Cardiovasc Diabetol [JOURNAL]
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200 papers
Associations of eight insulin resistance-related indices and genetic risk with incident cardiometabolic multimorbidity among participants with hypertension: a large prospective cohort study.
Ma S, Jiang M, Xuan Y … +3 more , Shen Y, Chen K, Li B
Cardiovasc Diabetol · 2026 Mar · PMID 41913237 · Full text
BACKGROUND: Cardiometabolic multimorbidity (CMM) is prevalent among individuals with hypertension. Although insulin resistance (IR)-related indices have been linked to CMM, their associations with incident CMM in hyperte...
BACKGROUND: Cardiometabolic multimorbidity (CMM) is prevalent among individuals with hypertension. Although insulin resistance (IR)-related indices have been linked to CMM, their associations with incident CMM in hypertensive populations remain unclear. This study examined the associations in this high-risk group, focusing on the roles of genetic factors and biomarkers. METHODS: This observational prospective cohort analysis used data from the UK Biobank, comprising 129,853 hypertensive patients free of pre-existing coronary heart disease, stroke, or type 2 diabetes. Eight IR-related indices were computed: triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), TyG-a body shape index (TyG-ABSI), TyG-weight-adjusted waist index (TyG-WWI), TyG-body roundness index (TyG-BRI), and triglyceride to high-density lipoprotein cholesterol ratio (TG-HDL-C). Associations were examined using Cox proportional hazards models. Incremental predictive value was quantified using the net reclassification improvement, integrated discrimination improvement, and the C index. We also analyzed their joint and interaction effects with genetic risk and conducted exploratory biomarker analyses. RESULTS: Over a median follow-up of 13 years, 28,455 incident CMM events were recorded. Multivariable-adjusted hazard ratios (95% CIs) the highest versus lowest tertiles were: 1.78 (1.73-1.83) for TyG index, 2.10 (2.04-2.17) for TyG-BMI, 2.29 (2.21-2.37) for TyG-WC, 2.23 (2.16-2.30) for TyG-WHtR, 2.08 (2.02-2.15) for TyG-WWI, 2.17 (2.10-2.24) for TyG-BRI, 1.90 (1.84-1.97) for TyG-ABSI, and 1.73 (1.68-1.79) for TG-HDL-C. Per standard deviation increment was associated with 18%-48% higher risks. All indices improved incremental predictive value, with TyG-WHtR showing the strongest performance. Individuals with high IR-related indices and high genetic risk exhibited the highest CMM risk, with additive interactions. High genetic risk appeared to strengthen the adverse associations between IR-related indices and CMM, with evidence of multiplicative interactions. Biomarker analyses suggested that systemic inflammation and biomarkers of liver and renal function might statistically account for part of the observed associations. CONCLUSION: Higher levels of IR-related indices, especially TyG-WHtR, were associated with an elevated risk of incident CMM in individuals with hypertension, particularly among those with high genetic risk. Inflammatory, hepatic, and renal biomarker abnormalities were related to the associations. IR-related indices, particularly TyG-WHtR, may provide useful information for risk stratification of CMM among individuals with hypertension.
Phenotypic heterogeneity of type 2 diabetes and risks of complications with a tree-like representation.
Che J, Li X, Qiu Z … +12 more , Li R, Yu H, Xie J, Guo T, Tang Z, Xia P, Xu K, Li R, Yang K, Geng T, Pan A, Liu G
Cardiovasc Diabetol · 2026 Mar · PMID 41913207 · Full text
BACKGROUND: Type 2 diabetes shows clinical heterogeneity which cannot be fully captured by glycemic metrics, highlighting the need to better define patient phenotypes and progression pathways. This study aims to elucidat...
BACKGROUND: Type 2 diabetes shows clinical heterogeneity which cannot be fully captured by glycemic metrics, highlighting the need to better define patient phenotypes and progression pathways. This study aims to elucidate the heterogeneity of type 2 diabetes and risks of major associated diseases, as well as underlying proteomic mechanism. METHODS: We applied discriminative dimensionality reduction with trees (DDRTree) algorithm to construct a tree from seven clinical variables (body mass index, high density lipoprotein cholesterol, triglyceride, HbA1c, systolic blood pressure, diastolic blood pressure, and total cholesterol). Disease risks were assessed using competing risk models. RESULTS: This study included 6406 individuals with newly diagnosed type 2 diabetes from the UK Biobank. All seven clinical variables formed a gradient distribution across the DDRTree-derived phenotypic structure, revealing three distinct disease risks patterns: participants with adiposity, hypertension and dyslipidemia exhibited elevated risks of macrovascular complications, diabetic kidney disease, Parkinson’s disease and non-alcohol fatty liver disease; those with hyperglycemia and dyslipidemia had higher risks of myocardial infarction, diabetic neuropathy, diabetic retinopathy, depression and chronic obstructive pulmonary disease; while elevated total cholesterol and high-density lipoprotein cholesterol were associated with increased risks of cancer and Alzheimer’s disease. Proteomic analyses identified pattern-specific pathways: metabolic dysregulation and extracellular matrix remodeling in the first pattern, inflammatory activation and lipid metabolism alterations in the second, and immune activation with chemical carcinogenesis in the third. Furthermore, sensitivity to lifestyle factors were phenotypic-specific. These patterns were similar in the Dongfeng-Tongji Diabetes cohort, though cardiovascular disease and retinopathy risks were strongly associated with hypertension. An online tool was provided for individual risk prediction. CONCLUSIONS: Our findings reveal distinct spatial distributions of clinical features and associated disease risks in type 2 diabetes, with subgroups exhibiting unique proteomic signatures and differential lifestyle responses, underscoring the importance for personalized management for diabetes care.
Correction: Effects of metabolic syndrome and its components on myocardial microcirculation in obstructive coronary artery disease patients: a CMR perfusion study.
Min CY, Gao Y, Shi K … +9 more , Guo YK, Liu J, Jiang YN, Yan WF, Fang H, Li X, Li Y, Fu H, Yang ZG
Cardiovasc Diabetol · 2026 Mar · PMID 41913180 · Full text
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High inflammatory burden may link non-albuminuric diabetic kidney disease to carotid atherosclerosis.
