphosphate (ATP) production induces intracellular acidosis and activates Na⁺/H⁺ exchange, resulting in massive sodium influx. This sodium influx, combined with elevated calcium concentrations, leads to calcium overload during reperfusion [62].

Furthermore, when intracellular Ca²⁺ concentrations in mitochondria become excessively high, calcium ions bind to and activate the calcium-binding domain of the mPTP, directly triggering mPTP opening and subsequent cell death [63]. This exacerbates post-hypoxic or ischemic myocardial cell injury [64]. During myocardial ischemia-reperfusion, disrupted calcium homeostasis and intracellular calcium overload are common pathways for irreversible cellular injury. Consequently, alterations in NHE function represent not only a compensatory mechanism for metabolic dysregulation in diabetic myocardium but also a potential therapeutic target for preventing IRI.

Endoplasmic reticulum stress (ERS)

Endoplasmic reticulum stress plays a crucial role in apoptosis in animal models of DM and myocardial ischemia. Under conditions of high glucose, ischemia, hypoxia, and Ca²⁺ homeostasis disruption, the internal equilibrium of the Endoplasmic Reticulum (ER) is compromised, leading to the accumulation of unfolded or misfolded proteins within the cell. This triggers ERS [65, 66] and induces cardiomyocyte apoptosis. Previous studies have confirmed that the unfolded protein response (UPR) participates in the pathogenesis and progression of DM [67]. Miki et al. demonstrated that DM-induced intensified endoplasmic reticulum stress promotes the opening of the mPTP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2–GSK-3β signaling pathway, leading to mitochondrial calcium overload [68]. Conversely, intervention to suppress endoplasmic reticulum stress significantly reduced the infarct size in a high-fat diet -induced type 2 diabetes mellitus model [69]. Activation of the endoplasmic reticulum stress response further amplifies downstream signaling pathways involved in apoptosis, thereby exacerbating myocardial tissue damage during ischemia and reperfusion [70]. Myocardial cells harbor numerous signaling molecules associated with endoplasmic reticulum stress, including activated transcription factor 6 (ATF6), CCAAT-element-binding protein homolog, and 78 kDa glucose-regulated protein (GRP78). Therapeutic approaches targeting endoplasmic reticulum stress signaling effectively reduce cell death rates in conditions such as myocardial ischemia-reperfusion injury [71, 72]. One study demonstrated that a newly identified adiponectin homologue—C1q/tumor necrosis factor-related protein 9—exerts protective effects against IRI in diabetic hearts by alleviating endoplasmic reticulum stress and inflammatory responses [73, 74] (Fig. 2).

Fig. 2.

Mechanisms of Endoplasmic Reticulum Stress: ER stress regulates the transcription of genes related to cell survival, apoptosis, inflammation, etc. through pathways such as ATF6, eIF2-α, and IRE1-α, thereby influencing cell

Pharmacological therapy

Traditional hypoglycemic agents such as insulin and sulfonylureas effectively control blood glucose levels but exhibit limitations in cardiovascular protection and may even increase the risk of cardiovascular events like heart failure. Recent large-scale cardiovascular clinical trials evaluating the safety and efficacy of hypoglycemic therapies have demonstrated that treatment modalities such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), not only deliver significant blood glucose-lowering effects but also demonstrate protective effects on the cardiovascular system.

Dipeptidyl Peptidase-4 (DPP-4) inhibitors

Dipeptidyl peptidase-4 (DPP-4), a membrane-bound X-prolyl dipeptidase, participates in the degradation of various cytokines such as stromal cell-derived factor 1 (SDF-1), macrophage-derived chemokine, and incretin hormones including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [75, 76]. Furthermore, DPP-4 inhibitors reduce myocardial infarction size by decreasing oxidative stress and apoptosis while increasing the activity of the rescue kinase in reperfusion injury (RISK), stabilizing cardiac electrophysiology during myocardial ischemia, mitigating ischemia/reperfusion injury, and preventing left ventricular remodeling after myocardial infarction [77, 78]. Thus, DPP-4 inhibitors exert bidirectional effects on the cardiovascular system, demonstrating both beneficial [80] and detrimental [81] actions beyond their antihyperglycemic role [79]. DPP-4 inhibitors are highly expressed in the cardiovascular system and endothelial cells [82]. Inhibiting their activity yields beneficial cardiovascular effects through mechanisms including upregulation of GLP-1 levels, suppression of substrates involved in cardiovascular homeostasis, and modulation of glucose metabolism [83].

