Anifrolumab In Refractory Systemic Lupus Erythematosus: A Real-Life, Multicenter Study.

OBJECTIVE: To report the real-world experience on the use of ANI in refractory SLE. METHODS: Multicenter retrospective study involving 9 Italian SLE referral centers participating in a compassionate use program for the use of ANI in active adult SLE patients in whom all the available treatment choices failed, were not tolerated or contraindicated.At baseline, at 1, 3, 6, 9 and 12 months of treatment, overall and organ specific disease activity, flares, daily glucocorticoid (GC) dose, and adverse events were recorded. RESULTS: A total of 26 patients were enrolled. At 4 weeks after starting ANI, a significant decrease in SLEDAI-2K (p=0.005), SLEDAS (p=0.005) and PGA (p=0.001) was recorded, and the same trend was maintained over time. A significant reduction in CLASI-activity (p<0.001) and in tender (p=0.026) and swollen (p=0.017) joint count was also recorded. At 3 months of follow-up, 33% of patients already achieved a remission state, while 46% were in LLDAS; at 6 months, 50% were in remission and 80% in LLDAS. A significant reduction in the mean GC daily dose was observed, starting from week 4 (p=0.04). A total of 4 disease flares according to the SELENA-SLEDAI Flare Index were recorded (three mild-moderate and one severe). Overall, 4 out of 20 patients with at least 24 weeks of follow-up (20%) were considered "non responders". CONCLUSION: This study provides a real-world experience on the use of ANI in refractory SLE patients, confirming its rapid effectiveness and an overall acceptable safety profile.

In-depth microbiological characterization of urine from subjects with type 2 diabetes.

CONTEXT: Lower urinary tract symptoms (LUTS) are common in type 2 diabetes (T2D), affecting quality of life and potentially leading to medication discontinuation. Among various factors contributing to LUTS, recent observations suggest a critical role of the urinary microbiota. Research on urinary dysbiosis in T2D remains underexplored. OBJECTIVE: We conducted a pilot study to investigate differences in the urinary microbiota between T2D patients and healthy individuals and its potential indirect association with LUTS risk. METHODS: This case-control study included 50 patients with T2D and no LUTS, and 25 healthy controls. Microbial DNAs were extracted from urinary sediments and bacterial populations quantified by Real-Time qPCR and qualitatively investigated by 16S rRNA gene sequencing. Validation experiments with Digital PCR were also performed. RESULTS: In T2D patients a higher total bacterial load and an increased abundance of Bacillota were found. After stratification by gender, these results were observed only in women. However, no significant quantitative differences were observed at the genus level. Alpha diversity analysis showed no significant differences between T2D and control groups, or by gender. At the species level, a substantial qualitative and often gender-dependent shift was present in T2D individuals. CONCLUSIONS: The urinary microbiome of subjects with T2D was found to be different from that of healthy controls. Specifically, T2D patients displayed higher total bacterial load and Bacillota levels, as well as qualitative changes in bacterial species. These changes suggested a dysbiotic condition of the urinary microbiota of T2D subjects, with some gender-related differences. Although causality cannot be inferred, these findings highlight the impact of T2D on the urinary microbiota and its potential relevance in developing LUTS and, from a broader perspective, metabolic abnormalities.

Neglected cardiometabolic risk factors and subclinical target organ damage in post-menopausal women with normal glucose tolerance.

