Background: The ketogenic diet (KD) is widely recognized for its potential benefits in individuals with type 2 diabetes, but findings from both human and animal studies remain inconsistent. Type 2 diabetes is often comorbid with liver steatosis and atherosclerosis which are characterized by inflammation and dysregulated lipid metabolism. Moreover, whereas KD has shown mixed, sometimes detrimental, effects on circulating cholesterol levels in humans, it is currently unclear the whole-body balance of risk and benefit across hepatic, atherosclerotic, and pancreatic effects.
Methods: We used lean, diet-induced obese, and diet-induced obese, atherosclerotic (PCSK9 overexpression (OE)) mouse models to assess the impact of an extreme KD on cardiometabolic outcomes. Obese and PCSK9 OE mice received 10 weeks of cholesterol-supplemented HFD before 12 weeks of KD intervention whereas lean mice received KD, chow, or HFD for 12 weeks.
Results: KD intervention induced weight loss in obese female and PCSK9 OE male mice, but not male, wildtype mice. Across models, KD did not improve glucose tolerance or ex vivo insulin secretion, despite elevated levels of insulinotropic GLP-1 after glucose gavage. Pancreas lipids were similar between diet groups in obese mice, but liver steatosis or inflammation were generally improved in all models on KD. All KD groups had increased hepatic expression of genes for fatty acid oxidation, ketone body production, and ketone utilization. KD-intervened PCSK9 OE mice had lower circulating TNFα and chemokines (CCL2, CCL4, CXCL1, CXCL2) as well as smaller atherosclerotic lesion area relative to mice that continued on the HFD. The PCSK9 OE male mice on KD intervention also had reduced circulating LDL cholesterol but this effect was lost in mice with intact LDL receptor signaling, which also had fasting hypertriglyceridemia in line with HFD continuers.
Conclusions: This study demonstrates that, in mice, a high cholesterol KD can improve hepatic steatosis particularly when weight loss is achieved, compared to maintaining the western-style HFD. However, no improvements to insulin secretion and glucose tolerance were observed despite elevated post-glucose GLP-1 levels and long-term diminished requirements for insulin.
Objective: The atherogenic index of plasma (AIP) is a marker of atherosclerosis, while frailty reflects cumulative physiological decline. However, the combined impact of AIP-frailty index (AIP-FI) has not been adequately explored. This study aimed to investigate the association between AIP-FI and the risk of cardiovascular disease (CVD), stroke, and heart disease.
Methods: This prospective cohort study included 6896 participants aged ≥ 45 years from the China Health and Retirement Longitudinal Study (CHARLS) without CVD, stroke, or heart disease at baseline. The Cox proportional hazard models and restricted cubic spline (RCS) analysis were applied to explore the association between AIP-FI with the risk of CVD, stroke, and heart disease.
Results: During a median follow-up period of 9 years, 1648 (23.9%) of CVD events, 548 (7.9%) of stroke events, and 1280 (18.6%) of heart disease events were recorded. Cox regression analysis revealed that each 1-unit increment in the AIP-FI was significantly associated with higher risk of CVD (HR: 2.95, 95% CI 2.15, 4.05), stroke (HR: 3.14, 95% CI 1.88, 5.26), and heart disease (HR: 2.72, 95% CI 1.06, 1.89, 3.92). The RCS revealed a significant positive nonlinear relationship between AIP-FI with the risk of CVD, stroke, and heart disease (all P-overall < 0.05, and all P for non-linear < 0.05).
Conclusions: Our study demonstrated that higher AIP-FI was significantly associated with increased risk of CVD, stroke, and heart disease. By integrating metabolic and frailty information, AIP-FI offers an effective and accessible tool for cardiovascular risk assessment, supporting earlier prevention and intervention strategies in the middle-aged and elderly Chinese populations.
Background: Patients with type 2 diabetes have an increased risk of tachyarrhythmias and more frequently require implantable cardioverter defibrillators (ICD) than those without diabetes (No-DM). This study aims to investigate whether there is a difference in the indication, prognosis and complication rates for ICD-implantation between patients with and without type 2 diabetes in different ICD prevention groups.
Research design and methods: This Swedish retrospective cohort study included patients with de novo ICDs implanted between 2010 and 2021. Data from six national registries were analyzed to compare type 2 diabetes and No-DM patients regarding indications, complications, and outcomes (major adverse cardiovascular events [MACE], all-cause mortality). Subgroup analyses compared type 2 diabetes and No-DM by primary (PP) or secondary prevention (SP) ICD indication, and within the type 2 diabetes and No-DM groups (PP vs. SP).
Results: The study cohort consisted of 12,885 patients, including 2,843 with type 2 diabetes. Patients with diabetes had a mean age of 67.9 years and 85.4% were male, compared with 62.1 years and 78.1% among No-DM patients (both p < 0.0001). PP was more frequent in patients with type 2 diabetes (62.7%) than No-DM (54.4%, p < 0.0001). Ischemic heart disease was the most common etiology in both patients with/without type 2 diabetes (47.7% vs. 32.6%, p < 0.0001). Non-ischemic etiologies were more common in No-DM patients, e.g. dilated cardiomyopathy (15.3% vs. 17.5%, p = 0.007). Type 2 diabetes patients had a higher adjusted risk of all-cause mortality (Hazard ratio 1.95 [95% CI: 1.81-2.11]) and MACE (1.87 [1.71-2.05]), with a more pronounced risk in SP than PP. Infection rates were comparable between patients with type 2 diabetes and No-DM (1.1% vs. 1.3%).
Conclusions: Patients with type 2 diabetes more often received ICDs for PP and ischemic indications than No-DM patients and had a worse prognosis despite similar one-year infection risk. This likely reflects greater comorbidity burden and diabetes-specific factors, indicating the need for tailored risk management strategies beyond device implantation in patients with type 2 diabetes.
Background: Dapagliflozin (DAPA) has shown major nephroprotective effects, improving kidney metabolism and oxigenation. Lipidomics and metabolomics are powerful tools for understanding such effects, providing a comprehensive look at how SGLT2 inhibitors might change the metabolic landscape beyond their primary glucose-lowering action. We investigated changes in plasma metabolomic/lipidomic profile and urinary excretion of metabolites that could occur independent of increased diuresis.
Methods: A two-armed, parallel-design, randomized clinical trial was conducted in subjects with type 2 diabetes and hypertension who received treatment with DAPA 10 mg/day or hydrochlorothiazide 12.5 mg/day for four weeks. Lipidomics and metabolomics were performed by high resolution mass spectrometry in fasting plasma and 24-hour urine samples collected before and after treatment.
Results: Compared to hydrochlorothiazide, DAPA significantly increased plasma isoleucine, methionine, citrate, β-hydroxybutyrate and decreased lactate. DAPA induced plasma lipid remodeling towards a significant raise in free fatty acids (FFAs) and some sphingomyelins and lysophosphatidylcholines containing these fatty acids. A significant change was observed in plasma medium- and short-chain acylcarnitines, positively correlated with changes in plasma FFAs and β-hydroxybutyrate. In addition, DAPA, but not hydrochlorothiazide, significantly increased 24-h urinary excretion of several amino-acids, lactate, TCA cycle metabolites, β-hydroxybutyrate and electrolytes, except for a decrease in malate excretion.
Conclusions: DAPA treatment has major effects on the plasma lipidomic and the urine metabolomic profiles, with significant increased renal excretion of several metabolites, especially amino-acids, independently of increased diuresis. These data offer insights into the complex metabolic pathways leading to kidney protection by SGLT2 inhibitors.
Clinical trial information: European Union Drug Regulating Authorities Clinical Trials No. 2015-004164-11.
Background: Current approaches to estimating the probability of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM) often fail to reflect the clinical complexity of the condition, as they tend to oversimplify it by neglecting its progressive nature, variability in glycemic control, and the influence of disease duration. The SCORE2-Diabetes (SCORE2-D) model was developed to offer a more nuanced cardiovascular risk estimate by incorporating continuous variables and individualized risk factor weighting. However, its correlation with the actual presence and severity of CAD in diabetic patients remains under-investigated.