Di Marco M, Scilletta S, Miano N … +14 more , Marrano N, Natalicchio A, Cignarelli A, Genchi VA, Giorgino F, Bosco G, Di Giacomo Barbagallo F, Scicali R, Galeano F, Tumminia A, Milluzzo A, Frittitta L, Piro S, Di Pino A
Cardiovasc Diabetol · 2026 Mar · PMID 41913173 · Full text
BACKGROUND: Individuals with diabetic kidney disease (DKD) exhibit markedly elevated cardiovascular (CV) risk, which may differ across DKD phenotypes. Non-albuminuric DKD (NA-DKD) has been proposed as a phenotype with hi...
BACKGROUND: Individuals with diabetic kidney disease (DKD) exhibit markedly elevated cardiovascular (CV) risk, which may differ across DKD phenotypes. Non-albuminuric DKD (NA-DKD) has been proposed as a phenotype with high CV risk. Inflammation may contribute to the link between DKD and cardiovascular disease, but inflammatory patterns across distinct DKD phenotypes remains insufficiently characterized. This study evaluated an extensive panel of inflammatory markers in DKD and examined their relationship with the presence of carotid atherosclerotic plaque, particularly focusing on NA-DKD. METHODS: A total of 180 adults with type 2 diabetes were stratified into patients with DKD (n = 132) and control group without DKD (n = 48) and subsequently in the different DKD phenotypes according to glomerular filtration rate (eGFR) and urinary to albumin creatinine ratio (UACR): albuminuric DKD (A-DKD, UACR ≥ 30 mg/g and eGFR ≥ 60 ml/min/1.73 m2; n = 46), NA-DKD (UACR < 30 mg/g and eGFR < 60 ml/min/1.73 m2; n = 44), albuminuric and low eGFR DKD (UACR ≥ 30 mg/g and eGFR < 60 ml/min/1.73 m2, n = 42). Participants underwent carotid and kidney ultrasonography, arterial stiffness assessment, and measurement of 37 inflammatory biomarkers. Logistic regression models adjusted for major confounders were used to assess associations between inflammatory markers and carotid atherosclerosis. RESULTS: Individuals with DKD showed a higher prevalence of carotid plaques in comparison to controls (61.8 vs 39.6%, P = 0.008), a trend toward higher pulse wave velocity (11.45 ± 4.02 vs 10.11 ± 3.69 m/s, P = 0.082), and higher renal resistive index (0.75 ± 0.09 vs 0.71 ± 0.08, P = 0.016). Multiple inflammatory biomarkers—including soluble tumor necrosis factor receptors (sTNF-Rs)—were higher in DKD than in controls. When considering DKD phenotypes, sTNF-R1 was higher in NA-DKD in comparison to both controls and individuals with A-DKD. In the overall population, several inflammatory biomarkers correlated with estimated eGFR but not with UACR. Among participants with DKD, TNF-R1 levels in the top tertile group were independently associated with the presence of carotid plaques (OR 4.92, 95% CI 1.41–17.18, P = 0.010, q value = 0.0494). CONCLUSIONS: This study showed a higher inflammatory burden in DKD and particularly in NA-DKD. sTNF-R1 was associated with the presence of carotid atherosclerotic plaque, and this could partially explain the elevated cardiovascular risk associated with this phenotype.
Inpatient safety, effectiveness of SGLT2 inhibitors and GLP-1 RAs in type 2 diabetes: ENDOCARE, a pragmatic prospective cohort study.
Moreno-Pérez Ó, Tejera-Muñoz A, Leiva-Mora N … +16 more , Santacruz E, Sánchez-Ortiga R, Arrarte V, Climent-Grana E, Sandin M, Riera G, Lopez-Mondejar P, López-Muñoz B, Navarro C, Guillen-Morote C, Roldán-Sánchez A, Sánchez-Pacheco M, Abad-González ÁL, Llorens P, Pico-Alfonso A, Serrano-Gotarredona J
Cardiovasc Diabetol · 2026 Mar · PMID 41913157 · Full text
BACKGROUND: Current guidelines recommend baseline insulin as the standard treatment for most people hospitalised with type 2 diabetes (PWT2D). However, they generally discourage the use of sodium–glucose cotransporter 2...
BACKGROUND: Current guidelines recommend baseline insulin as the standard treatment for most people hospitalised with type 2 diabetes (PWT2D). However, they generally discourage the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists due to safety concerns and a lack of randomised evidence. We aim to assess primarily safety, and secondarily, effectiveness of non-insulin glucose-lowering therapy for inpatients, as implemented within a structured start-stop clinical practice guideline. METHODS: We conducted a 9-month pragmatic prospective cohort study including PWT2D adults who were admitted to the medical and surgical wards of a tertiary hospital. Participants were managed either on oral antidiabetic drugs (with or without insulin) under a start–stop protocol (Group A) or with insulin-only therapy (Group B). The primary outcome was safety, defined as severe adverse events (level 2–3 hypoglycaemia or diabetic ketoacidosis). Secondary outcomes included median daily capillary glucose and glycaemic variability. Hospital stay, intensive care unit admission and mortality were exploratory outcomes. Multivariable logistic regression and propensity score matching were employed to adjust for confounding factors. RESULTS: A total of 979 participants were included in the study: 582 in the Group A and 397 in the Group B. Seventy-three severe adverse events occurred, primarily hypoglycaemia. Non-insulin therapy was independently associated with a lower risk of severe adverse events (aOR 0.53 [95%CI 0.29–0.97]), and these results remained consistent after propensity score matching (OR 0.31 [95%CI 0.15–0.61]). The Group A had a lower median daily glucose level (153 mg/dL vs. 179 mg/dL; p < 0.001), lower glycaemic variability and a shorter hospital stay (5 days vs. 7 days; p < 0.001). No differences were observed in intensive care unit admission or mortality. CONCLUSIONS: In real hospital settings, the use of non-insulin therapies, predominantly SGLT2 inhibitors and GLP-1 RAs guided by a start-stop CPG, was associated with a safe and effective glycemic management profile.
Associations of cumulative exposure and dynamic trajectories of the triglyceride-total cholesterol-body weight index with new-onset cardiometabolic multimorbidity in middle-aged and older Chinese adults: evidence from a nationwide prospective cohort study.
Chen X, Wang C, Huang Q … +4 more , Luo Y, Wu Z, Chen J, Gong H
Cardiovasc Diabetol · 2026 Mar · PMID 41906174 · Full text
BACKGROUND: The global prevalence of cardiometabolic multimorbidity (CMM) has created a substantial health burden. The triglyceride-total cholesterol-body weight index (TCBI), a novel and easily computed metabolic indica...
