Sodium-glucose transport protein-2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as potential cardioprotective agents, reducing cardiovascular mortality and improving heart failure outcomes. Recent evidence suggests that SGLT2 inhibitors exert anti-inflammatory effects, particularly through modulating the inflammasome pathway. This review explores the role of the inflammasome in acute myocardial infarction (AMI) in T2DM and discusses the mechanisms by which SGLT2 inhibitors influence this pathway. We evaluate current studies on the impact of SGLT2 inhibitors on key inflammatory mediators, particularly the NLRP3 inflammasome, and discuss their potential therapeutic implications for reducing inflammation and myocardial injury in patients with T2DM experiencing AMI. In summary, the key novelties in this review lie in its focused mechanistic approach on the inflammasome pathway, its integration of diabetes and cardiovascular research, and its potential to influence future therapeutic strategies for AMI in T2DM patients. It offers a novel angle by tying together molecular mechanisms of inflammation with clinical implications in a specific patient population that faces high cardiovascular risk.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) preserve cardiac and renal function by mechanisms that are not completely elucidated. Among other things, SGLT2i promote nutrient-deprivation signalling, which might affect the immune function. As the fate of immune cells is controlled by their metabolism, we aimed to study the mitochondrial integrity of lymphocytes isolated from renal transplant recipients with type 2 diabetes (T2D) upon SGLT2i therapy instauration and six-month follow up. In this real-world pilot study, the mitochondrial respiration of isolated peripheral blood mononuclear cells was monitored in a Seahorse XFp extracellular-flux analyzer and cells were photographed with a confocal microscope. Mitochondrial mass, membrane potential, and superoxide content of lymphocyte subpopulations were measured by flow cytometry (MitoTrackerTM Green, TMRM, and MitoSOXTM Red probes). Leveraging in vivo conditions of immune cells, we evaluated their metabolic profiles associated with immune activation. Herein, we identified changes in redox homeostasis with sustained membrane polarization, and an increased mitochondrial biogenesis upon PHA stimulation that significantly correlated with changes in body weight and LDL-cholesterol levels, and a resultant compensatory mitochondrial function of lymphocytes. Our data suggest novel mechanisms induced by SGLT2i to modulate immune cells, which probably underlie the observed beneficial effects in kidney transplant recipients. Nonetheless, further mechanistic studies are required to extend these exploratory findings and encourage the use of this therapeutic strategy.

SGLT-2 inhibitors, initially developed for type 2 diabetes, demonstrate profound cardiorenal and metabolic benefits. This review synthesizes evidence from clinical trials and mechanistic studies to elucidate their roles in cardiovascular diseases, chronic kidney disease, and non-alcoholic fatty liver disease. Key findings include a notable reduction in cardiovascular death/heart failure hospitalization, a marked decrease in heart failure hospitalization risk, and significant improvements in renal and hepatic outcomes. Emerging mechanisms, such as autophagy induction, ketone utilization, and anti-inflammatory effects, underpin these benefits. Ongoing trials explore their potential in non-diabetic populations, positioning SGLT-2 inhibitors as transformative agents in multisystem disease management.

The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.

Diabetic kidney disease (DKD) is recognized worldwide as a leading cause of end-stage renal failure. Although therapies that target glomerular hemodynamics and can inhibit disease progression have been developed, there is currently no fundamental cure for the disease. Mitochondria play an important role in cellular respiration, producing adenosine triphosphate (ATP) by oxidative phosphorylation, and are essential for renal function, especially in proximal tubular cells (PTCs). In diabetic conditions, maintaining mitochondrial health is vital for preserving renal function. Under diabetic conditions, excessive reactive oxygen species (ROS) can damage mitochondrial DNA (mtDNA), leading to renal dysfunction. Strategies targeting mitochondrial function, such as AMP-activated protein kinase (AMPK) activation and modulation of nitric oxide (NO) availability, are promising for suppressing diabetic nephropathy. The immune response to DKD, initiated by detecting damage- and pathogen-associated molecular patterns, has a significant impact on the progression of DKD, including leakage of mtDNA and RNA, leading to inflammation through various pathways. This contributes to renal impairment characterized by hyperfiltration, endothelial dysfunction, and albuminuria. Mitochondrial energy metabolism and dynamics induced by hyperglycemia precede the onset of albuminuria and histological changes in the kidneys. The increased mitochondrial fission and decreased fusion that occur under diabetic conditions result in ATP depletion and exacerbate cellular dysfunction. Therapeutic strategies focused on restoring mitochondrial function are promising for slowing the progression of DKD and reduce the adverse effects on renal function. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 (GLP-1) receptor agonists, already in clinical use, have been shown to be protective for mitochondria, and nuclear factor erythroid 2-related factor 2 (Nrf2) activation and mitochondrial dynamics are promising drug discovery targets for further research.