Objective: This study aims to evaluate the association between SCORE2-D scores and CAD characteristics, as assessed by computed tomography coronary angiography (CCTA), in patients with T2DM and no prior coronary revascularization. Specifically, it investigates the relationship between SCORE2-D risk categories and the presence, morphology, and severity of coronary plaques.
Methods: A retrospective analysis was conducted on patients aged 40-69 with T2DM, no history of atherosclerotic cardiovascular disease, and no severe target organ damage, who underwent CCTA at a tertiary care center. Clinical data, SCORE2-D values, and imaging results were collected. Patients were stratified into SCORE2-D risk categories, and coronary findings were compared across groups.
Results: The study included 104 patients (mean age 60.9 years; mean SCORE2-D 12.2 ± 4.9). Higher SCORE2-D scores were significantly associated with the presence of coronary plaques. In the low-moderate risk group, calcified and non-calcified plaques were similarly distributed, while in the high-very high risk group, non-calcified (lipid-rich and mixed) plaques predominated, indicating potentially more vulnerable lesions. Proximal coronary segments, especially the left anterior descending artery, were most frequently involved. A progressive increase in plaque burden and stenosis severity was observed with rising SCORE2-D risk category. Patients at higher risk were more often referred for invasive coronary angiography.
Conclusions: Higher SCORE2-D scores correlate with greater CAD burden, more severe stenosis, and a predominance of high-risk plaque features in patients with T2DM. These findings suggest that SCORE2-D may be a valuable tool in refining cardiovascular risk stratification and guiding clinical decision-making in diabetic populations.
Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors, primarily used to treat type 2 diabetes, exhibit cardioprotective effects by improving myocardial energy metabolism, reducing oxidative stress, and modulating inflammation and fibrosis, which are critical in the context of acute myocardial infarction (AMI). Our research aims to explore the molecular mechanisms of SGLT2 inhibitors, with a focus on their influence on non-coding RNAs through sirtuins pathways, to identify novel biomarkers and therapeutic strategies for preventing heart failure following AMI.
Methods: We identified microRNAs (miRNAs) that play a role in sirtuin pathways in AMI. We validated the expressions of precisely selected miRNAs along with sirtuin gene expressions (SIRT1-7) in a total of 227 patients with samples from baseline and after 26-week of either placebo or empagliflozin treatment by qRT-PCR. We also performed SHAP analysis of clinical data and miRNAs target predictions and advanced enrichment analyses.
Results: Empagliflozin treatment significantly modulated sirtuin and miRNA expression, with higher SIRT6 (p < 0.001) and lower SIRT4 (p = 0.018) expression compared to placebo after 26 weeks.(p (p In contrast, patients in the placebo group showed a reduction in SIRT6 expression (p = 0.006). Patients were divided according to the change in LVEF (ΔLVEF) between baseline and 26-weeks, using a cut-off of 11%. This threshold was derived from the third quartile distribution in the empagliflozin group. Baseline SIRT2 and SIRT4 levels independently predicted a ΔLVEF < 11% improvement (AUC: 0.806 and 0.765, respectively; both p < 0.01), as did miR-182-5p and miR-302a-3p (AUC: 0.716 and 0.757; both p < 0.01). A combined biomarker panel including SIRT2, SIRT4, miR-182-5p, and miR-302a-3p demonstrated superior predictive accuracy for ΔLVEF < 11% after 26-weeks of empagliflozin treatment (cross-validated AUC: 0.890; 81% sensitivity; 90% specificity). This association remained significant after multivariate adjustment for age, sex, hypertension, BMI, and ezetimibe treatment (OR: 18.70; 95% CI: 5.78-60.49). Importantly, baseline NT-proBNP levels did not significantly predict an unfavorable outcome after 26-weeks of empagliflozin treatment.
Conclusion: Baseline levels of SIRT2, SIRT4, miR-182-5p, and miR-302a-3p were identified as predictors of ΔLVEF < 11% changes after 26-weeks of treatment, which suggests their potential for stratifying responders and non-responders to empagliflozin. The combined panel of these markers demonstrated the highest predictive accuracy, suggesting the epigenetic influence of SGLT2 inhibitors and the potential for genomic characterization in personalized treatment approaches.
Background: Epicardial adipose tissue (EAT) is linked to both Atrial fibrillation (AF) and metabolic syndrome (MetS). Whether EAT inflammation relates to AF type, recurrence after ablation, or MetS, is incompletely known, likewise if it can be measured by CT angiography.
Aim: To establish the link between (1) atrial EAT inflammatory composition and AF type, AF recurrence, and metabolic comorbidities. (2) EAT inflammation and EAT-volume or density.
Methods: Patients undergoing thoracoscopic ablation for advanced AF (that is, usually persistent, with enlarged left atria and previous failed ablations) with a cardiac CT-scan before and 6 months after surgery were enrolled. CT-EAT atrial volume and attenuation (density), were used for analyses. Patients' left atrial appendages (LAA + EAT) were excised during ablation and stained for adipocytes and different inflammatory cells.
Results: Among the 134 included patients, 113 had a LAA available for (immuno)histo-chemistry. Patients with persistent versus paroxysmal AF had more EAT neutrophils: 155[257] versus 63[106] cells/mm2, (p = 0.003), and less anti-inflammatory CD163 + macrophages: 126[134] versus 224[179], (p = 0.03). The AUC curve for differentiating persistent from paroxysmal AF through neutrophil-count was 0.75 (p value < 0.001, CI 0.63-0.87). EAT neutrophil-count related to CT-EAT-attenuation (multivariable analysis: expB 1.01, CI 1.00-1.02, (p = 0.04)). CT-EAT-attenuation distinguished persistent from paroxysmal AF: - 73.0 ± 4.6 versus - 75.3 ± 5.3HU, (p = 0.03). Patients with versus without recurrence had similar inflammatory cell counts, but larger adipocytes, multivariable analysis: ExpB 1.002, CI 1.00-1.003, (p = 0.02). Hypertensive and diabetic patients also had an increased adipocyte size.
Conclusion: Patients with persistent versus paroxysmal AF exhibited increased EAT neutrophils, which is reflected by CT-EAT-attenuation. Those with AF recurrence, hypertension and diabetes had adipocyte hypertrophy which may imply a common mechanism underlying these conditions.
Background: Type 2 diabetes mellitus (T2DM) increases the risk of cardiovascular disease (CVD), largely by alterations in the blood lipids and the metabolism of circulating lipoproteins (LPs). We studied whether the presence of additional risk factors, such as hypertension, or CVD itself, is associated with further alterations in the LP profiles in individuals with T2DM.
Methods: We performed LP profiling using 1H NMR spectroscopy and quantified 65 parameters in 393 healthy controls (HC) and in 390 T2DM patients with and without cardiovascular comorbidities. Univariate and multivariate analyses were used to assess alterations in LPs in diabetic patients.
Results: Triglycerides in all major LP classes, as well as particle numbers of very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) were increased in T2DM compared to HC. In contrast, particle numbers of low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were reduced, suggesting slower lipolytic conversion of IDL to LDL and impaired clearance of triglyceride-enriched HDL. Univariate and multivariate analyses converged in identifying distinct LP profiles associated with T2DM, while differences between patients with and without hypertension or CVD were minor, indicating that T2DM is the primary factor driving LP dysregulation. T2DM, with or without cardiovascular comorbidities, also causes differential disruption of the correlation structure among LPs.
Conclusions: T2DM is associated with major alterations in LP metabolism independent of hypertension or CVD. Thus, early lipid management in T2DM is important to mitigate CVD risk. Further research is needed to elucidate how T2DM progresses to CVD in relation to atherogenic LPs.
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