According to research by Chinda et al. [84], acute administration of the DPP-4 inhibitor vildagliptin reduced myocardial infarction size by up to 44%. Another experiment demonstrated that pretreatment with sitagliptin reduces infarct size by activating the transient receptor potential/Calcitonin Gene-Related Peptide (TRP/CGRP) signaling pathway through GLP-1 upregulation prior to DPP-4 inhibition, thereby increasing NOS activity and eNOS expression to mitigate myocardial injury in an in vitro I/R model [85]. In Apaijai’s study, sitagliptin was also found to modulate oxidative stress and autophagy, thereby mitigating H/R-induced damage in cardiomyocytes [86]. Another investigation demonstrated that both vildagliptin and sitagliptin provide cardioprotection by preventing cardiac mitochondrial dysfunction through reducing ROS production, restoring mitochondrial membrane potential, and preventing mitochondrial swelling [87]. Furthermore, the pharmacological action of linagliptin significantly elevates physiological concentrations of GLP-1 and GIP in vivo, thereby enhancing pancreatic β-cell sensitivity to glucose and stimulating insulin secretion. This drug also inhibits glucagon secretion from pancreatic α-cells, thereby improving glucose metabolism through dual regulatory mechanisms. By reducing protein kinase B (AKT) and ‌mammalian target of rapamycin (mTOR) expression, liraglutide increases activated protein kinase (AMPK) expression in cardiomyocytes, thereby exerting a protective effect on the myocardium of rats with diabetes complicated by myocardial ischemia-reperfusion injury [88]. Compared to other hypoglycemic agents, these DPP-4 inhibitors exhibit glucose-dependent effects. They effectively control hyperglycemia while reducing hypoglycemia risk, significantly impact myocardial ischemia-reperfusion injury, and exert minimal effects on body weight, demonstrating favorable safety profiles [89, 90].

Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i)

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) significantly reduce blood glucose concentrations by specifically inhibiting sodium-glucose cotransporter-2 (SGLT2), which plays a key role in glucose reabsorption in the proximal tubules of the kidneys. SGLT2 is a high-affinity transporter responsible for approximately 90% of renal glucose reabsorption [91]. By reducing SGLT2’s affinity for glucose, SGLT2i decrease glucose reabsorption, increase urinary glucose excretion, and ultimately lower blood glucose levels. Beyond glycemic control, they offer additional benefits in the treatment of cardiovascular diseases [92]. Substantial experimental evidence indicates that SGLT2i possess vasoprotective effects, potentially independent of their hypoglycemic properties. SGLT2i can suppress inflammatory responses, mitigate oxidative stress, enhance autophagy flux, and improve mitochondrial function, thereby contributing to their cardiorenal/vascular benefits [93]. For example, dapagliflozin mitigates MIRI by inhibiting NLRP3 inflammasome assembly and activation, thereby reducing Cardiac Troponin I (cTnI), Creatine Kinase-MB (CK-MB), and Lactate Dehydrogenase (LDH) levels [94]. Chen’s study demonstrated that Dapagliflozin also alleviates MIRI by reducing hemochromatosis through the Mitogen-activated protein kinas (MAPK) signaling pathway [95]. Clinical trials revealed that empagliflozin reduces cardiovascular mortality in diabetic patients with cardiovascular disease [96]. Empagliflozin administration activates Adenosine Monophosphate (AMP-AMPK) and exhibits additional non-target effects on glucose transport [97]. Empagliflozin not only protects cardiomyocytes but also safeguards endothelial cells [98]. Experimental results indicate that this drug stimulates AMPKα1 activation, subsequently promoting UNC-51-like kinase 1 (ULK1) phosphorylation modification, and ultimately enhancing FUN14 domain-containing protein 1 (FUNDC1)-mediated mitochondrial autophagy [99]. This molecular cascade effectively restores mitochondrial dynamic equilibrium, suppresses excessive ROS production, and blocks activation of the mitochondrial-dependent apoptosis pathway. Consequently, it enhances microvascular endothelial function and maintains structural integrity. Findings reveal empagliflozin’s association with the AMPKα1/ULK1/FUNDC1 signaling pathway and confirm this pathway’s critical role in microvascular protection [100]. Furthermore, empagliflozin prevents endothelial aging and dysfunction by inhibiting NADPH oxidase activation and thereby mitigating oxidative stress [93]. This provides a potential target for developing novel intervention strategies targeting diabetes-associated MIRI.