BACKGROUND: Menopausal transition is a crucial step in the women's cardiovascular health, and the risk stratification in apparently health post-menopausal females has been rarely assessed. Heart ultrasonography, unusually performed in such subjects, would be able to detect initial signs of organ damage. We described the cardiovascular risk profile of non-diabetic post-menopausal women, evaluating how easily computed, biochemistry-derived scores were related to ultrasonographic measures of target organ damage. METHODS: We analyzed the characteristics of a cohort of two-hundred and seventy-three women consecutively referring to a prevention program of Azienda Ospedaliero-Universitaria Pisana (years 2017-2022) who underwent clinical evaluation, complete routine biochemical analyses with proxies of insulin resistance, heart and carotid ultrasonography. The cohort was further divided into four groups according to presence of isolated hypercholesterolemia (HC, 37%), isolated hypertension (HT, 5%), both HC/HT (38%), or none of them. RESULTS: In HC and HC/HT, LDL cholesterol was sharply above the recommended values (149 [134-171] mg/dL and 141 [123-159] mg/dL, respectively). E/e' ratio and left atrium size were augmented in HT women and further worsened in HT/HC, with an independent effect of hypertension (E/e' ß=0.055, P=0.013, left atrium volume ß=0.059, P=0.003). Presence of carotid plaques was independently linked to hypertension (ß=0.474, P=0.003). In HC and HC/HT, the Triglycerides-Glucose Index, a surrogate of insulin resistance, was higher than in the other classes (P=0.0013), and it was associated with E/A in HC and HT/HC, with a significative interaction (P=0.0004) with hypertension. Past hormone replacement therapy did not influence clinical, biochemical or echocardiographic parameters. CONCLUSIONS: Postmenopausal women display a high cardiovascular risk burden; a simple clinical and biochemistry screening would be advisable to identify and treat those more at risk. Cardiac ultrasonographic parameters were worse in hypertensive, hypercholesterolemic and insulin-resistant subjects, who may also deserve a deep and early instrumental characterization, especially when these conditions are associated.

Exploring relief for Behçet's disease refractory oral ulcers: a comparison of TNF inhibitors versus apremilast.

OBJECTIVES: Oral and genital ulcers are the hallmark manifestation of Behçet's disease (BD), significantly impacting patients' quality of life. Our study focuses on comparing the effectiveness and safety of TNF inhibitors (TNFis) and apremilast in controlling oral ulcers of BD, aiming to provide evidence-based guidance for physicians in selecting appropriate treatment modalities. METHODS: A retrospective analysis was performed on BD patients treated between December 2016 and December 2021 with TNFis or apremilast for refractory oral ulcers. The study assessed treatment response by the absence of oral ulcers at 3 and 6 months, with additional evaluations for genital ulcers and articular involvement. RESULTS: The study included 78 patients, equally allocated between TNFis and apremilast treatments. Both groups showed significant oral ulcer reduction at 3 (p< 0.001) and 6 months (p= 0.01) with no significant difference between the treatments. Apremilast had a notable corticosteroid-sparing effect by the 3-month follow-up, persisting through 6 months. Both treatments were equally effective in reducing genital ulcers, with TNFis showing greater effectiveness in addressing articular involvement. Apremilast had a higher discontinuation rate due to gastrointestinal side effects. CONCLUSION: TNFis and apremilast are both effective for treating BD refractory oral ulcers. While TNFis may offer broader benefits for other disease manifestations, apremilast is distinguished by its corticosteroid-sparing effect, especially for patients with a milder disease phenotype. Treatment selection should consider individual disease severity and clinical features to ensure a personalized and effective management strategy.

Canagliflozin on top of dual renin-angiotensin system blockade in a woman with partial acquired lipodystrophy, type 2 diabetes and severely proteinuric chronic kidney disease: a case report.