Diabetic cardiomyopathy (DCM) represents a significant health burden, exacerbated by the global increase in type 2 diabetes mellitus (T2DM). This condition contributes substantially to the morbidity and mortality associated with diabetes, primarily through myocardial dysfunction independent of coronary artery disease. Current treatment strategies focus on managing symptoms rather than targeting the underlying pathophysiological mechanisms, highlighting a critical need for specific therapeutic interventions. This review explores the multifaceted role of empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, in addressing the complex etiology of DCM. We discuss the key mechanisms by which hyperglycemia contributes to cardiac dysfunction, including oxidative stress, mitochondrial impairment, and inflammation, and how empagliflozin mitigates these effects. Empagliflozin's effects on reducing hospitalization for heart failure and potentially lowering cardiovascular mortality mark it as a promising candidate for DCM management. By elucidating the underlying mechanisms through which empagliflozin operates, this review underscores its therapeutic potential and paves the way for future research into its broader applications in diabetic cardiac care. This synthesis aims to foster a deeper understanding of DCM and encourage the integration of empagliflozin into treatment paradigms, offering hope for improved outcomes in patients suffering from this debilitating condition.

Epidemiological evidence has shown that diabetes is associated with overt heart failure (HF) and worse clinical outcomes. However, the presence of a distinct primary diabetic cardiomyopathy (DCM) has not been easy to prove because the association between diabetes and HF is confounded by hypertension, obesity, microvascular dysfunction, and autonomic neuropathy. In addition, the molecular mechanisms underlying DCM are not yet fully understood, DCM usually remains asymptomatic in the early stage, and no specific biomarkers have been identified. Nonetheless, several mechanistic associations at the systemic, cardiac, and cellular/molecular levels explain different aspects of myocardial dysfunction, including impaired cardiac relaxation, compliance, and contractility. In this review, we focus on recent clinical and preclinical advances in our understanding of the molecular mechanisms of DCM and the role of anti-hyperglycemic agents in preventing DCM beyond their glucose lowering effect.

Diabetes mellitus is one of the major causes of ischemic and nonischemic heart failure. While hypertension and coronary artery disease are frequent comorbidities in patients with diabetes, cardiac contractile dysfunction and remodeling occur in diabetic patients even without comorbidities, which is referred to as diabetic cardiomyopathy. Investigations in recent decades have demonstrated that the production of reactive oxygen species (ROS), impaired handling of intracellular Ca2+, and alterations in energy metabolism are involved in the development of diabetic cardiomyopathy. AMP deaminase (AMPD) directly regulates adenine nucleotide metabolism and energy transfer by adenylate kinase and indirectly modulates xanthine oxidoreductase-mediated pathways and AMP-activated protein kinase-mediated signaling. Upregulation of AMPD in diabetic hearts was first reported more than 30 years ago, and subsequent studies showed similar upregulation in the liver and skeletal muscle. Evidence for the roles of AMPD in diabetes-induced fatty liver, sarcopenia, and heart failure has been accumulating. A series of our recent studies showed that AMPD localizes in the mitochondria-associated endoplasmic reticulum membrane as well as the sarcoplasmic reticulum and cytosol and participates in the regulation of mitochondrial Ca2+ and suggested that upregulated AMPD contributes to contractile dysfunction in diabetic cardiomyopathy via increased generation of ROS, adenine nucleotide depletion, and impaired mitochondrial respiration. The detrimental effects of AMPD were manifested at times of increased cardiac workload by pressure loading. In this review, we briefly summarize the expression and functions of AMPD in the heart and discuss the roles of AMPD in diabetic cardiomyopathy, mainly focusing on contractile dysfunction caused by this disorder.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.

Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.

Atherosclerotic cardiovascular disease remains a prominent global cause of mortality, with coronary artery disease representing its most prevalent manifestation. Recently, a novel class of antidiabetic medication, namely sodium-glucose cotransporter-2 (SGLT2) inhibitors, has been reported to have remarkable cardiorenal advantages for individuals with type 2 diabetes mellitus (DM), and they may reduce cardiorenal risk even in individuals without pre-existing DM. Currently, there is no evidence regarding the safety and efficacy of these drugs in acute coronary syndrome (ACS), regardless of diabetes status. This review aims to comprehensively present the available preclinical and clinical evidence regarding the potential role of SGLT2 inhibitors in the context of ACS, as adjuncts to standard-of-care treatment for this patient population, while also discussing potential short- and long-term cardiovascular benefits.

A literature search was performed through MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, and Scopus until February 26, 2024. Eligible were preclinical and clinical studies, comprising randomized controlled trials (RCTs), real-world studies, and meta-analyses.

Evidence from preclinical models indicates that the use of SGLT2 inhibitors is associated with a blunted ischemia-reperfusion injury and decreased myocardial infarct size, particularly after prior treatment. Although RCTs and real-world data hint at a potential benefit in acute ischemic settings, showing improvements in left ventricular systolic and diastolic function, decongestion, and various cardiometabolic parameters such as glycemia,body weight, and blood pressure, the recently published DAPA-MI (Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure) trial did not establish a clear advantage regarding surrogate cardiovascular end points of interest. SGLT2 inhibitors appear to provide a benefit in reducing contrast-induced acute kidney injury events in patients with ACS undergoing percutaneous coronary intervention. However, data on other safety concerns, such as treatment discontinuation because of hypotension, hypovolemia, or ketoacidosis, are currently limited.

Despite the well-established cardiovascular benefits observed in the general population with type 2 DM and, more recently, in other patient groups irrespective of diabetes status, existing evidence does not support the use of SGLT2 inhibitors in the context of ACS. Definitive answers to this intriguing research question, which could potentially expand the therapeutic indications of this novel drug class, require large-scale, well-designed RCTs.

Ischemic heart disease (IHD) is a common clinical cardiovascular disease with high morbidity and mortality. Sodium glucose cotransporter protein inhibitor (SGLTi) is a novel hypoglycemic drug. To date, both clinical trials and animal experiments have shown that SGLTi play a protective role in IHD, including myocardial infarction (MI) and ischemia/reperfusion (I/R). The protective effects may be involved in mechanisms of energy metabolic conversion, anti-inflammation, anti-fibrosis, ionic homeostasis improvement, immune cell development, angiogenesis and functional regulation, gut microbiota regulation, and epicardial lipids. Thus, this review summarizes the above mechanisms and aims to provide theoretical evidence for therapeutic strategies for IHD.

Background: Real-world data on the implementation and prognostic impact of glucose-lowering drugs with proven cardiovascular benefits in patients with type 2 diabetes (T2D) following acute coronary syndrome (ACS) are limited. We investigated the utilization and treatment patterns of sodium-glucose contrasporter-2 inhibitors (SGLT2Is) and glucagon-like peptide-1 recepto-agonists (GLP1RAs) in patients with T2D experiencing ACS and analyzed their association with mortality and major adverse cardiovascular events (MACEs) including recurrent ACS, acute revascularization, heart failure, or ischemic stroke. Methods: We carried out a retrospective analysis of 9756 patients with T2D from a nationwide healthcare organization in Israel who were hospitalized with ACS between 01/2019 and 01/2022. Drug prescriptions were estimated pre-hospitalization, 90 days, and 1 year following hospitalization. The association between SGLT2I and/or GLP1RA treatment with MACE and mortality was investigated using a time-dependent Cox regression analysis with multivariable adjustment. Results: The prescription rates (pre-hospitalization, 90 days, and 1 year post-hospitalization) of GLP1RAs were 13%, 13.2%, and 18%, and those of SGLT2Is were 23.9%, 33.6%, and 42.7%, respectively. At 1 year, 13.9% of patients were prescribed both treatments. The use of SGLT2Is and/or GLP1RAs was higher in younger age groups and increased from 2019 to 2021 (38.1% to 59.2%). The adjusted hazard ratio for the association of pre- or post-hospitalization SGLT2I and/or GLP1RA treatment with mortality and MACE was 0.724 (0.654-0.801) and 0.974 (0.909-1.043), respectively. Conclusions: In the real-world practice of treating patients with T2D experiencing ACS, the implementation of SGLT2Is, particularly GLP1RAs, was suboptimal when prescribed both early and 1 year following hospitalization, emphasizing the need to improve medical care. Treatment with SGLT2Is and/or GLP1RAs was associated with a favorable impact on mortality but not MACE.