3.3 GLP-1Receptor agonists

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that exerts glucose-dependent regulatory effects by binding to GLP-1 receptors on pancreatic β-cells. GLP-1 possesses insulinotropic and anti-apoptotic properties [101]. Specifically, GLP-1 binding to its receptor activates adenylate cyclase, elevating intracellular cyclic Adenosine Monophosphate (cAMP) levels and increasing phosphoinositide 3-kinase (PI3K) activity. This promotes insulin gene transcription and insulin secretion [102]. GLP-1 also suppresses glucagon secretion, particularly under hyperglycemic conditions where this inhibition is more pronounced, thereby reducing hepatic glycogenolysis and gluconeogenesis to further lower blood glucose levels [103]. Moreover, GLP-1 receptor agonists demonstrate significant therapeutic efficacy not only in glucose regulation but also exhibit multifaceted cardiovascular protective effects. First, GLP-1 receptor agonists protect the cardiovascular system by improving endothelial function. Studies indicate that these agonists suppress the expression of plasminogen activator inhibitor-1 (PAI-1) and vascular adhesion molecule (VAM) in human vascular endothelial cells (HVECs), thereby mitigating endothelial dysfunction in the early stages of diabetic vascular disease [104]. Additionally, GLP-1 increases nitric oxide synthase (NOS) activity, promoting NO production and thereby improving endothelium-dependent vasodilation [105]. Second, GLP-1 receptor agonists play a crucial role in regulating apoptosis and counteracting oxidative stress. During myocardial ischemia-reperfusion injury, the restoration of blood flow may exacerbate myocardial cell apoptosis and oxidative stress, thereby worsening myocardial damage. GLP-1 limits cardiomyocyte apoptosis through cAMP and PI3K pathways [106], suppresses the expression of apoptosis-related proteins, and simultaneously enhances the activity of antioxidant enzymes, thereby mitigating oxidative stress damage to cardiomyocytes [105]. These cardiovascular protective effects provide a theoretical basis for the application of GLP-1 receptor agonists in the treatment of myocardial ischemia-reperfusion in diabetic patients.

Liraglutide is a GLP-1 analog [107]. It stimulates glucose-dependent insulin secretion and lowers blood glucose in a dose-dependent manner [108]. Clinical and experimental studies suggest that GLP-1 analogs may exert cardiovascular protective effects [109], such as improving cardiac function in patients with coronary heart disease and alleviating atherosclerotic lesions [110]. Experimental results demonstrate that liraglutide ameliorates MIRI in diabetic mice and H9C2 cells exposed to hyperglycemic H/R injury. Hyperglycemia and H/R injury reduce AMPK phosphorylation, promote mTOR phosphorylation, thereby decreasing the LC3 II/I ratio, increasing p62 levels, and inhibiting autophagy. Liraglutide promotes AMPK phosphorylation, inhibits mTOR phosphorylation, increases the Microtubule-Associated Protein Light Chain 3-II/I (LC3 II/I) ratio, reduces p62 levels, enhances autophagy, and diminishes myocardial injury [111]. These combined effects significantly activate the AMPK/mTOR signaling pathway to promote autophagy, thereby improving myocardial IRI in diabetic mice, highlighting liraglutide’s potential in managing myocardial ischemia-reperfusion in diabetes. Semaglutide, a novel long-acting GLP-1 receptor agonist, has been shown to promote GLP-1R expression and activate the PKG/PKCε/ERK1/2 signaling pathway in H/R-treated H9C2 cells, thereby reducing myocardial infarction (MI) and apoptosis in myocardial I/R rats [112]. Overall, semaglutide offers a novel therapeutic option for diabetes-associated myocardial ischemia-reperfusion injury due to its potent hypoglycemic effects, significant cardiovascular protective benefits, and convenient administration (Table 1).