Sodium glucose cotransporter 2 inhibitors have proven strong efficacy in reducing end-stage renal disease in patients with type 2 diabetes. We are presenting here the case of a 40-year-old woman with acquired partial lipodystrophy, type 2 diabetes and essential hypertension complicated by chronic kidney disease and proteinuria in the nephrotic range. She first came to our attention in 2012; estimated glomerular filtration rate (eGFR) was 41.5 ml/min/1.73 m2 and total proteinuria was 375 mg/24h; she was treated with dual renin angiotensin system blocking. Proteinuria significantly increased during the following years, reaching a nephrotic range (>5 g/day). A kidney biopsy revealed a tubule-interstitial involvement compatible with type 2 diabetes. Leptin replacement therapy, started in 2018, improved glycaemic control and lipid profile, also determining a reduction in insulin total daily dose. In 2019, after the publication of the CREDENCE study, canagliflozin was started on top of losartan and ramipril. After an initial, expected eGFR drop, kidney function stabilized, and albuminuria significantly reduced (from 4120 to 984 mg/24h), while serum potassium showed only minimal increase. At last follow-up (2022) total proteinuria was still reducing (510 mg/24h), while kidney function was substantially unchanged (eGFR 40 ml/min/1.73 m2). This case report suggests that, despite not recommended in international guidelines, the use of SGLT2i in combination with dual renin angiotensin system blockade should be considered in specific conditions and under close clinical monitoring.

Empagliflozin and Renal Sodium-Hydrogen Exchange in Healthy Subjects.

CONTEXT: Sodium glucose co-transporter-2 inhibitors exert clinically relevant cardiorenal protection. Among several mechanisms, inhibition of sodium-hydrogen exchanger-3 (NHE3) in proximal renal tubules has been proposed in rodents. Demonstration of this mechanism with the associated electrolyte and metabolic changes in humans is lacking. OBJECTIVE: The present proof-of-concept study was designed to explore the involvement of NHE3 in modulating the response to sodium glucose co-transporter-2 inhibitors in humans. METHODS: Twenty healthy male volunteers received 2 tablets of empagliflozin 25 mg during a standardized hydration scheme; freshly voided urines and blood samples were collected at timed intervals for 8 hours. Protein expression of relevant transporters was examined in exfoliated tubular cells. RESULTS: Urine pH levels increased after empagliflozin (from 5.81 ± 0.5 to 6.16 ± 0.6 at 6 hours, P = .008) as did urinary output (from median, 1.7; interquartile range [IQR, 0.6; 2.5] to 2.5 [IQR, 1.7; 3.5] mL/min-1, P = .008) and glucose (from median, 0.03 [IQR, 0.02; 0.04] to 34.8 [IQR, 31.6; 40.2] %, P < .0001), and sodium fractional excretion rates (from median, 0.48 [IQR, 0.34; 0.65] to 0.71 [IQR, 0.55; 0.85] %, P = .0001), whereas plasma glucose and insulin concentrations decreased and plasma and urinary ketones increased. Nonsignificant changes in NHE3, phosphorylated NHE3, and membrane-associated protein 17 protein expression were detected in urinary exfoliated tubular cells. In a time-control study in 6 participants, neither urine pH nor plasma and urinary parameters changed. CONCLUSIONS: In healthy young volunteers, empagliflozin acutely increases urinary pH while inducing a substrate shift toward lipid utilization and ketogenesis, without significant changes in renal NHE3 protein expression.

The P2X7R-NLRP3 and AIM2 Inflammasome Platforms Mark the Complexity/Severity of Viral or Metabolic Liver Damage.

P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD/NASH associated with chronic HCV infection than those with metabolic damage only (p ≤ 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.

High exposure to phthalates is associated with HbA1c worsening in type 2 diabetes subjects with and without edentulism: a prospective pilot study.

BACKGROUND: Phthalates exposure and complete edentulism are related to both low socioeconomic status. No study by far has verified if and to what extent these two conditions are related. We aimed to explore their potential association and interplay in the metabolic control and cardiovascular risk profile. METHODS: In our small (n = 48) prospective pilot study twenty-four patients with type 2 diabetes (DnE) and twenty-four patients with type 2 diabetes and edentulism (DE) followed for 19 ± 2 months were treated according to best clinical standards. Phthalates' exposure was evaluated by urinary concentration of di-2-ethylhexylphthalate (DEHP), metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP). RESULTS: No association between phthalates and edentulism was found, nor did edentulism affect glucose control. Higher phthalates exposure was associated with a glycated haemoglobin worsening. This association was found for all the measured phthalates metabolites, both as a whole (DEHP; r = 0.33, p = 0.0209) and individually: MEHP (r = 0.41, p = 0.0033), MEHHP (r = 0.32, p = 0.028), MEOHP (r = 0.28, p = 0.0386). CONCLUSIONS: Phthalates are not associated with edentulism but predict the worsening of glucose control in subjects with type 2 diabetes. These findings might prove relevant in identifying novel biomarkers of cardiometabolic risk. Further studies are needed to validate our results and estimate the true potential of phthalates in terms of risk assessment.

