Uric Acid Impairs Insulin Signaling by Promoting Enpp1 Binding to Insulin Receptor in Human Umbilical Vein Endothelial Cells

High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (IR) and it is overexpressed in insulin-resistant subjects. In keeping with this, we stimulated human umbilical vein endothelial cells (HUVECs) with insulin and UA to investigate the effects of UA on insulin signaling pathway, testing the hypothesis that UA can interfere with insulin signaling by the activation of ENPP1. Cultures of HUVECs were stimulated with insulin, UA and the urate transporter SLC22A12 (URAT1) inhibitor probenecid. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels were investigated by immunoblotting. ENPP1 binding to IR and its tyrosine phosphorylation levels were tested by immunoprecipitation and immunoblotting. UA inhibited insulin-induced Akt/eNOS axis. Moreover, UA induced ENPP1 binding to IR that resulted in an impairment of insulin signaling cascade. Probenecid reverted UA effects, suggesting that UA intracellular uptake is required for its action. In endothelial cells, UA directly interferes with insulin signaling pathway at receptor level, through ENPP1 recruitment. This evidence suggests a new molecular model of UA-induced insulin resistance and vascular damage

One-hour post-load hyperglycemia combined with HbA1c identifies individuals with augmented duodenal levels of sodium/glucose co-transporter 1

Aims: Individuals with HbA1c-defined prediabetes (HbA1c 5.7–6.4%) and 1-hour post-load plasma glucose (1hPG) 155 mg/dl have an increased risk to develop type 2 diabetes (T2DM). T2DM is associated with a higher intestinal expression of sodium/glucose cotransporter 1 (SGLT-1) and glucose transporter 2 (GLUT-2). It is currently unsettled whether HbA1c-defined dysglycemic conditions combined to 1hPG 155 mg/dl are associated with changes in SGLT-1 and GLUT-2 duodenal abundance. Methods: SGLT-1 and GLUT-2 protein levels were assessed by western blot on duodenal mucosa biopsies of 57 individuals underwent an upper gastrointestinal endoscopy. Results: Compared with the normal group (HbA1c < 5.7%), individuals with HbA1c-defined pre-diabetes and diabetes exhibit no significant change in duodenal SGLT-1 abundance. Conversely, duodenal GLUT-2 levels were progressively increased in subjects with prediabetes and diabetes. Stratifying participants according to HbA1c and 1hPG we found that amongst subjects with HbA1c-defined normal or prediabetes condition those having 1hPG 155 mg/dl displayed higher duodenal levels of SGLT-1 as compared to their counterparts with 1hPG < 155 mg/dl; in contrast to GLUT-2 levels, which were similar between normal and with prediabetes subjects, regardless of 1hPG value. Conclusion: A value of 1hPG 155 mg/dl may identify a subset of individuals within HbA1cdefined glycemic categories having a higher duodenal abundance of SGLT-1

Metabolic and cognitive effects of ranolazine in type 2 diabetes mellitus. data from an in vivo model

Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to possess hypoglycemic properties in pre-clinical and clinical studies. The aim of this study was to evaluate the effects of ranolazine on glucose metabolism and cognitive function in a T2DM model of Wistar rats. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ). The control group received a normal caloric diet (NCD) and sodium citrate buffer. Metformin, an effective hypoglycemic drug, was employed as a positive control. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine, and NCD + Metformin. Rats received ranolazine (20 mg/kg), metformin (300 mg/kg), or water, for 8 weeks. At the end of the treatments, all animals underwent to an intraperitoneal glucose tolerance test (IPGTT) and behavioral tests, including passive avoidance, novel object recognition, forced swimming, and elevate plus maze tests. Interleukin-6 plasma levels in the six treatment groups were assessed by Elisa assay. Body mass composition was estimated by nuclear magnetic resonance (NMR). Glucose responsiveness significantly improved in the HFD/STZ + Ranolazine (p < 0.0001) and HFD/STZ + Metformin (p = 0.003) groups. There was a moderate effect on blood glucose levels in the NCD + Ranolazine and NCD + Metformin groups. Lean body mass was significantly increased in the HFD/STZ + Ranolazine and HFD/STZ + Metformin animals, compared to HFD/STZ + Vehicle animals. Ranolazine improved learning and long-term memory in HFD/STZ + Ranolazine compared to HFD/STZ + Vehicle (p < 0.001) and ameliorated the pro-inflammatory profile of diabetic mice. These results support the hypothesis of a protective effect of ranolazine against cognitive decline caused by T2DM

Different Patterns of Left Ventricular Hypertrophy in Metabolically Healthy and Insulin-Resistant Obese Subjects