Table 1.

Demonstrates the mechanism of therapy for diabetes MIRI of the action of different medicines in specific animal models

Medicine	Model	Mechanism	References
Vildagliptin	All Male C57/BL6 mice	Reduce ROS production	[85]
Sitagliptin	Male Wistar rats	TRP/CGRP signaling pathway, increasing NOS activity and e-NOS expression	[87]
Linagliptin	Male SD rats	Reduce AKT, mTOR	[88]
Empagliflozin	AMPKα1f/f mutant mice	Activation of AMPKα1/ULK1/FUNDC1/mitochondria	[99]
Dapagliflozin	All Male C57/BL6 mice	MAPK signaling pathway reduces ferritinemia	[94]
	MIRI rat model	Decreases cTnI, CK-MB, and LDH levels, alleviating MIRI	[95]
Liraglutide	All Male C57/BL6 mice	Activation of AMPK/mTOR signaling improves myocardial IRI	[111]
Semaglutide	Male SD rats	Activation of the PKG/PKCε/ERK1/2 pathway inhibits cardiomyocyte apoptosis.	[112]

Conclusion and outlook

Diabetes aggravates MIRI because of the combination effects of changes in glucose and lipid energy metabolism, oxidative stress, and systemic inflammatory response. This review summarizes potential mechanisms for reducing myocardial ischemia-reperfusion injury in diabetes. Among known mechanisms, explanations for Ca²⁺ overload, ferroptosis, inflammation, oxidative stress, and endoplasmic reticulum stress are relatively comprehensive. Despite these advances, the roles of thermal spikes, necrosis, and ferroptosis, as well as downstream molecules of known signaling pathways, require further investigation. Multi-target, multi-pathway interventions using DPP-4, SGLT2, and GLP-1 drugs demonstrate significant potential in slowing the progression of diabetic myocardial ischemia-reperfusion injury. To fully realize the potential of these interventions, further experimental and clinical studies are required. Diabetes-associated myocardial ischemia-reperfusion injury represents a complex process involving multi-level, multifactorial interactions across genetic, molecular, cellular, and tissue levels. A thorough understanding of the pathophysiological mechanisms underlying this progression could identify novel therapeutic targets to improve MIRI outcomes and reduce cardiovascular disease-related mortality.

Abbreviations

DM

Diabetes mellitus

MIRI

Myocardial ischemia-reperfusion injury

ROS

Reactive oxygen species

IRI

Ischemia-reperfusion injury

HG

High glucose

GSH

Glutathione

GPX4

Glutathione Peroxidase 4

GSSG

Glutathione Disulfide

AGEs

Advanced glycation end products

NF-κB

Nuclear factor kappa-B

NADPH

Nicotinamide Adenine Dinucleotide Phosphate

mPTP

Mitochondrial permeability transition pore

eNOS

Endothelial nitric oxide synthase

NO

Nitric oxide

NLRP3

NLR-like receptor family pyrin domain containing 3

NHE

Na+-H + exchanger

ERS

Endoplasmic reticulum stress

ATP

Adenosine triphosphate

DPP-4

Dipeptidyl Peptidase-4

GLP-1

Glucagon-like peptide-1

mTOR

mammalian target of rapamycin‌

AMPK

Activated protein kinase

SGLT2i

Sodium-Glucose Cotransporter-2 Inhibitors

SGLT2

Sodium-glucose cotransporter-2

Author contributions

DPH: conceptualization, DataCuration. Formal Analysis, Writing-Original Draft, Writing-Review & Editing; LHX and LJH: Methodology, Supervision; KF(Corresponding Author): Conceptualization, Resources, Supervision, Validation, Writing-Original Draft, Writing-Review & Editing; XLP and LAN: Supervision, Validation; WCH: Data Curation.All authors read and approved the final manuscript.

Funding

The authors declare that they have received no finding.

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.