Myocardial infarction (MI) is a significant cause of death in diabetic patients. Growing evidence suggests that mitochondrial dysfunction contributes to heart failure in diabetes. However, the molecular mechanisms of mitochondrial dysfunction mediating heart failure in diabetes are still poorly understood.

We examined MRPL12 levels in right atrial appendage tissues from diabetic patients undergoing coronary artery bypass graft (CABG) surgery. Using AC-16 cells overexpressing MRPL12 under normal and hyperglycemic conditions we performed mitochondrial functional assays OXPHOS, bioenergetics, mitochondrial membrane potential, ATP production and cell death.

We observed elevated MRPL12 levels in heart tissue samples from diabetic patients with ischemic heart disease compared to non-diabetic patients. Overexpression of MRPL12 under hyperglycemic conditions did not affect oxidative phosphorylation (OXPHOS) levels, cellular ATP levels, or cardiomyocyte cell death. However, notable impairment in mitochondrial membrane potential (MMP) was observed under hyperglycemic conditions, along with alterations in both basal respiration oxygen consumption rate (OCR) and maximal respiratory capacity OCR.

Overall, our results suggest that MRPL12 may have a compensatory role in the diabetic myocardium with ischemic heart disease, suggesting that MRPL12 may implicate in the pathophysiology of MI in diabetes.

A previous study showed that high-glucose (HG) conditions induce mitochondria fragmentation through the calcium-mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) in H9C2 cells. This study tested whether empagliflozin could prevent HG-induced mitochondria fragmentation through this pathway. We found that exposing H9C2 cells to an HG concentration decreased cell viability and increased cell apoptosis and caspase-3. Empagliflozin could reverse the apoptosis effect of HG stimulation on H9C2 cells. In addition, the HG condition caused mitochondria fragmentation, which was reduced by empagliflozin. The expression of mitochondria fission protein was upregulated, and fusion proteins were downregulated under HG stimulation. The expression of fission proteins was decreased under empagliflozin treatment. Increased calcium accumulation was observed under the HG condition, which was decreased by empagliflozin. The increased expression of ERK 1/2 under HG stimulation was also reversed by empagliflozin. Our study shows that empagliflozin could reverse the HG condition, causing a calcium-dependent activation of the ERK 1/2 pathway, which caused mitochondria fragmentation in H9C2 cells.

Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson's trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.

Although good glycemic control in patients with type 2 diabetes (T2D) can prevent cardiovascular complications, many diabetic patients still have poor optimal control. A new class of antidiabetic drugs (e.g., glucagon-like peptide-1-GLP-1 receptor agonists, sodium-glucose co-transporters-SGLT2 inhibitors), in addition to the low hypoglycemic effect, exert multiple beneficial effects at a metabolic and cardiovascular level, through mechanisms other than antihyperglycemic agents. This review aims to discuss the effects of these new antidiabetic drugs, highlighting cardiovascular and metabolic benefits, through the description of their action mechanisms as well as available data by preclinical and clinical studies. Moreover, new innovative tools in the T2D field will be described which may help to advance towards a better targeted T2D personalized care in future.

