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Oxidative stress (OS) is defined as a disturbance in the prooxidant-antioxidant balance of the cell, in favor of the former, which results in the antioxidant capacity of the cell to be overpowered. Excess reactive oxygen species (ROS) production is very harmful to cell constituents, especially proteins, lipids, and DNA, thus causing damage to the cell. Oxidative stress has been associated with a variety of pathologic conditions, including diabetes mellitus (DM), cancer, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and accelerated aging. Regarding DM specifically, previous experimental and clinical studies have pointed to the fact that oxidative stress probably plays a major role in the pathogenesis and development of diabetic complications. It is postulated that hyperglycemia induces free radicals and impairs endogenous antioxidant defense systems through several different mechanisms. In particular, hyperglycemia promotes the creation of advanced glycation end-products (AGEs), the activation of protein kinase C (PKC), and the hyperactivity of hexosamine and sorbitol pathways, leading to the development of insulin resistance, impaired insulin secretion, and endothelial dysfunction, by inducing excessive ROS production and OS. Furthermore, glucose variability has been associated with OS as well, and recent evidence suggests that also hypoglycemia may be playing an important role in favoring diabetic vascular complications through OS, inflammation, prothrombotic events, and endothelial dysfunction. The association of these diabetic parameters (i.e., hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress will be reviewed here.

Glucose levels in blood must be constantly maintained within a tight physiological range to sustain anabolism. Insulin regulates glucose homeostasis via its effects on glucose production from the liver and kidneys and glucose disposal in peripheral tissues (mainly skeletal muscle). Blood levels of glucose are regulated simultaneously by insulin-mediated rates of glucose production from the liver (and kidneys) and removal from muscle; adipose tissue is a key partner in this scenario, providing nonesterified fatty acids (NEFA) as an alternative fuel for skeletal muscle and liver when blood glucose levels are depleted. During sleep at night, the gradual development of insulin resistance, due to growth hormone and cortisol surges, ensures that blood glucose levels will be maintained within normal levels by: (a) switching from glucose to NEFA oxidation in muscle; (b) modulating glucose production from the liver/kidneys. After meals, several mechanisms (sequence/composition of meals, gastric emptying/intestinal glucose absorption, gastrointestinal hormones, hyperglycemia mass action effects, insulin/glucagon secretion/action, de novo lipogenesis and glucose disposal) operate in concert for optimal regulation of postprandial glucose fluctuations. The contribution of the liver in postprandial glucose homeostasis is critical. The liver is preferentially used to dispose over 50% of the ingested glucose and restrict the acute increases of glucose and insulin in the bloodstream after meals, thus protecting the circulation and tissues from the adverse effects of marked hyperglycemia and hyperinsulinemia.

Despite advances in technology, the overall management of type 1 diabetes mellitus (T1DM) remains suboptimal. The idea of restricting carbohydrate intake to decrease glycemic spikes and insulin requirements has been revisited in recent years. After impressive results in the fields of type 2 diabetes (T2DM) and epilepsy, low-carbohydrate (LCD) and ketogenic (KD) diets have gained renewed interest as a possible treatment option for T1DM. In this narrative review, we discuss the available data regarding LCDs and KDs in both the adult and pediatric populations. Research data is still scarce, as most studies are short-term and show considerable heterogeneity in dietary composition and patient outcomes. In general, carbohydrate restriction enhances glycemic control by reducing postprandial glucose excursions, improving time-in-range, and lowering HbA1c, with conflicting effects on other parameters such as lipid profile and body weight. Adverse effects such as hypoglycemia and diabetic ketoacidosis are rarely reported, although some concerns have been raised regarding growth in children. The correct implementation of these diets requires a multidisciplinary approach by highly specialized healthcare professionals, who will address the medical, social, and psychological concerns that a restrictive diet entails. Large-scale and long-term studies are needed to provide more robust data before carbohydrate restriction can be widely applied to patients with T1DM.

MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) is a growing global concern. Nutraceuticals offer an appealing approach by targeting key mechanisms, such as oxidative stress, inflammation, lipid metabolism, and insulin resistance. This narrative review examines the role of various nutraceuticals in MASLD treatment, including silymarin, vitamin E, omega-3, curcumin, berberine, and coenzyme Q10. Some of them show promising biochemical and metabolic changes, while others produce conflicting results due to relevant studies’ design and endpoints. To bridge the gap between research and reality, we summarize the data, create an interpretation heatmap, and develop a practical supplement guide. Regardless of their potential, nutraceuticals should be viewed as add-ons to lifestyle interventions rather than standalone treatments. Future research should focus on well-designed, long-term studies to prove efficacy, dosing, and combination strategies for personalized MASLD management.

The role of nutrition in the pathogenesis of cardiovascular disease has long been debated. The established notion of the deleterious effects of fat is recently under question, with numerous studies demonstrating the benefits of low-carbohydrate, high-fat diets in terms of obesity, diabetes, dyslipidemia, and metabolic derangement. Monounsaturated and polyunsaturated fatty acids, especially n-3 PUFAs (polyunsaturated fatty acids), are the types of fat that favor metabolic markers and are key components of the Mediterranean Diet, which is considered an ideal dietary pattern with great cardioprotective effects. Except for macronutrients, however, micronutrients like polyphenols, carotenoids, and vitamins act on molecular pathways that affect oxidative stress, endothelial function, and lipid and glucose homeostasis. In relation to these metabolic markers, the human gut microbiome is constantly revealed, with its composition being altered by even small dietary changes and different microbial populations being associated with adverse cardiovascular outcomes, thus becoming the target for potential new treatment interventions. This review aims to present the most recent data concerning different dietary patterns at both the macro- and micronutrient level and their association with atherosclerosis, obesity, and other risk factors for cardiovascular disease.

Background Randomized controlled clinical trials (RCT) have demonstrated varied efficacy of glucagon-like peptide-1 receptor (GLP-1R) agonists for cardiovascular outcomes. We sought to evaluate the efficacy and safety of GLP-1R agonists among patients with Type 2 diabetes mellitus (DM) for stroke prevention. Methods We conducted a systematic review and meta-analysis of RCTs reporting the following outcomes among patients with Type 2 DM treated with GLP-1R agonists (vs. placebo): nonfatal or fatal strokes, all-cause or cardiovascular mortality, myocardial infarction (MI) and major adverse cardiovascular events (MACE). The protocol of our systematic review and meta-analysis was registered to the PROSPERO database. We pooled odds ratios (OR) using random-effect models, and assessed the heterogeneity using Cochran Q and I 2 statistics. Results We identified 8 RCTs, comprising 56,251 patients. In comparison to placebo, GLP-1R agonists reduced nonfatal strokes (OR 0.84; 95% CI 0.76–0.94, p  = 0.002; I 2  = 0%) and all strokes (OR 0.84; 95% CI 0.75–0.93, p  = 0.001; I 2  = 0%) by 16%. Overall, GLP-1R agonists reduced MACE by 13% (OR 0.87; 95% CI 0.81–0.94, p  = 0.0003; I 2  = 42%), cardiovascular mortality by 12% (OR 0.88; 95% CI 0.81–0.95; p  = 0.002; I 2  = 0%) and all-cause mortality by 12% (OR 0.88; 95% CI 0.82–0.95, p  = 0.0007; I 2  = 15%). Additional analyses demonstrated that GLP-1R agonists reduced the risk of incident MACE (OR 0.86; 95% CI 0.80–0.92; p  < 0.0001; I 2  = 0%) among patients with prior history of MI or nonfatal strokes. Conclusions Among patients with type 2 DM, GLP-1R agonists are beneficial for primary stroke, MACE, and cardiovascular mortality prevention. Further RCTs are needed to evaluate their role for secondary stroke prevention.

Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes. Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population. Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke. Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71–0.89; p < 0.01; I2 = 0) and all-cause mortality (OR: 0.80; 95% CI: 0.70–0.92; p < 0.01; I2 = 0), while there was a trend toward lower cardiovascular-mortality (OR: 0.84; 95% CI: 0.71–1.01; p = 0.06; I2 = 0%) compared to placebo. Additionally, GLP-1 or GIP/GLP-1 RAs reduced the odds of MI (OR: 0.72; 95% CI: 0.61–0.86; p < 0.01; I2 = 0%) and nonfatal-MI (OR: 0.72; 95% CI: 0.61–0.85; p < 0.01; I2 = 0%); while no associations between antiobesity treatment and fatal-MI, stroke, nonfatal, or fatal stroke were uncovered. Conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and all-cause mortality in overweight or obese adults without diabetes. Additionally, GLP-1 RAs and GIP/GLP-1 RAs attenuate the risk of MI. Since data on stroke are still limited, future RCTs are warranted to evaluate the neuroprotective potential of these novel antiobesity agents. Trial registration: PROSPERO CRD42024515966.