BACKGROUND: The global prevalence of cardiometabolic multimorbidity (CMM) has created a substantial health burden. The triglyceride-total cholesterol-body weight index (TCBI), a novel and easily computed metabolic indicator, has shown a robust association with stroke and cardiovascular disease (CVD). However, research on the risk assessment of CMM remains limited. This study aims to investigate the relationships between cumulative exposure to the TCBI (CumTCBI) and its longitudinal trajectories with the risk of incident CMM in middle-aged and older adults, as well as to develop a survival-based risk prediction model. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) were utilized. Cox proportional hazards models and restricted cubic spline (RCS) analyses were applied to evaluate the associations between CumTCBI and the risk of CMM. Trajectory patterns of TCBI were discerned through K-means clustering. Subgroup and interaction analyses were conducted. Extensive sensitivity analyses were performed, including lag analysis, complete-case analysis, trimmed RCS analysis, interval-censored survival analysis, and Fine-Gray competing risk models. The proportional hazards assumption was verified using Schoenfeld residuals test. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were calculated to assess incremental predictive value. A survival nomogram prediction model based on Cox regression was developed, with discrimination assessed using the time-dependent area under the receiver operating characteristic curve (ROC) and clinical utility evaluated through decision curve analysis (DCA). RESULTS: Among 5068 participants, 424 individuals (8.4%) developed incident CMM during the follow-up period. Following multivariable adjustment, each 1-SD increase in CumTCBI was associated with an 18% higher risk of CMM (HR = 1.18, 95%CI 1.09-1.28), and the highest tertile was linked to an increased risk of CMM compared to the lowest tertile (HR = 1.90, 95% CI 1.43-2.52). A significant nonlinear dose-response relationship between CumTCBI and the riks of CMM (P for nonlinearity < 0.001). Three distinct trajectories are identified (low-stable, moderate-stable, and high-stable), with participants in the high-stable group facing a 61% greater risk of CMM than those with consistently low TCBI (HR = 1.61, 95% CI 1.10-2.36). These associations remained consistent across subgroups and were robust in all sensitivity. The proportional hazards assumption was satisfied (global P = 0.86). NRI and IDI analyses confirmed that TCBI provided incremental predictive value beyond its individual components (NRI = 0.158, P < 0.001). The nomogram prediction model exhibited acceptable discrimination (AUC: 0.715 in the training cohort and 0.694 in the validation cohort), and DCA indicated a favorable clinical net benefit. CONCLUSION: Higher cumulative TCBI exposure and unfavorable TCBI trajectories are independently associated with increased CMM risk in middle-aged and older Chinese adults. The Cox-based nomogram provides a practical tool for early risk stratification, supporting targeted preventino and personalized management of CMM.
Association between estimated glucose disposal rate and incident heart failure in patients with coronary heart disease: a prospective cohort study.
Xu J, Niu J, Li H … +5 more , Ren Q, Zhang Y, Miao Z, Huang K, Wu Z
Cardiovasc Diabetol · 2026 Mar · PMID 41904572 · Full text
BACKGROUND: Estimated glucose disposal rate (eGDR) is a composite index of insulin resistance (IR). However, its association with incident heart failure (HF) in coronary heart disease (CHD) patients remains unknown. METH...
BACKGROUND: Estimated glucose disposal rate (eGDR) is a composite index of insulin resistance (IR). However, its association with incident heart failure (HF) in coronary heart disease (CHD) patients remains unknown. METHODS: This prospective cohort study included 20,329 CHD patients from the UK Biobank. Baseline eGDR and several IR indices were calculated. Associations between eGDR, IR indices and incident HF were assessed separately based on Cox regression models. Also, receiver operating characteristic (ROC) analyses were conducted to evaluate the performance of the eGDR and other IR index in predicting the 10-year risk of HF. Finally, we specifically analyzed the temporal trajectory of eGDR levels in the 15 years leading up to HF onset based on time trajectory curves. RESULTS: 3364 participants developed incident HF over the follow-up. eGDR demonstrated superior risk stratification ability compared to other IR indices. Specifically, each 1-unit increase was associated with a 51% reduction in risk (HR = 0.49, 95% CI 0.38-0.64). Furthermore, eGDR exhibited the highest discriminative ability for participants at high risk of HF among all insulin resistance indices (AUC = 0.612, 95% CI 0.601-0.623). Trajectory analysis revealed that eGDR levels in individuals who eventually developed HF remained at a low level starting 15 years prior to the onset of HF. CONCLUSION: eGDR is closely linked to HF risk in the CHD population and exhibits stronger predictive power than other IR indices. Notably, eGDR levels change up to 15 years before the occurrence of HF, suggesting that eGDR could serve as an early predictor for HF among CHD patients.
Association between triglyceride-glucose index and related indicators with heart failure-related mortality in individuals with early-stage cardiovascular-kidney-metabolic syndrome.
Jin X, Feng Y, Liu C … +10 more , Cheng T, Jin Y, Shao Z, Bian Y, Wu H, Li J, Liu Y, Wei L, Qi Z, Qi X
Cardiovasc Diabetol · 2026 Mar · PMID 41904528 · Full text
BACKGROUND: Insulin resistance is a central pathophysiological feature of cardiovascular-kidney-metabolic (CKM) syndrome and has been implicated in adverse cardiovascular outcomes. However, the association between trigly...
BACKGROUND: Insulin resistance is a central pathophysiological feature of cardiovascular-kidney-metabolic (CKM) syndrome and has been implicated in adverse cardiovascular outcomes. However, the association between triglyceride-glucose (TyG) index-related indicators and heart failure (HF)-related mortality in individuals with early-stage CKM syndrome remains unclear. METHODS: This research conducted a prospective analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. Participants with CKM stages 0-2 and without clinical cardiovascular disease at baseline were included. TyG and related indices (TyG-BMI, TyG-WC, and TyG-WHtR) were analyzed as continuous and quartile-based variables. The primary outcome was HF-related mortality, ascertained via linkage to the National Death Index. Associations were assessed using Cox proportional hazards and Fine-Gray competing risk models with hierarchical adjustment, including additional adjustment for CKM stage in extended models. Machine learning approaches (Boruta and SHAP) were applied for covariate selection. Nonlinear associations, predictive performance, mediation by HbA1c, and subgroup effects were further evaluated. RESULTS: Among 14,830 participants, higher TyG-related indices were associated with increased HF-related mortality during follow-up. After full adjustment, each 1-SD increase in TyG-WC and TyG-WHtR was associated with a 2.27-fold and 2.94-fold higher risk of HF-related mortality, respectively (all P < 0.05). The associations remained consistent after additional adjustment for CKM stage. Restricted cubic spline analyses demonstrated predominantly linear dose-response relationships. TyG-WHtR exhibited the strongest discriminatory ability (AUC = 0.641, 95% CI 0.601-0.680). Mediation analyses indicated that HbA1c accounted for approximately 15%-30% of the observed associations. Associations were generally consistent across clinically relevant subgroups and remained robust in competing risk analyses and sensitivity analyses. CONCLUSIONS: In individuals with early-stage CKM syndrome, TyG-related indices-particularly those incorporating central adiposity-are independently associated with HF-related mortality. These findings highlight the prognostic relevance of insulin resistance-related metabolic burden in the early stages of CKM syndrome.
Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease.
Gan C, Zhou X, Qiu L … +12 more , Chen D, Shi Y, Yang Q, Jiang H, Xiao H, Chen W, Yang X, Chen Y, Wang M, Yang H, Jiang W, Li Q
Cardiovasc Diabetol · 2026 Mar · PMID 41904515 · Full text
OBJECTIVE: Diabetic kidney disease (DKD) progression involves early proximal tubular injury, which precedes podocyte injury. The protective role of the protein Klotho in DKD is well-documented, but its impact on early tu...
OBJECTIVE: Diabetic kidney disease (DKD) progression involves early proximal tubular injury, which precedes podocyte injury. The protective role of the protein Klotho in DKD is well-documented, but its impact on early tubular injury and mitochondrial dysfunction in proximal tubule epithelial cells (PTECs) remains underexplored. This study aimed to determine whether Klotho alleviates DKD by targeting mitochondrial dysfunction in PTECs and to uncover the molecular mechanisms involved. METHODS: The role of Klotho was investigated using human kidney biopsies from patients at different DKD stages and a diabetic mouse model (induced by high-fat diet and streptozotocin). In vivo and in vitro techniques, including immunofluorescence, Western blot, transmission electron microscopy, and single-cell RNA sequencing, were used to assess tubular injury, mitochondrial integrity, and key protein interactions. The function of a newly identified protein, CYB5R4, was validated using knockdown and overexpression approaches in mouse models and human kidney (HK-2) cells. RESULTS: Our results reveal a novel molecular pathway where Klotho alleviates early tubular injury in DKD by targeting the mitochondrial protein CYB5R4. We demonstrate that CYB5R4 is critically downregulated in DKD and that its restoration is both necessary and sufficient for Klotho's protective effect on mitochondrial function in PTECs. This regulation follows a defined signaling cascade where Klotho suppresses PKCα, which in turn inhibits the transcription factor ETS1. This inhibition of ETS1 leads to the de-repression of the CYB5R4 promoter, ultimately reducing tubular apoptosis and injury. This CYB5R4-dependent mechanism positions CYB5R4 as a key therapeutic target. CONCLUSION: Our findings uncover a novel Klotho/PKCα/ETS1/CYB5R4 signaling axis in PTECs that restores mitochondrial function and mitigates DKD progression, offering a promising therapeutic target for managing DKD.
Multiblock proteomic profiling identifies novel biomarkers linking prediabetes with preclinical atherosclerosis in apparently healthy adults.
Zieleniewska N, Jamiołkowski J, Kondraciuk M … +4 more , Chlabicz M, Duabtówka M, Kowalska I, Kamiński K
Cardiovasc Diabetol · 2026 Mar · PMID 41904484 · Full text
BACKGROUND: Preclinical atherosclerosis and prediabetes are key targets of preventive medicine as their prevalence rises. Therefore, it is crucial to identify early processes and limit confounders such as lipid-lowering...
BACKGROUND: Preclinical atherosclerosis and prediabetes are key targets of preventive medicine as their prevalence rises. Therefore, it is crucial to identify early processes and limit confounders such as lipid-lowering or antidiabetic therapy and advanced atherosclerosis. Proteomics enables the identification of biomarkers and molecular pathways related to atherogenesis in prediabetes. PURPOSE: To investigate the relationship between prediabetes and preclinical atherosclerosis in apparently healthy individuals using a comprehensive proteomic approach. METHODS: This cross-sectional, population-based study included 389 participants (mean age 49 ± 10 years; 47% males) from the Białystok PLUS cohort in Poland. Individuals with known diabetes, major cardiovascular, inflammatory, or malignant diseases, or those receiving steroidal or lipid-lowering therapy were excluded. Carotid ultrasound was used to assess preclinical atherosclerosis, and prediabetes was defined as impaired fasting glucose, impaired glucose tolerance, or HbA1c 5.7–6.4%. Proteomic profiling was performed using the Olink® Reveal platform, enabling deep profiling of 1050 proteins with the Proximity Extension Assay and next-generation sequencing readout, yielding log2-scaled NPX (Normalized Protein eXpression) values. In preliminary analyses, we identified proteins associated with prediabetes and then linked them to early atherosclerotic lesions. RESULTS: A block-sPLS-DA model integrating clinical and proteomic data revealed clear separation between participants with and without prediabetes. The clinical block comprised eight variables reflecting cardiometabolic status, whereas the proteomic block retained 45 proteins across two components. The heatmap shows pairwise Pearson correlations between selected serum proteins and clinical variables (Fig. 1). Vascular and age measures cluster together and share correlation patterns distinct from those of BMI and glycaemic parameters. A protein module including the ectodysplasin A2 receptor (EDA2R) and leiomodin 1 (LMOD1) correlates positively with age and vascular parameters, and inversely with GFR and HDL-C. Multivariable linear regression analyses were performed with selected vascular parameters as dependent variables and clinical covariates, together with proteins identified in Component 2, which are weakly related to clinical parameters and thus may represent novel biomarkers associated with prediabetes (Fig. 2). Expression of EDA2R (B = 0.05; P = 0.001), C16orf89 (B = 0.05; P = 0.001), and LMOD1 (B = 0.039; P = 0.016) was associated with increased IMT. Functional enrichment analysis of selected proteins revealed significant overrepresentation of proteins associated with synapse maturation. CONCLUSION: An integrative block-sPLS-DA approach separated individuals with prediabetes from those without and revealed a proteomic signature independent of clinical covariates. Within this signature, the expression of LMOD1, EDA2R, and C16orf89 showed robust associations with atherosclerosis-related vascular traits. Enrichment analyses highlighted proteins involved in neuronal processes as candidate pathways linking early glucose disturbances with preclinical atherosclerosis.