Molecular Characterization of Peritoneal Involvement in Primary Colon and Ovary Neoplasm: The Possible Clinical Meaning of the P2X7 Receptor-Inflammasome Complex.

INTRODUCTION: Colon cancer (CC) and epithelial ovarian cancer (EOC) are common and severe neoplasms frequently sharing a massive inflammatory involvement of peritoneum. A detailed molecular characterization of such carcinomatosis has not been performed, so far. METHODS: Omental adipocytes were isolated from thirty-three adult women who underwent primary surgery for CC or EOC. Expression of several pro-inflammatory genes was determined by real-time PCR and immunofluorescence. Data were related to the clinical phenotype of the patients. RESULTS: CD68, FGFR1, and IL-6 were significantly more expressed in adipocytes from CC patients and VEGF in adipocytes from EOC. TNFα, TGFß, or MCP-1, as well as the pro-inflammatory platform P2X7R-NLRP3, did not differ between the 2 cancers. White blood cell count, mirroring systemic inflammation, was related to adipocyte P2X7R (R = 0.508, p = 0.003), NLRP3 (R = 0.405; p = 0.02), and MCP-1 (R = 0.448; p = 0.009). P2X7R and NLRP3 were the only inflammatory factors significantly more expressed in patients carrying both omental and peritoneal carcinosis, who were also characterized by a higher leukocytosis. None of the tested inflammatory markers was associated with tumor grading for both neoplasms; however, the presence of metastases was associated with a higher adipocyte expression of FGFR1 and TGFß. CONCLUSION: We show here that rarely measured molecules seem to specifically characterize omental carcinomatosis of CC or EOC, while more common inflammatory agents like TNFα, TGFß, or MCP-1 do not; the P2X7R-NLRP3 complex marks omental and peritoneal carcinosis and is related to circulating white blood cells and MCP-1, involved in monocyte-macrophage tissue infiltration; increased TGFß and FGFR1 characterize the tumoral dissemination.

Remdesivir, Renal Function and Short-Term Clinical Outcomes in Elderly COVID-19 Pneumonia Patients: A Single-Centre Study.

BACKGROUND: Remdesivir, an antiviral agent able to reduce inflammatory cascade accompanying severe, life-threatening pneumonia, became the first drug approved by the Food and Drug Administration for the treatment of hospitalized patients with coronavirus 2 related severe acute respiratory syndrome (SARS CoV2). As from its previously known clinical indications, the use of remdesivir in the presence of severe renal impairment is contraindicated; however, the impact of remdesivir on renal function in aging patients has not been elucidated. SUBJECTS AND METHODS: This retrospective observational study involved 109 individuals consecutively admitted in internal medicine section, Azienda Ospedaliero Universitaria Pisana hospital, in November-December 2020 due to a confirmed diagnosis of SARS CoV2 and receiving remdesivir according to international inclusion criteria. Biochemical variables at admission were evaluated, together with slopes of estimated glomerular filtration rate (eGFR) built during remdesivir treatment. Participants were followed until discharge or exitus. RESULTS: Patients were stratified according to age (80 formed the study cohort and 29 served as controls); CKD stage III was present in 46% of them. No patients showed any sign of deteriorated renal function during remdesivir. Fourteen patients in the elderly cohort deceased; their eGFR at baseline was significantly lower. Recovered patients were characterized by a relevant eGFR gaining during remdesivir treatment. CONCLUSION: We show here for the first time as remdesivir does not influence eGFR in a cohort of elderly people hospitalized for SARS CoV2, and that eGFR gain during such treatment is coupled with a better prognosis.