Obese subjects showed different cardiovascular risk depending by different insulin sensitivity status. We investigated the difference in left ventricular mass and geometry between metabolically healthy (MHO) and unhealthy (MUHO) obese subjects. From a cohort of 876 obese subjects (48.3 ± 14.1 years) without cardio-metabolic disease and stratified according to increasing values of Matsuda index after 75 g oral glucose tolerance test, we defined MHO (n = 292) those in the upper tertile and MUHO (n = 292) those in the lower tertile. All participants underwent echocardiographic measurements. Left ventricular mass was calculated by Devereux equation and normalized by height2,7 and left ventricular hypertrophy (LVH) was defined by values >44 g/m2.7 for females and >48 g/m2.7 for males. Left ventricular geometric pattern was defined as concentric or eccentric if relative wall thickness was higher or lower than 0.42, respectively. MHO developed more commonly a concentric remodeling (19.9 vs. 9.9%; p = 0.001) and had a reduced risk for LVH (OR 0.46; p < 0.0001) than MUHO, in which the eccentric type was more prevalent (40.4 vs. 5.1%; p < 0.0001). We demonstrated that obese subjects-matched for age, gender and BMI-have different left ventricular mass and geometry due to different insulin sensitivity status, suggesting that diverse metabolic phenotypes lead to alternative myocardial adaptation

The impact of COVID-19 pandemic on well-being of Italian physicians. a report from the Italian Society of Internal Medicine (SIMI) national survey

Over the past few years, COVID-19 pandemic has imposed a high toll worldwide, with a high burden of morbidity and mortality. Healthcare practitioners (HCPs) have been in the frontline since the beginning of the outbreak, and the high level of stress have affected their physical and mental status, as well as their relationships. We aimed at exploring the self-reported changes in comprehensive well-being in a cohort of Italian physicians. An online-based survey was administered to the members of the Italian Society of Internal Medicine (SIMI) between March and June 2021. The survey was based on 32 multiple-choice questions exploring self-reported physical and mental well-being, as well as changes in workloads, work-related feelings and physicians' relationship with patients, colleagues and families. 228 physicians (mean age: 35.7 ± 9.8 years) participated in the survey; 120 (52.6%) were residents, 196 (86.0%) worked in COVID-19 units and 65 (28.5%) had COVID-19 during the pandemic. A significant proportion of respondents reported to have experience onset or worsening of physical and mental symptoms, with insomnia/sleep disorders (58.3%) and mood swings (47.8%) being the most common, respectively. The burden of physical and mental consequences was broadly higher among residents compared to specialists, with the former reporting more frequently an increase in the number of worked hours (p = 0.020) and being more frequently infected with COVID-19 (35.0% vs. 21.3, p = 0.032). Moreover, familiar and doctor-patient relationships were also considerably affected. Physicians have been suffering a wide spectrum of physical, mental and relational consequences during COVID-19 pandemic, with youngest doctors being more likely to present several physical and mental health symptoms. Further studies are needed to evaluate long-term consequences of COVID-19 pandemic on the well-being of HCPs, and potential preventive strategies

Levels and Factors Associated with Resilience in Italian Healthcare Professionals during the COVID-19 Pandemic: A Web-Based Survey

Background: Resilience is defined as the capacity to cope successfully with change or adversity. The aims of our study were to investigate levels of resilience in Italian healthcare professionals (HCPs) during the Coronavirus disease 2019 (COVID-19) pandemic and to identify potential predictors of resilience. Methods: We performed a web-based survey of HCPs (n = 1009) working in Italian hospitals during the COVID-19 pandemic. The survey contained a 14-item resilience scale (RS14) and questionnaires to evaluate depression and anxiety symptoms. Non-HCP individuals (n = 375) from the general population were used for comparison. Results: HCPs showed significantly lower resilience compared to the control group (p = 0.001). No significant differences were observed after stratification for geographical area, work setting, role, or suspected/confirmed diagnosis of COVID-19. In a linear regression analysis, RS14 was inversely correlated with depression (R2 = 0.227, p < 0.001) and anxiety (R2 = 0.117, p < 0.001) and directly correlated with age (R2 = 0.012, p < 0.001) but not with body mass index (BMI, R2 = 0.002, p = 0.213). In male HCPs, higher depression score (odds ratio (OR) 1.147, p < 0.001) or BMI (OR 1.136, p = 0.011) significantly predicted having low resilience. In female HCPs, higher depression score (OR 1.111, p < 0.0001) and working in a COVID-19 free setting (OR 2.308, p = 0.002) significantly predicted having low resilience. HCPs satisfied with personal protective equipment had higher levels of resilience (p < 0.010). Conclusions: Our findings suggest that resilience was lower in Italian HCPs than in the general population after the first COVID-19 wave. Specific factors can be identified, and targeted interventions may have an important role to foster resilience of HCP

Impact of the COVID-19 Outbreak on the Behavior of Families in Italy: A Focus on Children and Adolescents

The COVID-19 pandemic has changed individuals' lifestyles to a great extent, particularly in Italy. Although many concerns about it have been highlighted, its impact on children and adolescents has scarcely been examined. The purpose of this study was to explore behavioral consequences and coping strategies related to the pandemic among families in Italy, by focusing on developmental ages from the caregivers' perspective, 3 weeks into quarantine. An exploratory cross-sectional online survey was conducted over 14 days. Google Forms was employed to conduct the survey. Demographic variables and pre-existing Psychological Weaknesses (PsW) were asked. Adults' sleep difficulties (SleepScore) and coping strategies during quarantine were assessed. Behavioral changes related to quarantine of both subjects completing the form (COVIDStress) and their children (when present) were questioned. Of the 6,871 respondents, we selected 6,800 valid questionnaires; 3,245 declared children aged under 18 years of age (caregivers). PsWs were recognizable in 64.9% among non-caregivers and in 61.5% of caregivers, with a mean PsW score of 1.42 \ub1 1.26 and 1.30 \ub1 1.25 over 3 points, respectively. The 95.5% of the non-caregivers and the 96.5% of caregivers presented behavioral changes with a mean COVIDStress of 3.85 \ub1 1.82 and 4.09 \ub1 1.79 over 8, respectively (p<0.001). Sleep difficulties were present in the 61.6% of the non-caregivers and in the 64.4% of the caregivers (p < 0.001), who showed higher SleepScores (2.41 \ub1 1.26 against 2.57 \ub1 1.38 points over 6, p < 0.001). COVIDStress (and SleepScore) strongly correlated with PsW (p < 0.001). Caregivers observed behavioral changes in their children in the 64.3% of the <6 years old and in 72.5% of 6-18 years old. Caregivers' discomfort related to quarantine (COVIDStress, SleepScore) was strongly associated to behavioral changes in both age groups of <6 and 6-18 (p < 0.001). Presence of caregivers' coping strategies was less associated to behavioral changes in the <6 sample (p = 0.001) but not in the 6-18 (p = 0.06). The COVID-19 pandemic has adversely impacted families in Italy with regard to behavioral changes, especially in high-risk categories with PsWs and caregivers, especially the ones with children aged <6 years. While coping strategies functioned as protective factors, a wide array of stress symptoms had implications for children's and adolescents' behaviors. It is recommended that public children welfare strategies be implemented, especially for higher-psychosocial-risk categories

Monoclonal Antibodies and Antivirals against SARS-CoV-2 Reduce the Risk of Long COVID: A Retrospective Propensity Score-Matched Case–Control Study

Long COVID is a complex condition affecting quality of life, with limited therapeutic options. We investigated the occurrence of long COVID in subjects receiving early therapy with monoclonal antibodies (mAbs) or antivirals to reduce the risk of COVID-19 progression. In this retrospective study we enrolled 737 adult patients (aged 65.16 ± 13.46; 361F), who experienced COVID-19 between January 2021 and March 2022. Antiviral or mAbs were administered to symptomatic patients who did not require oxygen therapy or hospital admission for SARS-CoV-2 infection, and who were at high risk of progression to severe disease, as identified by age > 65 years or the presence of comorbidities. Long COVID, defined as newly or persistent long-term symptoms 4 weeks after the onset of the acute illness, was reported in 204 cases (28%). Age (OR 1.03; p < 0.001), gender (OR 1.88; p < 0.001) and at least three comorbidities (OR 3.49; p = 0.049) were directly associated with long COVID; conversely, vaccination (OR 0.59; p = 0.005) and mAbs/antivirals (OR 0.44; p = 0.002) were independently associated with a reduced risk of long COVID. At a propensity-score-matched analysis, the mAbs/antivirals group had a significantly lower occurrence of long COVID in comparison with untreated controls (11% vs. 34%; p = 0.001). In conclusion, mAbs and antivirals administered against the progression of COVID-19 were associated with a reduced risk of long COVID

Antihypertensive treatment changes and related clinical outcomes in older hospitalized patients

Background: Hypertension management in older patients represents a challenge, particularly when hospitalized. Objective: The objective of this study is to investigate the determinants and related outcomes of antihypertensive drug prescription in a cohort of older hospitalized patients. Methods: A total of 5671 patients from REPOSI (a prospective multicentre observational register of older Italian in-patients from internal medicine or geriatric wards) were considered; 4377 (77.2%) were hypertensive. Minimum treatment (MT) for hypertension was defined according to the 2018 ESC guidelines [an angiotensin-converting-enzyme-inhibitor (ACE-I) or an angiotensin-receptor-blocker (ARB) with a calcium-channel-blocker (CCB) and/or a thiazide diuretic; if >80 years old, an ACE-I or ARB or CCB or thiazide diuretic]. Determinants of MT discontinuation at discharge were assessed. Study outcomes were any cause rehospitalization/all cause death, all-cause death, cardiovascular (CV) hospitalization/death, CV death, non-CV death, evaluated according to the presence of MT at discharge. Results: Hypertensive patients were older than normotensives, with a more impaired functional status, higher burden of comorbidity and polypharmacy. A total of 2233 patients were on MT at admission, 1766 were on MT at discharge. Discontinuation of MT was associated with the presence of comorbidities (lower odds for diabetes, higher odds for chronic kidney disease and dementia). An adjusted multivariable logistic regression analysis showed that MT for hypertension at discharge was associated with lower risk of all-cause death, all-cause death/hospitalization, CV death, CV death/hospitalization and non-CV death. Conclusions: Guidelines-suggested MT for hypertension at discharge is associated with a lower risk of adverse clinical outcomes. Nevertheless, changes in antihypertensive treatment still occur in a significant proportion of older hospitalized patients