Metabolic syndrome (MetS) has a large clinical population nowadays, usually due to excessive energy intake and lack of exercise. During MetS, excess nutrients stress the mitochondria, resulting in relative hypoxia in tissues and organs, even when blood supply is not interrupted or reduced, making mitochondrial dysfunction a central pathogenesis of cardiovascular disease in the MetS. Sodium-glucose cotransporter 2 inhibitors were designed as a hyperglycemic drug that acts on the renal tubules to block sugar reabsorption in primary urine. Recently they have been shown to have anti-inflammatory and other protective effects on cardiomyocytes in MetS, and have also been recommended in the latest heart failure guidelines as a routine therapy. Among these inhibitors, empagliflozin shows better clinical promise due to less influence from glomerular filtration rate. This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new class of glucose-lowering drugs traditionally used to control blood glucose levels in patients with type 2 diabetes mellitus, have been proven to reduce major adverse cardiovascular events, including cardiovascular death, in patients with heart failure irrespective of ejection fraction and independently of the hypoglycemic effect. Because of their favorable effects on the kidney and cardiovascular outcomes, their use has been expanded in all patients with any combination of diabetes mellitus type 2, chronic kidney disease and heart failure. Although mechanisms explaining the effects of these drugs on the cardiovascular system are not well understood, their effectiveness in all these conditions suggests that they act at the intersection of the metabolic, renal and cardiac axes, thus disrupting maladaptive vicious cycles while contrasting direct organ damage. In this systematic review we provide a state of the art of the randomized controlled trials investigating the effect of SGLT2i on cardiovascular outcomes in patients with chronic kidney disease and/or heart failure irrespective of ejection fraction and diabetes. We also discuss the molecular targets and signaling pathways potentially explaining the cardiac effects of these pharmacological agents, from a clinical and experimental perspective.

Clinical studies demonstrated beneficial effects of sodium-glucose-transporter 2 inhibitors on the risk of cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes for cardioprotection remain unclear. The present study focused on the impact of empagliflozin (Empa) on myocardial function in a rat model with established HFpEF and analyzed underlying molecular mechanisms.

Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to standard care (HFpEF, n=18) or Empa (HFpEF/Empa, n=18). ZSF1 lean rats (con, n=18) served as healthy controls. Echocardiography was performed at baseline and after 4 and 8 weeks, respectively. After 8 weeks of treatment, hemodynamics were measured invasively, mitochondrial function was assessed and myocardial tissue was collected for either molecular and histological analyses or transmission electron microscopy.

In HFpEF Empa significantly improved diastolic function (E/é: con: 17.5±2.8; HFpEF: 24.4±4.6; P<0.001 versus con; HFpEF/Empa: 19.4±3.2; P<0.001 versus HFpEF). This was accompanied by improved hemodynamics and calcium handling and by reduced inflammation, hypertrophy, and fibrosis. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation. Cardiac mitochondrial respiration was significantly impaired in HFpEF but restored by Empa (Vmax complex IV: con: 0.18±0.07 mmol O2/s/mg; HFpEF: 0.13±0.05 mmol O2/s/mg; P<0.041 versus con; HFpEF/Empa: 0.21±0.05 mmol O2/s/mg; P=0.012 versus HFpEF) without alterations of mitochondrial content. The expression of cardiolipin, an essential stability/functionality-mediating phospholipid of the respiratory chain, was significantly decreased in HFpEF but reverted by Empa (con: 15.9±1.7 nmol/mg protein; HFpEF: 12.5±1.8 nmol/mg protein; P=0.002 versus con; HFpEF/Empa: 14.5±1.8 nmol/mg protein; P=0.03 versus HFpEF). Transmission electron microscopy revealed a reduced size of mitochondria in HFpEF, which was restored by Empa.