All-cause mortality prediction models in type 2 diabetes: applicability in the early stage of disease.

AIMS: The rate of all-cause mortality is twofold higher in type 2 diabetes than in the general population. Being able to identify patients with the highest risk from the very beginning of the disease would help tackle this burden. METHODS: We tested whether ENFORCE, an established prediction model of all-cause mortality in type 2 diabetes, performs well also in two independent samples of patients with early-stage disease prospectively followed up. RESULTS: ENFORCE's survival C-statistic was 0.81 (95%CI: 0.72-0.89) and 0.78 (95%CI: 0.68-0.87) in both samples. Calibration was also good. Very similar results were obtained with RECODe, an alternative prediction model of all-cause mortality in type 2 diabetes. CONCLUSIONS: In conclusion, our data show that two well-established prediction models of all-cause mortality in type 2 diabetes can also be successfully applied in the early stage of the disease, thus becoming powerful tools for educated and timely prevention strategies for high-risk patients.

P2X7 receptor/NLRP3 inflammasome complex and α-synuclein in peripheral blood mononuclear cells: a prospective study in neo-diagnosed, treatment-naïve Parkinson's disease.

BACKGROUND AND PURPOSE: Neuroinflammation and probably systemic inflammation, with abnormal α-synuclein deposition, participate in the development of Parkinson's disease (PD). The P2X7 receptor/NLRP3 inflammasome complex is upregulated in the brain of PD patients. By a prospective approach, the degree of systemic activation of such complex, and its regulatory mechanisms, were explored in treatment-naïve PD individuals. METHODS: The expression and functional activity of the inflammasome were measured in peripheral blood mononuclear cells of 25 newly diagnosed PD patients and 25 controls at baseline and after 12 months of pharmacological treatment, exploring the intracellular signalling involved and its epigenetic regulation. RESULTS: De novo PD patients were characterized by a systemic hyper-expression of the P2X7R/NLRP3 inflammasome platform, probably able to modulate lymphomonocyte α-synuclein, whose brain deposits represent the main pathogenetic factor of PD. A reduced c-Jun N-terminal kinase (JNK) phosphorylation might be the intracellular signalling mediating this effect. miR-7 and miR-30, implied in the pathogenesis of PD and in the post-transcriptional control of α-synuclein and NLRP3 expression, were also increased in PD. After 1 year of usual anti-Parkinson treatments, such inflammatory platform was significantly reduced. CONCLUSIONS: Mononuclear cells of newly diagnosed PD subjects display a hyper-expression of the P2X7R/NLRP3 inflammasome platform that seems to modulate cellular α-synuclein content and is reduced after PD treatment; an impaired JNK phosphorylation might be the intracellular signalling mediating this effect, undergoing an epigenetic regulation by miR-7 and miR-30.

Clinical and epigenetic determinants of edentulism in type 2 diabetic subjects referring to a tertiary center.

AIMS: Edentulism, extreme consequence of severe periodontitis, carries a high cardiovascular and all-cause death risk. The prevailing phenotype of edentulous patients with type 2 diabetes (T2D) has never been defined, neither it is known whether an epigenetic signature of such condition exists. METHODS: We collected clinical and biochemical data and administered a questionnaire on oral health in 248 consecutive T2D individuals. Vital status was checked after 17 ±â€¯7 months. miRNAs involved in periodontal inflammation were measured. RESULTS: Forty-seven patients (19%) were edentulous (ED), a higher prevalence than in the Italian general population (10.9% from ISTAT data). ED were older, with low level of instruction and higher fasting glucose vs not edentulous (noED). Participants displayed a scarce awareness of the association periodontitis-T2D. ED showed a specific epigenetic signature (lower miR214-5p and higher miR126-5p urinary levels). At the follow-up, metabolic profile similarly improved in ED and noED; death occurrence was similar. CONCLUSIONS: In this cohort of T2D, age is the only variable associated with edentulism; such condition displays an epigenetic signature, independent of the clinical phenotype; awareness of the clinical relevance and implications of periodontitis and edentulism are scarce. However, edentulism does not mark an increased rate of micro-macrovascular complications or mortality.

Normal Versus Slowly Processed Pasta and Post-Prandial Glucose Homeostasis in Healthy Subjects: A Pilot Study.

Nutritional science is gaining increasing attention due to the implicit potential to prevent cardio-metabolic diseases. It is also becoming clear that food-making process might influence the metabolic response to the meal. We have conducted a proof-of-concept study to investigate whether slowly processed pasta might positively impact glucose homeostasis. A total of 14 healthy male volunteers underwent two different mixed-meal tests in a randomized order. One meal was composed of 100 g of normally processed pasta and the other 100 g of slowly processed pasta. Each meal was completed with 10 g of olive oil and 10 g of parmesan cheese. Glucose, insulin, and incretin post-prandial responses were assessed at 15, 30, 60, 90, 120, 150, and 180 min. Glucose tolerance, insulin, and incretin response were unaffected by the two different pasta types. However, a slight difference was evident in the shape of the curve of post-prandial insulin (i.e., mildly delayed with the slowly processed pasta). Despite the common belief of a different impact of normally processed and slowly processed pasta on glucose metabolism, they show a superimposable post-prandial metabolic response after a single meal in male healthy individuals. Further studies are required to confirm these results also in chronic, real-life settings and then to translate them to metabolically impaired individuals.

Short-term impact of COVID-19 lockdown on metabolic control of patients with well-controlled type 2 diabetes: a single-centre observational study.

AIMS/HYPOTHESIS: The strict rules applied in Italy during the recent COVID-19 pandemic, with the prohibition to attend any regular outdoor activity, are likely to influence the degree of metabolic control in patients with type 2 diabetes. We explored such putative effect immediately after the resolution of lockdown rules, in the absence of any variation of pharmacologic treatment. METHODS: One-hundred and fourteen patients with adequate metabolic control took part in this single-centre, prospective, observational study. The metabolic profile tested 1 week after the end of the lockdown was compared with the last value and the mean of the last three determinations performed before the pandemic emergency (from 6 months to 2 years before). RESULTS: After 8 weeks of lockdown, an increase of HbA1c > 0.3% (mean +0.7%) was observed in 26% of the participants; these were also characterized by a persistent elevation in serum triglycerides able to predict the worsening of glucose control. CONCLUSIONS: Lockdown determined a relevant short-term metabolic worsening in approximately one-fourth of previously well-controlled type 2 diabetic individuals; pre-lockdown triglycerides were the only parameter able to predict such derangement of glucose control.

SGLT2 inhibitors and thiazide enhance excretion of DEHP toxic metabolites in subjects with type 2 diabetes: A randomized clinical trial.

OBJECTIVE: Phthalates are non-persistent pollutants related to impaired metabolism and high cardiovascular risk. Their toxic metabolites are eliminated through urine and feces. Prevention policies are considered by the governments, although no therapeutic strategy to facilitate their elimination from the human body has been proposed so far. Aim of the present study was to verify, for the first time in humans, whether diuretics might be able to enhance phthalates' toxic metabolites urinary output. DESIGN AND METHODS: We conducted a two-armed, parallel-design, randomized clinical trial. Thirty patients with type 2 diabetes and hypertension received a four week-treatment with Dapagliflozin 10 mg or Hydrochlorothiazide 12.5 mg. 24-hours urine were collected to measure urinary excretion of three major 2-ethylhexyl-phthalate (DEHP) metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP). RESULTS: 24-h urinary excretion of DEHP and MEHP was increased (+44%, p = 0.036; +49%, p = 0.0016) while MEOHP e MEHHP showed only a positive trend (+25%, p = 0.016; +36%, p = 0.062). Irrespective of the specific treatment, induced variations of daily urinary eliminations of MEHP metabolites were related with the 24-h urinary sodium (r = 0.42, p = 0.0226) and potassium (r = 0.54, p = 0.0026) excretion. Also, DEHP and MEOHP were related to sodium (r = 0·43, p = 0.0205; r = 0·44, p = 0.0168 respectively) but not to potassium. CONCLUSIONS: Urinary phthalates excretion seems to occur mainly through sodium- and potassium-related mechanisms, apparently independent from the different diuretic effect. Both thiazide diuretics and SLGT2 inhibitors are effective into the removal of phthalates metabolites from the human body, reducing the human tissues' exposure to their toxicity.

Protein and amino acids in nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: In this review, the latest evidence on the influence of dietary protein and plasma amino acids in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) is discussed. RECENT FINDINGS: Increasing protein consumption during weight loss and maintenance may help reduce liver fat content. Conversely, high protein intake characteristic of the unhealthy Western diet is associated with increased NAFLD prevalence and severity. Plasma concentration of several amino acids, including branched-chain (BCAA) and aromatic amino acids (AAA), is altered in NAFLD. Excess amino acid availability contributes to intrahepatic fat accumulation and may reflect poor dietary habits and dysregulation of amino acid metabolic processing in both liver and peripheral tissues. Specific amino acid patterns, characterized by increased BCAA, AAA, alanine, glutamate, lysine levels, and decreased glycine and serine levels, may be used for early detection of NAFLD and noninvasive assessment of its histological severity. SUMMARY: Mechanistic studies in NAFLD have been mostly focused on carbohydrate and fat metabolism, while little is known about the influence of protein and amino acids. Moreover, intervention and observational studies on the relation between protein intake and NAFLD yielded conflicting results. Filling the current knowledge gaps would help define the optimal diet composition for NAFLD prevention and management. Furthermore, metabolomics studies may provide insight into the pathogenesis of NAFLD, identify useful diagnostic and prognostic biomarkers, and unravel novel pharmacological targets and treatment options.

Phenotyping individuals with newly-diagnosed type 2 diabetes at risk for all-cause mortality: a single centre observational, prospective study.

BACKGROUND: Type 2 diabetes (T2D) shows a high mortality rate, dependent on disease duration, comorbidities and glucose control over time. Data on patients with short disease duration are scanty. METHODS: We prospectively followed a cohort of newly-diagnosed T2D patients referring to a single diabetes centre, treated according to the international guidelines and checked every 6-12 months. All-cause mortality and major cardiovascular (CV) events were registered. RESULTS: 289 patients out of 3019 consecutive first attendances matched inclusion criteria and were included in the observation. Mean follow-up was 51.2 months. At 31 December 2018, 253 patients were alive and 36 deceased. At baseline, deceased individuals were older, with lower eGFR and lower uric acid, higher prevalence of atrial fibrillation. During the follow-up, 18 non-fatal CV events were adjudicated; patients with incident CV disease (CVD) differed at baseline for sex, previous history of CVD and retinopathy, higher use of secretagogues and lower use of metformin. At multivariate analysis, age and previous CVD were the only independent determinants of all-cause mortality and incident CVD, respectively. In deceased individuals, eGFR slope was markedly unstable and ΔeGFR at the end of the follow-up was higher (p < 0.001), and predicted mortality. CONCLUSION: Newly-diagnosed T2D patients followed according to the best clinical practice show a mortality rate similar to that reported in more complicated patients with longer disease duration; none of the clinical and biochemical variables commonly measured at baseline can predict mortality or incident CVD; early metformin use seems to be associated with no risk of prevalent or incident retinopathy.

The Effects of Dapagliflozin on Systemic and Renal Vascular Function Display an Epigenetic Signature.