Dapagliflozin-induced integrated improvements in left ventricular diastole, endothelial function, and arterial load: a randomized clinical trial.
Kimura-Medorima ST, Oliveira DC, Breder I … +13 more , Wolf VLW, Soares AAS, Barreto J, Munhoz DB, Cunha JS, Bonilha I, de Carvalho LSF, Coelho-Filho OR, Matos-Souza JR, Moura FA, Nadruz W, Quinaglia T, Sposito AC
Cardiovasc Diabetol · 2026 Mar · PMID 41888924 · Full text
BACKGROUND: Dapagliflozin has been shown in preclinical and clinical settings to improve arterial function and left ventricular (LV) diastolic performance, yet the interrelationship between these effects has not been est...
BACKGROUND: Dapagliflozin has been shown in preclinical and clinical settings to improve arterial function and left ventricular (LV) diastolic performance, yet the interrelationship between these effects has not been established. OBJECTIVE: To determine whether improvements in endothelial function accompany-and relate to-early changes in LV diastolic function after short-term dapagliflozin in type 2 diabetes (T2D). METHODS: We conducted a prespecified secondary analysis of a prospective, open-label, active-controlled trial of patients with T2D on background metformin that were randomized to daily dapagliflozin 10 mg or glibenclamide 5 mg for 12 weeks. All patients underwent echocardiographic and endothelial function assessments at baseline and 12 weeks. The primary endpoint for echocardiographic diastolic parameters was the change in E/e'. Endpoints for endothelial function were change in brachial artery flow-mediated dilation (FMD) and nitric oxide (NO) bioavailability. Arterial load comprises arterial impedance, measured as the brachial artery resistivity index, and the afterload components, the systemic vascular resistance and the ventriculo-arterial coupling index, as a marker of arterial stiffness. RESULTS: Among 96 patients (mean age 59 years; 40% female; baseline HbA1c 7.8%; 75% at intermediate risk H2FPEF score), glycemic control improved similarly in both groups (median [IQR] HbA1c change: -0.78 [0.11]% vs. -0.80 [0.10]%; between-group p = 0.887). Dapagliflozin reduced the E/e' ratio (mean change - 0.38 [0.24]; within-group p = 0.184), whereas glibenclamide increased (+ 0.79 [0.24]; p = 0.001), resulting in a significant between-group difference of - 1.17 (0.34; p = 0.001). Dapagliflozin treatment was associated with a 67% lower likelihood of being in a higher E/e' quartile (OR 0.325; 95% CI 0.147-0.715; p = 0.005). In the pooled cohort, changes in E/e' correlated directly with changes in brachial resistive index (r = 0.28; p = 0.005) and inversely with changes in NO bioavailability (r = - 0.26; p = 0.010) and FMD (r = - 0.23; p = 0.023). No significant correlations were observed for systemic vascular resistance or ventricle-arterial coupling. CONCLUSIONS: In patients with T2D at intermediate risk for HFpEF, dapagliflozin was associated with more favorable changes in left ventricular diastolic function parameters compared with glibenclamide, accompanied by improvements in endothelial function and reductions in arterial impedance. These observations support the hypothesis of a vascular-myocardial pathway through which SGLT2 inhibition may exert cardioprotective effects in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02919345.
Associations of triglyceride-glucose-related composite obesity indices with cardiovascular diseases and mortality: a systematic review and meta-analysis.
Liu H, Guo F, Fu H … +6 more , Xu X, Wang Z, Kang J, Feng J, Shen Y, Liu W
Cardiovasc Diabetol · 2026 Mar · PMID 41888845 · Full text
BACKGROUND: The triglyceride-glucose (TyG) index is a surrogate marker of insulin resistance. TyG-based composite adiposity indices (e.g., TyG-WHtR and TyG-WC) have been used for cardiovascular risk assessment. However,...
BACKGROUND: The triglyceride-glucose (TyG) index is a surrogate marker of insulin resistance. TyG-based composite adiposity indices (e.g., TyG-WHtR and TyG-WC) have been used for cardiovascular risk assessment. However, the evidence has not been systematically synthesized, and differences in risk increments across indices, as well as their dose-response relationships, remain unclear. METHODS: We searched PubMed, EMBASE, and Web of Science through October 8, 2025, for observational studies evaluating associations of TyG-based composite adiposity indices (TyG-BMI, TyG-WC, TyG-WHtR, TyG-ABSI, and TyG-BRI) with major cardiovascular and mortality outcomes. Random-effects models were used to pool effect estimates from continuous analyses (per 1-SD increase) and categorical comparisons (highest vs lowest quantile). Within each outcome, we additionally synthesized between-index differences in risk increments. In addition, we conducted linear and non-linear dose-response meta-analyses for the primary outcomes. Subgroup and sensitivity analyses were performed to explore heterogeneity and robustness, and publication bias was assessed using Egger's regression test. RESULTS: A total of 85 studies were included (15 cross-sectional and 70 cohort studies). In continuous analyses, per 1-SD increase, cardiovascular disease (CVD) risk increased by 17%, 20%, and 19% for TyG-BMI, TyG-WC, and TyG-WHtR, respectively (28 studies), whereas TyG-BRI was not significantly associated with CVD. For stroke (19 studies), the corresponding increases were 18%, 18%, 37%, and 17% for TyG-BMI, TyG-WC, TyG-WHtR, and TyG-BRI, respectively. For coronary artery disease (CAD) (11 studies), risk increased by 17%, 18%, and 22% per 1-SD for TyG-BMI, TyG-WC, and TyG-WHtR, respectively. For mortality outcomes, per 1-SD increase, cardiovascular mortality increased by 22%, 24%, 32%, and 31% for TyG-BMI, TyG-WC, TyG-WHtR, and TyG-ABSI (24 studies), and all-cause mortality increased by 5%, 18%, 21%, and 23% (37 studies). In categorical analyses, the highest vs lowest quantile was associated with higher risk for most indices, except that TyG-BMI was not significantly associated with all-cause mortality. Between-index comparisons suggested slightly greater risk increments for TyG-WHtR and TyG-WC than for TyG-BMI for some outcomes. Dose-response analyses further indicated non-linear increasing associations of TyG-BMI, TyG-WC, and TyG-WHtR with incident CVD and cardiovascular mortality, whereas TyG-BMI showed a U-shaped association with all-cause mortality. TyG-BRI was linearly associated with CVD, and TyG-ABSI was linearly associated with cardiovascular mortality. Region, population type, and sample size were potential sources of heterogeneity. CONCLUSIONS: TyG-based composite obesity indices are associated with various cardiovascular outcomes and mortality risk, suggesting they may serve as a supplement to traditional risk assessment for risk stratification and early identification in primary prevention. Future multicenter prospective studies are still needed to further validate their causal associations and generalizability across diverse populations.
The joint association of the combined triglyceride-glucose index and atherogenic index of plasma with hypertension on stroke risk across different glycemic status: a prospective cohort study.
Zou X, Zhou C, Zhou R … +7 more , Zhu T, Zhao J, Qing W, Xie J, Yu R, Zhang F, Li J
Cardiovasc Diabetol · 2026 Mar · PMID 41888823 · Full text
BACKGROUND: The triglyceride-glucose index (TyG) and the atherogenic index of plasma (AIP) are well-established indicators of insulin resistance and lipid metabolism, respectively, and both are associated with stroke ris...
BACKGROUND: The triglyceride-glucose index (TyG) and the atherogenic index of plasma (AIP) are well-established indicators of insulin resistance and lipid metabolism, respectively, and both are associated with stroke risk. However, the joint impact of TyG and AIP-expressed as their product (TyG-AIP)-and its longitudinal trajectory on stroke risk have not been investigated. Moreover, it remains unclear whether TyG-AIP interacts synergistically with hypertension to improve stroke risk prediction. METHODS: This prospective cohort study included 5786 participants, categorized into dysglycemia (PDM, n = 3,490) and normoglycemia (NDM, n = 2,296) groups. TyG-AIP was calculated as the product of TyG and AIP. K-means clustering was applied to identify distinct patterns of TyG-AIP change between the two measurement points. Multivariable Cox proportional hazards models, restricted cubic splines, and receiver operating characteristic (ROC) analyses evaluated associations and predictive performance. RESULTS: Over 8 years of follow-up, 460 incident stroke cases occurred. Higher TyG-AIP levels were independently associated with an increased risk of stroke (per SD increase: HR = 1.35, 95% CI 1.21-1.51; P < 0.001), with a stronger effect among those with dysglycemia (HR = 1.54, 95% CI 1.21-1.95; P < 0.001). A nonlinear association was observed (P for nonlinearity = 0.002). TyG-AIP synergistically interacted with hypertension, and individuals with both high TyG-AIP and hypertension had the greatest risk (HR = 2.89, 95% CI 2.22-3.76). The "high-and-declining" TyG-AIP trajectory conferred the highest stroke risk in the PDM group (HR = 2.26, 95% CI 1.62-3.15; P < 0.001). ROC analysis showed that a model combining TyG-AIP with hypertension (AUC = 0.643) provided improved discrimination compared to hypertension alone (AUC = 0.571). CONCLUSIONS: TyG-AIP is associated with increased stroke risk, particularly in dysglycemic individuals, and exhibits joint effects with hypertension. The integration of TyG-AIP assessment with hypertension status enhances risk stratification, supporting comprehensive management of both metabolic and hemodynamic factors in stroke prevention.
Circulating amino acids and Type 2 diabetes in a Latin American population-based cohort.
Huidobro L, Cofre S, Santos JL … +8 more , Godoy F, Paredes F, Bambs C, Cortés S, Connolly J, Qu HQ, Hakonarson H, Ferreccio C
Cardiovasc Diabetol · 2026 Mar · PMID 41888767 · Full text
BACKGROUND AND AIMS: Metabolomics enables the identification of circulating biomarkers for Type 2 diabetes (T2D). Most studies of circulating amino acids and T2D are from European and Asian, few from Latin America. We ai...
BACKGROUND AND AIMS: Metabolomics enables the identification of circulating biomarkers for Type 2 diabetes (T2D). Most studies of circulating amino acids and T2D are from European and Asian, few from Latin America. We aimed to evaluate plasma amino acids and risk of T2D in an agricultural population from Molina County, Central Chile. METHODS: MAUCO is a population-based prospective cohort of 9462 participants aged 38 to 74 years at enrollment in 2014. From 2000 participants (47% women) selected for metabolomic analysis 1738 had enough serum sample for this study. We quantified circulating branched-chain amino acids (BCAAs), as well as phenylalanine, tyrosine, alanine, glutamine, glycine, and histidine using nuclear magnetic resonance, while T2D was diagnosed according to the American Diabetes Association guidelines at enrollment and follow-up. We analyzed the association of the circulating amino acids on T2D prevalence and incidence, using multiple logistic and Cox regression models adjusted by sex, age, education, body mass index, smoking, alcohol consumption, physical activity, and Mediterranean diet score. RESULTS: In the cross-sectional analysis, plasma BCAAs (aOR 2.1; 95% CI 1.80-2.50), and plasma alanine (aOR 1.57; 95% CI 1.37-1.80) were associated with T2D, while histidine, glycine, and glutamine were inversely associated with T2D risk (aOR 0.80; 95% CI 0.69-0.91; 0.68; 95% CI 0.57-0.80, and 0.64; 95% CI 0.56-0.74, respectively). After a median follow-up of 4.3 years, we diagnosed 127 (10.5% incidence) new T2D cases. Prevalence and incidence analysis yielded a similar pattern, but only high isoleucine reached statistical significance in the incidence of T2D (aHR 1.31; 95% CI 1.10-1.56). CONCLUSION: Elevated plasma BCAA concentrations in Chilean adults were significantly associated with the prevalence of T2D, while only high isoleucine was associated with the incidence of T2D. These findings could inform risk stratification by specific metabolic mechanisms and guide future research on targeted interventions.
Triglyceride-glucose index and mortality in critically ill patients with cardiovascular-kidney-metabolic syndrome stage 4.
Yin X, Han S, Zheng Z … +3 more , Tang L, Liu J, Zhang Y
Cardiovasc Diabetol · 2026 Mar · PMID 41877216 · Full text
The triglyceride-glucose (TyG) index is a well-established surrogate marker of insulin resistance (IR). Previous studies have linked higher TyG levels to an increased risk of cardiovascular events in individuals with ear...
