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Abstract Background Insulin resistance (IR) is the cornerstone of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD), pathophysiologically being the key link between MASLD, metabolic disorders, and cardiovascular (CV) diseases. There are no prospective studies comparing the predictive values of different markers of insulin resistance (IR) in identifying the presence of MASLD and the associated risk of cardiovascular events (CVEs). Methods Post hoc analysis of the prospective Plinio Study, involving dysmetabolic patients evaluated for the presence of MASLD. The IR markers considered were Homeostatic Model Assessment for IR (HOMA-IR), Triglycerides-Glycemia (TyG) index, Triglycerides to High-Density Lipoprotein Cholesterol ratio (TG/HDL-C), Lipid Accumulation Product (LAP) and Visceral Adiposity Index (VAI). Receiver operative characteristic (ROC) analyses were performed to find the optimal cut-offs of each IR marker for detecting MASLD and predicting CVEs in MASLD patients. Logistic and Cox multivariable regression analyses were performed, after dichotomizing the IR markers based on the optimal cut-offs, to assess the factors independently associated with MASLD and the risk of CVEs. Results The study included 772 patients (age 55.6 ± 12.1 years, 39.4% women), of whom 82.8% had MASLD. VAI (Area Under the Curve [AUC] 0.731), TyG Index (AUC 0.723), and TG/HDL-C ratio (AUC: 0.721) predicted MASLD but was greater with HOMA-IR (AUC: 0.792) and LAP (AUC: 0.787). After a median follow-up of 48.7 (25.4–75.8) months, 53 MASLD patients experienced CVEs (1.8%/year). TyG index (AUC: 0.630), LAP (AUC: 0.626), TG/HDL-C (AUC: 0.614), and VAI (AUC: 0.590) demonstrated comparable, modest predictive values in assessing the CVEs risk in MASLD patients. Conclusion In dysmetabolic patients HOMA-IR and LAP showed the best accuracy in detecting MASLD. The possible use of lipid-based IR markers in stratifying the CV risk in patients with MASLD needs further validation in larger cohorts.

The growing recognition of the public health impact of cognitive impairment and dementia has sparked a global initiative to identify risk factors and develop strategies to prevent or slow the progression of these cognitive disorders. Uric acid, the end product of the metabolism of purine nucleotides, has been reported as a key factor of many conditions potentially involved in cognitive dysfunction/dementia. In addition, some studies support the hypothesis that elevated uric acid levels could reduce the risk of Alzheimer’s disease, slow down the decline of cognition, and delay the progression of Alzheimer’s disease, while other evidence achieves opposite positions. These discrepancies might reflect a biological ambivalence for uric acid depending on a very complex interplay of factors that include its concentrations achieved in biological fluids, the nature, and concentration of free radicals, the presence and concentration of other antioxidant molecules, potentially responsible for bi-directional effects of uric acid on brain health/functioning. In this narrative review, we attempt to elucidate the influential role of uric acid metabolism in cognitive functioning by discussing pathophysiological mechanisms putatively involved, being well aware that none of them can be considered one-sided due to the complexity of the human organism.

Dementia is an age-related syndrome characterized by the progressive deterioration of cognition and capacity for independent living. Diabetes is often associated with cognitive decline and shares similar pathophysiological mechanisms with dementia, such as systemic inflammation, oxidative stress, insulin resistance, and advanced glycation end-products formation. Therefore, adequate diabetes management may reduce the risk of cognitive decline, especially in patients with other comorbidities and risk factors. The sodium glucose cotransporter inhibitors (SGLT2i) regulate renal glucose reabsorption by blocking the SGLT2 cotransporters located in the proximal tubules, causing glycosuria and intraglomerular pressure reduction. Their use helps to lower blood pressure by modifying sodium and water homeostasis; these drugs are also commonly used in the treatment of heart failure and chronic kidney disease, while recently, a potential neuroprotective role in the central nervous system has been suggested. The aim of our scoping review is to analyze current evidence about the potential neuroprotective effects of SGLT2i in adult patients. We performed a scoping literature review to evaluate the effect of SGLT2i on dementia, mild cognitive impairment (MCI) and Alzheimer’s disease incidence and progression. The screening process was performed through different searches on PubMed and EMBASE, evaluating original works published up to January 2024. In conclusion, the use of SGLT2i could be associated with a neuroprotective effect in patients with diabetes, reducing the incidence or the progression of MCI and dementia. Further prospective studies are needed to validate this hypothesis and to evaluate the effectiveness of this class of drugs in normal glycemic profile patients.

IntroductionThe Very Low-Calorie Ketogenic Diet (VLCKD) has emerged as a safe and effective intervention for the management of metabolic disease. Studies examining weight loss predictors are scarce and none has investigated such factors upon VLCKD treatment. Among the molecules involved in energy homeostasis and, more specifically, in metabolic changes induced by ketogenic diets, Fibroblast Growth Factor 21 (FGF21) is a hepatokine with physiology that is still unclear.MethodsWe evaluated the impact of a VLCKD on weight loss and metabolic parameters and assessed weight loss predictors, including FGF21. VLCKD is a severely restricted diet (

Sodium–glucose co-transporter-2 inhibitors or gliflozins, the newest anti-hyperglycemic class, induce cardioprotective benefits in patients with type 2 diabetes (T2D). As platelet activation and oxidative stress play a key role in atherothrombotic-related complications, we hypothesized that gliflozins might modulate oxidative stress, platelet activation and thrombus formation. We performed an interventional open-label single-arm before-after study in 32 T2D patients on top of their ongoing metformin therapy. The population was divided into two groups: treatment with GLP-1 receptor agonists (GLP-1RA, Group A) and gliflozins (Group B). Oxidative stress, platelet activation and thrombus growth were assessed before and after 15 days of treatment. Compared to the baseline, gliflozins treatment significantly decreased sNOX2-dp (−45.2%, p < 0.001), H2O2 production (−53.4%, p < 0.001), TxB2 (−33.1%, p < 0.001), sP-selectin (−49.3%, p < 0.001) and sCD40L levels (−62.3%, p < 0.001) as well as thrombus formation (−32%, p < 0.001), whereas it potentiated anti-oxidant power (HBA, +30.8%, p < 0.001). Moreover, a significant difference in oxidative stress, platelet activation and thrombus formation across groups A and B was found. In addition, an in vitro study on stimulated platelets treated with gliflozins (10–30 μM) showed a reduction in oxidative stress, platelet activation and thrombus growth. Our results showed that gliflozins have antiplatelet and antithrombic activity related to an NOX2 down-regulation, suggesting a new mechanism responsible for cardiovascular protection.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted in the liver, is a key regulator of cholesterol homeostasis inducing LDL receptors’ degradation. Beyond lipid metabolism, PCSK9 is involved in the development of atherosclerosis, promoting plaque formation in mice and human, impairing the integrity of endothelial monolayer and promoting the events that induce atherosclerosis disease progression. In addition, the PCSK9 ancillary role in the atherothrombosis process is widely debated. Indeed, recent evidence showed a regulatory effect of PCSK9 on redox system and platelet activation. In particular, the role of PCSK9 in the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2) system, of MAP-kinase cascades and of CD36 and LOX-1 downstream pathways, suggests that PCSK9 may be a significant cofactor in atherothrombosis development. This evidence suggests that the serum levels of PCSK9 could represent a new biomarker for the occurrence of cardiovascular events. Finally, other evidence showed that PCSK9 inhibitors, a novel pharmacological tool introduced in clinical practice in recent years, counteracted these phenomena. In this review, we summarize the evidence concerning the role of PCSK9 in promoting oxidative-stress-related atherothrombotic process.

The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in non-metabolic adults and children, but the genetic impact on NAFLD-CKD association is still a matter of debate. The aim of the study was to investigate the impact of PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and glucokinase regulatory protein (GCKR) gene variants rather than metabolic syndrome features on renal function in a large population of NAFLD patients. The present study is a post hoc analysis of the Plinio Study (ClinicalTrials.gov: NCT04036357). PNPLA3, TM6SF2, MBOAT7 and GCKR genes were analyzed by using real-time PCR with TaqMan probes. Glomerular filtration rate (GFR) was estimated with CKD-EPI. We analyzed 538 NAFLD; 47.2% had GFR < 90 mL/min/1.73 m2 while 5.9% had GFR < 60 mL/min/1.73 m2. The distribution of genotypes was superimposable according to GFR cut-offs. Results from the multivariable regression model did not show any correlation between genotypes and renal function. Conversely, metabolic syndrome was highly associated with GFR < 90 mL/min/1.73 m2 (odds ratio (OR): 1.58 [1.10–2.28]) and arterial hypertension with GFR < 60 mL/min/1.73 m2 (OR: 1.50 [1.05–2.14]). In conclusion, the association between NAFLD and CKD might be related to the shared metabolic risk factors rather than the genetic NAFLD background.

Nonalcoholic fatty liver disease (NAFLD) is associated with several extrahepatic manifestations such as cardiovascular disease and sleep apnea. Furthermore, NAFLD is reported to be associated with an increased risk of incident chronic kidney disease (CKD). Inflammation and oxidative stress are suggested to be the key factors involved in the inflammatory mechanisms and pathways linking NAFLD to CKD and are responsible for both the pathogenesis and the progression of CKD in NAFLD patients. This review aims to provide a more comprehensive overview of the association between CKD and NAFLD, also considering the effect of increasing severity of NAFLD. A PubMed search was conducted using the terms “non-alcoholic fatty liver disease AND kidney”. In total, 537 articles were retrieved in the last five years and 12 articles were included in the qualitative analysis. Our results showed that CKD developed more frequently in NAFLD patients compared to those without NAFLD. This association persisted after adjustment for traditional risk factors and according to the severity of NAFLD. Therefore, patients with NAFLD should be considered at high risk of CKD. Intensive multidisciplinary surveillance over time is needed, where hepatologists and nephrologists must act together for better and earlier treatment of NAFLD patients.

Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether CEC and CLC differ between metabolically- vs. genetically-determined NAFLD. Methods: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type PNPLA3 genotype (Group M), 10 patients with genetic NAFLD carrying M148M PNPLA3 genotype (Group G), and 10 controls PNPLA3 wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. Results: Compared with Group G, Group M showed reduced total CEC (−18.6%; p < 0.001) as well as that mediated by cholesterol transporters (−25.3% ABCA1; −16.3% ABCG1; −14.8% aqueous diffusion; all p < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (p < 0.001). Conclusions: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired.

Non-alcoholic fatty liver disease (NAFLD) is characterized by intra-hepatic fat accumulation and mechanisms involved in its pathogenesis are not fully explained. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with fatty liver. LAL activity (nmol/spot/h) was measured in 100 adult healthy subjects (HS) and in 240 NAFLD patients. A sub-analysis on 35 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) was performed. Median LAL activity was 1.15 (0.95–1.72) in HS. It was significantly reduced in NAFLD [0.78 (0.61–1.01), p

Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging form of chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to steatohepatitis, which may progress to cirrhosis, liver cancer, and liver mortality. Common metabolic diseases, which are well established cardiovascular risk factors, have been associated to NAFLD and cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. The pathogenesis of NAFLD appears multifactorial and many mechanisms have been proposed as possible causes of fatty liver infiltration. Management of fatty liver has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide. First-line management focuses on lifestyle modifications. Moderate weight reduction either by dietary restriction or by increased habitual physical activity is safe and highly recommended. Several therapeutic interventions have been proposed. These include insulin sensitizer agents, lipid lowering drugs, antioxidants such as vitamin E and supplementation of vitamin D3. However, therapeutic strategies have been largely empirical so far, and experimental trials have mostly been carried out in uncontrolled settings with small sample sizes. Metabolic conditions such as diabetes mellitus, obesity, hypertension and hyperlipidemia, should be strongly considered and a multidisciplinary approach should be personalized for individual patients. Treatment of co-morbidities should be regarded as of paramount importance in the management of these patients. The purpose of this review is to examine different approaches for the clinical management of non-alcoholic fatty liver disease.