The study demonstrates beneficial effects of Empa on diastolic function, hemodynamics, inflammation, and cardiac remodeling in a rat model of HFpEF. These effects were mediated by improved mitochondrial respiratory capacity due to modulated cardiolipin and improved calcium handling.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD) with low albuminuria levels have not been established. This study aimed to compare the effects of dapagliflozin on kidney injury biomarkers in patients with CKD stratified by albuminuria level. We prospectively enrolled healthy volunteers (HVs; n = 20) and patients with CKD (n = 54) with and without diabetes mellitus. Patients with CKD were divided into two age-matched and sex-matched subgroups according to urinary albumin-creatinine ratio (uACR) levels (<300 mg/g and ≥300 mg/g). The CKD group received dapagliflozin (10 mg/day). Urine samples were collected before treatment and after 3 and 6 months of dapagliflozin. Urinary kidney injury molecule-1 (KIM-1), interleukin-1β (IL-1β), and mitochondrial DNA nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND1) copy number were measured. The estimated glomerular filtration rate (eGFR) of patients with CKD was lower than that of HVs (P < 0.001). During the study period, eGFR decreased and uACR did not change in the CKD group. Kidney injury markers were significantly elevated in patients with CKD compared with those in HVs. Dapagliflozin reduced urinary KIM-1, IL-1β, and mtDNA copy number in patients with CKD after 6 months of treatment. In further, the levels of urinary KIM-1 and IL-1β, patients with CKD decreased after 6 months of dapagliflozin treatment regardless of albuminuria level. Dapagliflozin reduced urinary kidney injury biomarkers in patients with CKD, regardless of albuminuria level. These findings suggest that SGLT2 inhibitors may also attenuate the progression of low albuminuric CKD.

Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions. Empagliflozin, a novel glucose-lowering agent, has been confirmed to reduce the risk of hospitalization for HF in diabetic patients. Nevertheless, the molecular mechanisms by which this agent provides cardioprotection remain unclear.

To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.

Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase (AMPK) and myosin phosphatase target subunit 1 (MYPT1), as well as the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and active caspase-3 protein levels.

In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylated MYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressing PGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes.

Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.

To investigate the specific effects of s odium-glucose transporter 2 inhibitor (SGLT2i) on cardiac energy metabolism.

A systematic literature search was conducted in eight databases. The retrieved studies were screened according to the inclusion and exclusion criteria, and relevant information was extracted according to the purpose of the study. Two researchers independently screened the studies, extracted information, and assessed article quality.

The results of the 34 included studies (including 10 clinical and 24 animal studies) showed that SGLT2i inhibited cardiac glucose uptake and glycolysis, but promoted fatty acid (FA) metabolism in most disease states. SGLT2i upregulated ketone metabolism, improved the structure and functions of myocardial mitochondria, alleviated oxidative stress of cardiomyocytes in all literatures. SGLT2i increased cardiac glucose oxidation in diabetes mellitus (DM) and cardiac FA metabolism in heart failure (HF). However, the regulatory effects of SGLT2i on cardiac FA metabolism in DM and cardiac glucose oxidation in HF varied with disease types, stages, and intervention duration of SGLT2i.

SGLT2i improved the efficiency of cardiac energy production by regulating FA, glucose and ketone metabolism, improving mitochondria structure and functions, and decreasing oxidative stress of cardiomyocytes under pathological conditions. Thus, SGLT2i is deemed to exert a benign regulatory effect on cardiac metabolic disorders in various diseases.

https://www.crd.york.ac.uk/, PROSPERO (CRD42023484295).

Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.

Diabetic cardiomyopathy is a well-recognized clinical entity and reflects a complex relationship between metabolic substrates and myocardial function. Sodium glucose co-transporter 2 (SGLT2) inhibitors are antidiabetic agents that are found to exert multiple cardioprotective effects. Large clinical trials showed their beneficial effects on patients with heart failure, reducing the rates of rehospitalizations and improving kidney function. The aim of this review is to summarize the latest evidence in the literature regarding the multiple effects of SGLT2 inhibitors on patients across the spectrum of cardiovascular diseases.

Population aging combined with higher susceptibility to cardiovascular diseases in older adults is increasing the incidence of conditions such as atherosclerosis, myocardial infarction, heart failure, myocardial hypertrophy, myocardial fibrosis, arrhythmia, and hypertension. sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally developed as a novel oral drug for patients with type 2 diabetes mellitus. Unexpectedly, recent studies have shown that, beyond their effect on hyperglycemia, SGLT2i also have a variety of beneficial effects on cardiovascular disease. Experimental models of cardiovascular disease have shown that SGLT2i ameliorate the process of aging-related cardiovascular disease by inhibiting inflammation, reducing oxidative stress, and reversing endothelial dysfunction. In this review, we discuss the role of SGLT2i in aging-related cardiovascular disease and propose the use of SGLT2i to prevent and treat these conditions in older adults.