Background Incretin-based therapies are used in the treatment of type 2 diabetes mellitus (T2DM) and obesity. We investigated the changes in arterial stiffness and left ventricular (LV) myocardial deformation after 6-month treatment with the GLP-1 analogue liraglutide in subjects with newly diagnosed T2DM. Methods We randomized 60 patients with newly diagnosed and treatment-naive T2DM to receive either liraglutide (n = 30) or metformin (n = 30) for 6 months. We measured at baseline and after 6-month treatment: (a) carotid-femoral pulse wave velocity (PWV) (b) LV longitudinal strain (GLS), and strain rate (GLSR), peak twisting (pTw), peak twisting velocity (pTwVel) and peak untwisting velocity (pUtwVel) using speckle tracking echocardiography. LV untwisting was calculated as the percentage difference between peak twisting and untwisting at MVO (%dpTw–Utw MVO ), at peak (%dpTw–Utw PEF ) and end of early LV diastolic filling (%dpTw–Utw EDF ) (c) Flow mediated dilatation (FMD) of the brachial artery and percentage difference of FMD (FMD%) (d) malondialdehyde (MDA), protein carbonyls (PCs) and NT-proBNP. Results After 6-months treatment, subjects that received liraglutide presented with a reduced PWV (11.8 ± 2.5 vs. 10.3 ± 3.3 m/s), MDA (0.92 [0.45–2.45] vs. 0.68 [0.43–2.08] nM/L) and NT-proBNP (p < 0.05) in parallel with an increase in GLS (− 15.4 ± 3 vs. − 16.6 ± 2.7), GLSR (0.77 ± 0.2 vs. 0.89 ± 0.2), pUtwVel (− 97 ± 49 vs. − 112 ± 52°, p < 0.05), %dpTw–Utw MVO (31 ± 10 vs. 40 ± 14), %dpTw–Utw PEF (43 ± 19 vs. 53 ± 22) and FMD% (8.9 ± 3 vs. 13.2 ± 6, p < 0.01). There were no statistically significant differences of the measured markers in subjects that received metformin except for an improvement in FMD. In all subjects, PCs levels at baseline were negatively related to the difference of GLS (r = − 0.53) post-treatment and the difference of MDA was associated with the difference of PWV (r = 0.52) (p < 0.05 for all associations) after 6-month treatment. Conclusions Six-month treatment with liraglutide improves arterial stiffness, LV myocardial strain, LV twisting and untwisting and NT-proBNP by reducing oxidative stress in subjects with newly diagnosed T2DM. ClinicalTrials.gov Identifier NCT03010683

Backround Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) has been associated with increased cardiovascular risk. The aim of this Randomized Double-blind clinical Trial was to evaluate the effects of coenzyme-Q10 supplementation in patients with MASLD in terms of endothelial, vascular and myocardial function. Methods Sixty patients with MASLD were randomized to receive daily 240 mg of coenzyme-Q10 or placebo. At baseline and at 6-months, the a)Perfused boundary region of sublingual vessels using the Sideview Darkfield imaging technique, b)pulse-wave-velocity, c)flow-mediated dilation of the brachial artery, d)left ventricular global longitudinal strain, e)coronary flow reserve of the left anterior descending coronary artery and f)controlled attenuation parameter for the quantification of liver steatosis were evaluated. Results Six months post-treatment, patients under coenzyme-Q10 showed reduced Perfused boundary region (2.18 ± 0.23vs.2.29 ± 0.18 μm), pulse-wave-velocity (9.5 ± 2vs.10.2 ± 2.3 m/s), controlled attenuation parameter (280.9 ± 33.4vs.304.8 ± 37.4dB/m), and increased flow-mediated dilation (6.1 ± 3.8vs.4.3 ± 2.8%), global longitudinal strain (-19.6 ± 1.6vs.-18.8 ± 1.9%) and coronary flow reserve (3.1 ± 0.4vs.2.8 ± 0.4) compared to baseline ( p  < 0.05). The placebo group exhibited no improvement during the 6-month follow-up period ( p  > 0.05). In patients under coenzyme-Q10, the reduction in controlled attenuation parameter score was positively related to the reduction in Perfused boundary region and pulse wave velocity and reversely related to the increase in coronary flow reserve and flow-mediated dilation ( p  < 0.05 for all relations). Conclusions Six-month treatment with high-dose coenzyme-Q10 reduces liver steatosis and improves endothelial, vascular and left ventricle myocardial function in patients with MASLD, demonstrating significant improvements in micro- and macro-vasculature function. Trial Registration NCT05941910

Background and Objectives: Diabetic retinopathy (DR) is a significant complication of Diabetes Mellitus. Several studies have indicated Lipoprotein (a) [Lp(a)] plays a role in atherosclerotic alterations. Materials and Methods: This meta-analysis/systematic review aims to investigate the connection between Lp(a) and DR. All relevant studies indexed in PubMed and Scopus from up to January 2025 were included. A total of 29 studies (7007 subjects) were included, and the results were synthesized according to the PRISMA Guidelines. The results are presented as standardized mean differences (SMDs) with 95% confidence intervals (CIs) derived using random effects models. Results: The mean age of the included subjects was 52.6 ± 9.4 years, with 52.5% being male. The primary analysis included 25 observational studies involving a total of 6291 subjects (2770 patients with DR vs. 3521 controls). Notably, Lp(a) levels were significantly higher in patients with DR compared to those in controls, with an SMD of 0.85 (95% CI: 0.48–1.22; p < 0.001, I2 = 98%). Interestingly, a secondary analysis of the patients with Proliferative Diabetic Retinopathy (PDR) and Non-Proliferative Diabetic Retinopathy (NPDR) yielded an SMD of 0.28 (95% CI: 0.09–0.47; p = 0.004, I2 = 97%) between the two compared groups. In this analysis, a total of 1066 patients (465 PDR patients vs. 601 NPDR patients) were included. Conclusions: Elevated Lp(a) levels may have a compelling relationship with the development and progression of DR based on the evidence analyzed.