CONTEXT: Mechanisms mediating the cardiovascular and renal protection exerted by SGLT2 inhibitors are still partially unknown. We investigated whether dapagliflozin modulates systemic and renal vascular function and structure, and induces epigenetic modifications. SUBJECTS AND METHODS: Forty hypertensive patients with type 2 diabetes were randomly assigned to 4-week treatment with dapagliflozin 10 mg or hydrochlorothiazide (HCT) 12.5 mg. Routine analyses; plasma renin activity; aldosterone, catecholamine, and 24-hour urinary electrolyte levels; flow-mediated dilation (FMD) of the brachial artery; carotid-femoral pulse-wave velocity (PWV); augmentation index; and resistive index and dynamic renal resistive index (DRIN) were measured at baseline and after treatment. Circulating miRNAs (miRs) related to heart failure (miR30e-5p, miR199a-3p), endothelial dysfunction (miR27b and miR200b), and renal function (miR130b-3p, miR21-5p) were assessed and related to the effects of treatments. RESULTS: Dapagliflozin and HCT marginally lowered blood pressure. Fasting glucose was lowered, whereas 24-hour diuresis, glycosuria, and osmolar clearance were increased by dapagliflozin (P < 0.001 for all), without affecting sodium excretion and glomerular filtration rate. Magnesium levels significantly increased after dapagliflozin treatment (P = 0.02). Neither dapagliflozin nor HCT modified FMD or PWV. DRIN did not vary in the dapagliflozin group, whereas it increased in the HCT group (P = 0.047 for time by treatment interaction). Both treatments induced variations in the expression of some miRs; dapagliflozin, but not HCT, significantly up-regulated miR30e-5p and downregulated miR199a-3p. CONCLUSION: A putative epigenetic regulation of the protecting cardiovascular effect exerted by SGLT2 inhibitors was found. Dapagliflozin might exert nephroprotection by preserving renal vasodilating capacity.

Phthalates Exposure as Determinant of Albuminuria in Subjects With Type 2 Diabetes: A Cross-Sectional Study.

CONTEXT: Recent epidemiological observations have reported an association among phthalates exposure and insulin resistance, obesity, and diabetes but have not related exposure to these environmental pollutants with microvascular complications of diabetes. OBJECTIVE: To explore the relationship between phthalates and renal function in subjects with diabetes. DESIGN: Cross-sectional, case-only study. Concentrations of three urinary metabolites of di-2-ethylhexylphthalate were quantified in a spot morning urine sample, normalized for creatinine urinary excretion, and related to clinical parameters and phenotype, adjusting for confounders. PATIENTS: Two hundred and nine patients with diabetes consecutively referred to our clinic. MAIN OUTCOME MEASURES: Relationship between phthalates and renal function [evaluated with estimated glomerular filtration rate (eGFR) and albuminuria]. RESULTS: Creatinine-adjusted urinary concentrations of mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and mono-2-ethyl-5-hydroxyhexyl phthalate were 7.53 µg/g (range, 4.84 to 12.60), 3.04 µg/g (range, 1.03 to 5.14), and 10.70 µg/g (7.02 to 17.40), respectively. Age, sex, body mass index, diabetes duration, smoking, blood pressure, glycated Hb, and eGFR did not influence their levels. Exposure to MEHP and MEOHP was greater in individuals with microalbuminuria/macroalbuminuria (MEHP, P = 0.0173; MEOHP, P = 0.0306). The fourth vs first quartile showed a greater risk of albuminuria (MEHP: OR, 4.83; 95% CI, 1.45 to 16.06; P = 0.0297; MEOHP: OR, 3.29; 95% CI, 1.08 to 10.04); P = 0.0352). MEOHP was greater (P = 0.034) in subjects with cardiovascular events; MEHP showed a positive trend (P = 0.061). CONCLUSION: Our findings have revealed an association between exposure to di-2-ethylhexylphthalate metabolites and the degree of albuminuria in subjects with diabetes; the lack of a relationship with eGFR suggests their urinary levels are independent of renal function.