The introduction of sodium-glucose cotransporter 2 (SGLT2) inhibitors as a new and effective class of therapeutic agents for type 2 diabetes (T2D) preventing the reabsorption of glucose in the kidneys and thus facilitating glucose excretion in the urine, but also as agents with cardiovascular benefits, particularly in patients with heart failure (HF), regardless of the diabetic status, has ushered in a new era in treating patients with T2D and/or HF. In addition, data have recently emerged indicating an antiarrhythmic effect of the SGLT2 inhibitors in patients with and without diabetes. Prospective studies, randomized controlled trials and meta-analyses have provided robust evidence for a protective and beneficial effect of these agents against atrial fibrillation, ventricular arrhythmias and sudden cardiac death. The antiarrhythmic mechanisms involved include reverse atrial and ventricular remodeling, amelioration of mitochondrial function, reduction of hypoglycemic episodes with their attendant arrhythmogenic effects, attenuated sympathetic nervous system activity, regulation of sodium and calcium homeostasis, and suppression of prolonged ventricular repolarization. These new data on antiarrhythmic actions of SGLT2 inhibitors are herein reviewed, potential mechanisms involved are discussed and pictorially illustrated, and treatment results on specific arrhythmias are described and tabulated.

Objective The cardiac function, blood distribution, and oxygen extraction in the muscles as well as the pulmonary function determine the oxygen uptake (VO2) kinetics at the onset of exercise. This factor is called the VO2 time constant, and its prolongation is associated with an unfavorable prognosis for heart failure (HF). The mitochondrial function of skeletal muscle is known to reflect exercise tolerance. Morphological changes and dysfunction in cardiac mitochondria are closely related to HF severity and its prognosis. Although mitochondria play an important role in generating energy in cardiomyocytes, the relationship between cardiac mitochondria and the VO2 time constant has not been elucidated. Methods We calculated the ratio of abnormal cardiac mitochondria in human myocardial biopsy samples using an electron microscope and measured the VO2 time constant during cardiopulmonary exercise testing. The VO2 time constant was normalized by the fat-free mass index (FFMI). Patients Fifteen patients with non-ischemic cardiomyopathy (NICM) were included. Patients were divided into two groups according to their median VO2 time constant/FFMI value. Results Patients with a low VO2 time constant/FFMI value had a lower abnormal mitochondria ratio than those with a high VO2 time constant/FFMI value. A multiple linear regression analysis revealed that the ratio of abnormal cardiac mitochondria was independently associated with a high VO2 time constant/FFMI. Conclusion An increased abnormal cardiac mitochondria ratio might be associated with a high VO2 time constant/FFMI value in patients with NICM.

Autophagy is a very active process that plays an important role in cell and organ differentiation and remodelling, being a crucial system to guarantee health. This physiological process is activated in starvation and inhibited in the presence of nutrients. This short review comments on the three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy, as well as different aspects that control autophagy and its relationship with health and degenerative diseases. As autophagy is highly dependent on functional autophagy (ATG) proteins integrating the phagophore, the role of some key ATG genes and epigenes are briefly commented on. The manuscript deepens discussing some central aspects of type-2 diabetes mellitus and their relationship with the cell cleaning process and mitochondria homeostasis maintenance, as well as the mechanisms through which antidiabetic drugs affect autophagy. Well-designed studies are needed to elucidate whether autophagy plays a casual or causal role in T2DM.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i) demonstrated cardiovascular and renal protection. Whether their benefits occur also during hospitalization for acute myocardial infarction (AMI) in patients with diabetes mellitus (DM) is not known. We evaluated in-hospital outcomes of patients hospitalized with AMI according to their chronic use of GLP-1 RA and/or SGLT-2i.

Using the health administrative databases of Lombardy, patients hospitalized with AMI from 2010 to 2019 were included. They were stratified according to DM status, then grouped into three cohorts using a propensity score matching: non-DM patients; DM patients treated with GLP-1 RA and/or SGLT-2i; DM patients not treated with GLP-1 RA/SGLT-2i. The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy.