The triglyceride-glucose (TyG) index is a well-established surrogate marker of insulin resistance (IR). Previous studies have linked higher TyG levels to an increased risk of cardiovascular events in individuals with early-stage (0-3) Cardiovascular-Kidney-Metabolic Syndrome (CKM). However, its prognostic value in critically ill patients with CKM stage 4 remains unclear. In this retrospective study, we analyzed clinical data from critically ill CKM stage 4 patients in the MIMIC-IV database. The TyG index was calculated and patients were categorized into tertiles. Cox proportional hazards models and restricted cubic spline (RCS) analyses were used to evaluate the association between the TyG index and all-cause mortality. A total of 3,125 patients were included, of whom 65.22% were male.= The 1-year all-cause mortality was 34.18% overall (28.79% in Q1, 35.06% in Q2, and 38.68% in Q3; P < 0.05). In multivariable Cox regression, each 1-standard deviation increase in the TyG index was associated with a 23% higher risk of 1-year mortality (HR = 1.23, 95% CI 1.09-1.39). Compared with the Q1 group, patients in Q3 had a 30% higher 1-year mortality risk (HR = 1.30, 95% CI 1.08-1.55). RCS analysis showed a linear positive relationship between the TyG index and mortality (P for non-linearity > 0.05). These findings indicate that higher TyG levels are independently associated with increased short- and long-term mortality in critically ill patients with CKM stage 4. The TyG index may provide a simple indicator of acute metabolic disturbances and could support early risk stratification in this population. However, its role in clinical decision-making and potential utility in guiding interventions require confirmation in prospective studies.
Dynamic association between triglyceride-glucose-body mass index and hospital mortality in critically ill patients with heart failure: a multicenter retrospective cohort study.
Liu S, Cai Y, Shi C … +2 more , Zhang T, Zeng Y
Cardiovasc Diabetol · 2026 Mar · PMID 41877141 · Full text
BACKGROUND: The triglyceride-glucose-body mass index (TYG-BMI) is a surrogate marker of insulin resistance associated with cardiovascular outcomes in stable populations. However, its physiological meaning in critically i...
BACKGROUND: The triglyceride-glucose-body mass index (TYG-BMI) is a surrogate marker of insulin resistance associated with cardiovascular outcomes in stable populations. However, its physiological meaning in critically ill patients-where glucose and triglyceride levels are influenced by acute stress, inflammation, and treatment-remains uncertain, and the dynamic relationship between TYG-BMI and mortality in critically ill heart failure (HF) patients has not been investigated. OBJECTIVES: To examine the association between TYG-BMI intensity, exposure duration, and hospital mortality in critically ill HF patients, and to evaluate the robustness of these associations through comprehensive sensitivity analyses. METHODS: This multicenter retrospective study analyzed data from MIMIC-III, MIMIC-IV, and eICU databases. Adult HF patients with daily TYG-BMI measurements during the 7 day observation period (day 0 through day 7) were included. Restricted cubic spline regression characterized the baseline dose-response relationship. Generalized additive models with tensor product smooth functions examined the three-dimensional TYG-BMI-time-mortality association. Weighted linear regression quantified temporal trends. Multiple sensitivity analyses addressed selection bias, time-varying confounding, treatment effect modification, and temporal heterogeneity. RESULTS: Among 5133 patients (pooled mortality: 27.9%), restricted cubic spline analysis confirmed a non-linear U-shaped dose-response relationship in MIMIC-IV (non-linear P < 0.001), with consistent directional patterns across MIMIC-III and eICU. Generalized additive models demonstrated a reproducible U-shaped association across all three databases. The optimal TYG-BMI range was 250-275 (OR = 0.76, 95% CI 0.68-0.85, P < 0.001 in MIMIC-IV), with each additional day within this range reducing mortality risk by 0.4% (P < 0.01). TYG-BMI > 425 was associated with progressively increased mortality (OR = 1.61, 95% CI 1.35-1.93 for the 425-450 range), with time-dependent risk amplification reaching 2.5% per day at the highest stratum. Combining TYG-BMI with the SOFA score significantly improved discriminative performance beyond SOFA alone (AUC: 0.780 versus 0.720, DeLong P < 0.001). All sensitivity analyses yielded consistent findings. CONCLUSIONS: TYG-BMI demonstrates a reproducible, U-shaped association with hospital mortality in critically ill HF patients. Both intensity and exposure duration contribute to risk stratification, though prospective validation is warranted given the observational design and uncertain physiological specificity of TYG-BMI in the ICU setting.
Ancestry-specific genetics of amino acids and microbiota-related metabolites reveal causal effects on cardiometabolic disease in Chinese populations.
Ding Y, Lin H, Yin Y … +47 more , Li M, Xu Y, Wang S, Xu M, Zheng J, Wang T, Zhao Z, He X, Liu R, Qiao H, Qin G, Qin Y, Tang X, Ye Z, Hu R, Shi L, Su Q, Yu X, Yan L, Wan Q, Chen G, Gao Z, Wang G, Shen F, Gu X, Luo Z, Chen L, Hou X, Huo Y, Li Q, Zhang Y, Zeng T, Liu C, Wang Y, Wu S, Yang T, Deng H, Li D, Lai S, Chen L, Zhao J, Mu Y, Ning G, Wang W, Bi Y, Lu J, 4C Study Group
Cardiovasc Diabetol · 2026 Mar · PMID 41877115 · Full text
BACKGROUND: The genetic architecture of circulating amino acids (AAs) and microbiota-related metabolites (MRMs) in relation to cardiometabolic disease remains poorly characterized in East Asian populations, limiting ance...
BACKGROUND: The genetic architecture of circulating amino acids (AAs) and microbiota-related metabolites (MRMs) in relation to cardiometabolic disease remains poorly characterized in East Asian populations, limiting ancestry-specific insights. METHODS: In a prospective cohort of 2953 Chinese individuals, we performed a large-scale genome-wide association study (GWAS) of 28 serum AAs and 22 MRMs. We conducted a cross-ancestry comparison of variant-metabolite associations. Using colocalization and Mendelian randomization (MR), we further investigated causal roles of 50 AAs and MRMs in 25 cardiometabolic diseases from the BioBank Japan. Furthermore, we explored differences in the genetic regulation of these metabolites between incident T2DM cases and healthy controls. RESULTS: We identified 33 metabolite-variant associations, 22 of which were previously unreported, and revealed several loci specific to East Asian ancestry. Integrative colocalization and MR analyses established 49 causal relationships between metabolite levels and cardiometabolic diseases, most notably implicating genetically predicted N-acetyltryptophan to increased risk of type 2 diabetes. Moreover, we observed distinct patterns of genetic regulation between T2DM cases and controls, highlighting substantial heterogeneity of effects and dynamic gene-disease interplay. CONCLUSIONS: These findings offer crucial insights into the ancestry-specific genetic determinants of metabolic traits, and shed new light on their causal roles in the etiology of cardiometabolic diseases in East Asian populations.
Reamputation risk and mortality after lower-limb amputation in patients with diabetes: predictors, effects of antidiabetic medications and temporal trends.
Radlinger B, Blasinger J, Köllenberger N … +9 more , Streitberger V, Kopp L, Bifano E, Landolfo M, Aziz F, Sourij H, Göbel G, Klocker J, Kaser S
Cardiovasc Diabetol · 2026 Mar · PMID 41872915 · Full text
BACKGROUND: Diabetes is associated with a high incidence of diabetic foot and peripheral artery disease and with markedly increased lifetime amputation risk. Here we investigated predictors of reamputation risk and morta...
BACKGROUND: Diabetes is associated with a high incidence of diabetic foot and peripheral artery disease and with markedly increased lifetime amputation risk. Here we investigated predictors of reamputation risk and mortality including antidiabetic medication in patients undergoing non-traumatic lower limb amputation (LLA). METHODS: In an observational longitudinal study, we analyzed 607 patients with diabetes and 500 patients without diabetes who underwent non-traumatic LLA between 2006 and 2022. The primary endpoint was reamputation-free survival. Predictors of subsequent amputations or mortality were analyzed using Cox regression and joint frailty models. RESULTS: Diabetes was independently associated with increased combined reamputation and mortality risk (HR 1.28, 95% CI [1.08, 1.52], p = 0.004). Reduced reamputation-free survival in patients with diabetes was triggered by a marked higher reamputation risk. Higher HbA1c levels were associated with lower reamputation-free survival. Older age, presence of atrial fibrillation and chronic kidney disease were associated with increased reamputation risk in patients with diabetes. Metformin usage in patients with type 2 diabetes was associated with a marked reduction in combined risk of reamputation and mortality (HR 0.59, 95% CI [0.43, 0.81] p = 0.001). While overall sodium-glucose transporter 2 inhibitor (SGLT2i) usage was low in this cohort, it was associated with an increased reamputation risk (HR 2.00, 95% CI [1.47, 2.72], p > 0.001) although safe with respect to mortality. Over time, reamputation risk peaked between 2020 and 2022, whereas mortality declined compared with the period from 2006 to 2010 in patients with diabetes. CONCLUSION: Diabetes remains to be associated with reduced reamputation-free survival; an association that is independent of increased prevalence of comorbidities in our data. Although reamputation risk has increased in recent years, overall survival has improved in patients with diabetes. Metformin usage is associated with improved reamputation-free survival while our limited data suggest increased risk of reamputation but safety with respect to mortality in patients treated with SGLT2i. Further studies are warranted to evaluate the effect of SGLT2i therapy on outcome in patients undergoing LLA.
Advances in the differentiation of induced pluripotent stem cells into vascular cells for the treatment of diabetic microvascular disease.
Wang S, Zhong H, Wu Y … +6 more , Zhang Y, Sha A, Zhu Z, Fang X, Bao M, Sun D
Cardiovasc Diabetol · 2026 Mar · PMID 41872879 · Full text
The core pathological mechanisms of diabetic microvascular diseases, such as nephropathy, diabetic retinopathy (DR), and neuropathy, involve the dysfunction and loss of microvascular endothelial cells (ECs), vascular smo...
The core pathological mechanisms of diabetic microvascular diseases, such as nephropathy, diabetic retinopathy (DR), and neuropathy, involve the dysfunction and loss of microvascular endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and pericytes (PCs). Conventional therapeutic approaches struggle to achieve structural repair and functional regeneration of damaged vessels. Induced pluripotent stem cell (iPSC) technology offers revolutionary prospects for an autologous, limitless source of functional vascular cells, significantly advancing regenerative medicine in the field of diabetic vascular complications. This review systematically summarizes recent developments in differentiating iPSCs into key microvascular cell types. Combined with advanced co-culture, three-dimensional (3D) modeling, organoids, and microfluidic chip technologies, these developments have not only deepened our understanding of diabetic microvascular pathology but also demonstrated substantial clinical potential in cell transplantation therapies, vascular tissue engineering constructs, and personalized drug screening.
Metabolic rewiring through succinate-GPR91 signaling: a fresh perspective on HFpEF energetics.
Telesca M, Masciovecchio V, Costantino S
Cardiovasc Diabetol · 2026 Mar · PMID 41872865 · Full text
Succinate has recently emerged as a signaling metabolite that extends beyond its canonical role in the tricarboxylic acid (TCA) cycle to influence cellular adaptation and stress responses. In their study, Jia et al. iden...
Succinate has recently emerged as a signaling metabolite that extends beyond its canonical role in the tricarboxylic acid (TCA) cycle to influence cellular adaptation and stress responses. In their study, Jia et al. identify the succinate-GPR91 axis as a key regulator of cardiomyocyte metabolic reprogramming and NAD homeostasis in heart failure with preserved ejection fraction (HFpEF). Their findings suggest that restoring succinate-GPR91 signaling enhances mitochondrial energetics, improves redox balance, and alleviates diastolic dysfunction. This commentary discusses the significance of these results in the broader context of cardiometabolic disease, highlighting the conceptual novelty of metabolic rewiring as a form of cardioprotection, while also addressing unresolved questions regarding tissue specificity, long-term signaling balance, and translational potential. In recent years, succinate has emerged as a multifaceted player not merely a tricarboxylic acid (TCA) cycle intermediate but also a stress‑responsive metabolite that conveys cellular metabolic state to neighbouring cells and distant tissues. It accumulates during ischemia, hypoxia, or mitochondrial dysfunction and can drive reverse electron transport at complex I, thereby increasing reactive oxygen species (ROS) production [1, 3]. This biochemical duality on the one hand enabling damaging ROS generation, and on the other acting extracellularly via the G protein-coupled receptor GPR91-raises a central question: is succinate-GPR91 signaling protective, maladaptive, or fundamentally context‑dependent? Demonstrating that succinate can act extracellularly through GPR91 to reprogram cardiac metabolism would recast it from a metabolic by‑product into a bona fide signaling molecule with therapeutic implications. In this issue, Jia et al. provide compelling evidence that the succinate-GPR91 axis functions as a molecular conduit linking mitochondrial metabolism to cardiomyocyte energy reprogramming, restoring NAD + and attenuating diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF).
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