We identified 146,798 patients hospitalized with AMI (mean age 71 ± 13 years, 34% females, 47% STEMI; 26% with DM). After matching, 3,090 AMI patients (1030 in each group) were included in the analysis. Overall, the primary endpoint rate was 16% (n = 502) and progressively increased from non-DM patients to DM patients treated with and without GLP-1 RA/SGLT-2i (13%, 16%, and 20%, respectively; P < 0.0001). Compared with non-DM patients, DM patients with GLP-1 RA/SGLT-2i had a 30% higher risk of the primary endpoint, while those not treated with GLP-1 RA/SGLT-2i had a 60% higher risk (P < 0.0001).

Chronic therapy with GLP-1 RA and/or SGLT-2i has a favorable impact on the clinical outcome of DM patients hospitalized with AMI.

Systemic branched-chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long-Evans-Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched-chain α-keto acid dehydrogenase (BCKDH), a rate-limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long-Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH-E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3-E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3-BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3-BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a class of newly introduced antidiabetic drugs with potent hypoglycemic effects. Recent evidence suggests that these drugs have extraglycemic impacts and are therefore able to provide additional benefits beyond glucose lowering. Mitochondrial dysfunction is a central facet of many disorders that negatively impacts many tissues and organs, especially in the setting of diabetes. Therefore, it would be hugely beneficial if an antidiabetic drug could also provide mitochondrial benefits to improve cellular function and reduce the risk of diabetic complications. In this review, we have surveyed the literature for possible mitochondrial benefits of SGLT2is and we discuss the possible mechanisms involved.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drugs that exert a hypoglycemic effect by blocking the reabsorption of glucose in the proximal renal tubules, thus promoting the excretion of glucose from urine. Their hypoglycemic effect is not dependent on insulin. Increasing data shows that SGLT2 inhibitors improve cardiovascular outcomes in patients with type 2 diabetes. Previous studies have demonstrated that SGLT2 inhibitors can reduce pathological myocardial hypertrophy with or without diabetes, but the exact mechanism remains to be elucidated. To clarify the relationship between SGLT2 inhibitors and pathological myocardial hypertrophy, with a view to providing a reference for the future treatment thereof, this study reviewed the possible mechanisms of SGLT2 inhibitors in attenuating pathological myocardial hypertrophy. We focused specifically on the mechanisms in terms of inflammation, oxidative stress, myocardial fibrosis, mitochondrial function, epicardial lipids, endothelial function, insulin resistance, cardiac hydrogen and sodium exchange, and autophagy.

Diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose levels and has become the third leading threat to human health after cancer and cardiovascular disease. Recent studies have shown that autophagy is closely associated with diabetes. Under normal physiological conditions, autophagy promotes cellular homeostasis, reduces damage to healthy tissues and has bidirectional effects on regulating diabetes. However, under pathological conditions, unregulated autophagy activation leads to cell death and may contribute to the progression of diabetes. Therefore, restoring normal autophagy may be a key strategy to treat diabetes. High-mobility group box 1 protein (HMGB1) is a chromatin protein that is mainly present in the nucleus and can be actively secreted or passively released from necrotic, apoptotic, and inflammatory cells. HMGB1 can induce autophagy by activating various pathways. Studies have shown that HMGB1 plays an important role in insulin resistance and diabetes. In this review, we will introduce the biological and structural characteristics of HMGB1 and summarize the existing knowledge on the relationship between HMGB1, autophagy, diabetes, and diabetic complications. We will also summarize potential therapeutic strategies that may be useful for the prevention and treatment of diabetes and its complications.

This review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions.

Mitochondrial dysfunction is associated with the development of type 2 diabetes mellitus (T2DM). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2DM. ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes.

In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman's correlation coefficients, and the association with the risk of NOD was determined using Cox proportional-hazards models.

In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, P   = 0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the body mass index (r = -0.20, P  = 0.0005) and homeostasis model assessment of insulin resistance (HOMA-IR). (r = -0.37, P < 0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, P  <  0.0001) and apoA-I (r = 0.33, P  <  0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2DM after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], P   = 0.012).

We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2DM.

The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM).

We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis.

Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i.

SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients.