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Context Patients with type 1 diabetes (T1D) have higher cardiovascular disease (CVD) risk than the general population. Objective This observational study aims to evaluate sex-related differences in CVD prevalence and CVD risk estimates in a large cohort of T1D adults. Methods We conducted a multicenter, cross-sectional study involving 2041 patients with T1D (mean age 46 years; 44.9% women). In patients without pre-existing CVD (primary prevention), we used the Steno type 1 risk engine to estimate the 10-year risk of developing CVD events. Results CVD prevalence (n = 116) was higher in men than in women aged ≥55 years (19.2 vs 12.8%, P = .036), but comparable between the 2 sexes in those aged Conclusion Both men and women with T1D are at high CVD risk. The 10-year estimated CVD risk was higher in men aged

Although selective estrogen receptor modulators (SERMs) have been proposed as a treatment for men with central functional hypogonadism, only few data have been produced in men with obesity-related functional androgen deficiency (ORFAD).To determine whether and to what extent SERMs are an effective and safe therapy in men with ORFAD.A thorough search of PubMed, Web of science, Scopus and Cochrane Library databases was performed to identify studies comparing testosterone (T) levels before and after treatment with SERMs in men with ORFAD. Mean differences (MDs) with 95% coefficient intervals (CIs) were combined using random effects models. Funnel plot, Egger's test and trim-and-fill analysis were used to assess publication bias.Seven studies met the inclusion criteria providing information on 292 men with ORFAD treated with clomiphene citrate (CC, 12.5-50 mg daily) or enclomiphene citrate (EC, 12.5-25 mg daily) for 1.5-4 months. The pooled estimates indicated a significant increase in T levels both with CC (MD: 11.56 nmol/L; 95% CI: 9.68, 13.43; ITreatment with CC and EC may be an effective and safe alternative to T replacement therapy in men with ORFAD. Further long-term studies are warranted to define clinical reflections of the SERMs-induced increase in T levels and to better clarify the safety profile. This article is protected by copyright. All rights reserved.

BACKGROUND Whether and to what extent an association exists between hyperuricemia and erectile dysfunction (ED) has not yet been fully determined. OBJECTIVE To define pooled prevalence estimates and correlates of erectile dysfunction in men with hyperuricemic disorders. MATERIALS AND METHODS A thorough search of Medline, Scopus, and Cochrane Library databases was performed. Data were combined using random-effects models and the between-study heterogeneity was assessed by Cochrane's Q and I2 tests. A funnel plot was used to assess publication bias. RESULTS Overall, 8 studies included gave information about 85,406 hyperuricemic men, of whom 5023 complained of erectile dysfunction, resulting in a pooled erectile dysfunction prevalence estimate of 33% (95% Confidence Interval: 13-52%; I² = 99.9%). The funnel plot suggested the presence of a publication bias. At the meta-regression analyses, among the available covariates that could affect estimates, only type 2 diabetes mellitus was significantly associated with a higher prevalence of erectile dysfunction (β = 0.08; 95% Confidence Interval: 0.01, 0.15, p = 0.025). At the sub-group analysis, the pooled erectile dysfunction prevalence decreased to 4% (95% Confidence Interval: 0%-8%) when only the largest studies with the lowest prevalence of type 2 diabetes mellitus were included and increased up to 50% (95% Confidence Interval: 17%-84%) when the analysis was restricted to studies enrolling smaller series with higher prevalence of type 2 diabetes mellitus. CONCLUSIONS A not negligible proportion of men with hyperuricemia can complain of erectile dysfunction. While a pathogenetic contribution of circulating uric acid in endothelial dysfunction cannot be ruled out, the evidence of a stronger association between hyperuricemia and erectile dysfunction in type 2 diabetes mellitus points to hyperuricemia as a marker of systemic dysmetabolic disorders adversely affecting erectile function.

Background and aim: To compare cardiometabolic risk profile and preclinical signs of target organ damage in youth with normal and elevated blood pressure (BP), according to the American Academy of Pediatrics (AAP) guidelines. Methods and results: This cross-sectional multicenter study included 2739 youth (5-17 year-old; 170 normal-weight, 610 overweight and 1959 with obesity) defined non hypertensive by the AAP guidelines. Anthropometric, biochemical and liver ultrasound data were available in the whole population; carotid artery ultrasound and echocardiographic assessments were available respectively in 427 and 264 youth. Elevated BP was defined as BP >= 90th to = 120/80 to

Aims To compare the association of high serum uric acid (HUA) or metabolic syndrome (MetS) with fatty liver disease (FLD) in youths with overweight/obesity (OW/OB). Materials and Methods Cross-sectional study of anthropometrics, biochemical variables, and liver ultrasound of 3104 individuals with OW/OB (age 5-17 years). Metabolic syndrome was defined by >= 3 criteria among (1) high waist circumference; (2) high triglycerides; (3) low high-density lipoproteins; (4) fasting glucose >= 100 mg/dl; (5) blood pressure >= 95(th) percentile in children, and >= 130/80 mmHg in adolescents. High serum uric acid was defined as serum UA value >= 75(th) percentile adjusted for sex. Fatty liver disease was determined by echography. Results The sample was stratified in four categories: (1) no HUA, no MetS (reference category); (2) MetS; (3) HUA; (4) HUA and MetS (HUA + MetS). The prevalence of FLD increased across the four categories from 29.9%, 44.0%, 52.2%, to 67.1%, respectively (p < 0.0001). The ORs for the categorical variables were 1.33 (1.06-1.68) for MetS (p = 0.02), 3.19 (2.51-4.05) for HUA (p < 0.0001) and 3.72 (2.65-5.21) for HUA + MetS (p < 0.0001), versus the reference category regardless of the body mass index. Conclusions HUA represents a useful marker of FLD in youths with OW/OB, given its greater ability to identify those at increased risk of the disease compared to MetS. The ability of both to predict incident FLD must be investigated in longitudinal study.

Although preclinical research has revealed disrupting effects on male reproductive functions of bisphenol A (BPA), as yet clinical studies have led to inconsistent results. The present meta‑analysis aims to establish the existence and the extent of the association between BPA exposure and semen quality. A thorough search of PubMed, Scopus and Web of Science databases was carried out. Only studies reporting data from multivariable linear regression analyses (β-coefficients with 95% CI), assessing the association between urinary levels of BPA and standard semen parameters were included. Nine studies provided information about an overall sample of 2,399 men. Only the negative association between urinary BPA levels and sperm motility reached statistical significance (pooled β-coefficient = -0.82; 95% CI: -1.51 to -0.12, p = 0.02; P

Neurotensin (NT) is a small peptide with pleiotropic functions, exerting its primary actions by controlling food intake and energy balance. The first evidence of an involvement of NT in metabolism came from studies on the central nervous system and brain circuits, where NT acts as a neurotransmitter, producing different effects in relation to the specific region involved. Moreover, newer interesting chapters on peripheral NT and metabolism have emerged since the first studies on the NT-mediated regulation of gut lipid absorption and fat homeostasis. Intriguingly, NT enhances fat absorption from the gut lumen in the presence of food with a high fat content, and this action may explain the strong association between high circulating levels of pro-NT, the NT stable precursor, and the increased incidence of metabolic disorders, cardiovascular diseases, and cancer observed in large population studies. This review aims to provide a synthetic overview of the main regulatory effects of NT on several biological pathways, particularly those involving energy balance, and will focus on new evidence on the role of NT in controlling fat homeostasis, thus influencing the risk of unfavorable cardio–metabolic outcomes and overall mortality in humans.

Type 2 diabetes mellitus (T2DM) is associated with an increased fracture risk. Our study aimed to explore differences in bone alterations between T2DM women and controls and to assess clinical predictors of bone impairment in T2DM. For this observational case control study, we recruited 126 T2DM female patients and 117 non-diabetic, age- and BMI-comparable women, who underwent clinical examination, routine biochemistry and dual-energy X-ray absorptiometry (DXA) scans for bone mineral density (BMD) and trabecular bone score (TBS) assessment-derived indexes. These were correlated to metabolic parameters, such as glycemic control and lipid profile, by bivariate analyses, and significant variables were entered in multivariate adjusted models to detect independent determinants of altered bone status in diabetes. The T2DM patients were less represented in the normal bone category compared with controls (5% vs. 12%; p = 0.04); T2DM was associated with low TBS (OR: 2.47, C.I. 95%: 1.19–5.16, p = 0.016) in a regression model adjusted for age, menopausal status and BMI. In women with T2DM, TBS directly correlated with plasma high-density lipoprotein cholesterol (HDL-c) (p = 0.029) and vitamin D (p = 0.017) levels. An inverse association was observed with menopausal status (p < 0.001), metabolic syndrome (p = 0.014), BMI (p = 0.005), and waist circumference (p < 0.001). In the multivariate regression analysis, lower HDL-c represented the main predictor of altered bone quality in T2DM, regardless of age, menopausal status, BMI, waist circumference, statin treatment, physical activity, and vitamin D (p = 0.029; R2 = 0.47), which likely underlies common pathways between metabolic disease and bone health in diabetes.

Neurotensin (NT) is a small protein implicated in the regulation of energy balance which acts as both a neurotransmitter in the central nervous system and as a gastrointestinal peptide. In the gut, NT is secreted after fat ingestion and promotes the absorption of fatty acids. The circulating levels of its precursor, pro-NT, predicts the presence and development of metabolic and cardiovascular diseases. Despite the extensive knowledge on the dynamic changes that occur to pro-NT = after fat load, the determinants of fasting pro-NT are unknown. The aim of this study was to determine the possible genetic regulation of plasma pro-NT. The NT gene (NTS) was sequenced for potential functional variants, evaluating its entire genomic and potentially regulatory regions, in DNA from 28 individuals, stratified by low and high pro-NT levels. The identified variant differently distributed in the two pro-NT subgroups was genotyped in a cohort of nine hundred and thirty-two overweight/obese children and adolescents. A total of seven sequence variations across the NTS gene, none of them located in coding regions, were identified. The rs2234762 polymorphism, sited in the NTS gene promoter, was statistically more frequent in the lowest pro-NTS level group. Carriers of the rs2234762 variant showed lower pro-NT levels, after adjusting for sex, age, BMI, triglycerides and the Tanner stage. Having NTS rs2234762 predicted less pronounced insulin resistance at the 6.5-year follow-up with OR: 0.46 (0.216–0.983), at the logistic regression analysis adjusted for age, sex and BMI. In conclusion, the NTS rs2234762 gene variant is a determinant of reduced circulating pro-NT levels in overweight and obese children, which predisposes this group to a more favorable metabolic profile and a reduced insulin resistance later in life, independently from metabolic confounders.

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1–5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11–0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105–0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136–5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion.

This study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D).A nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested.When all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08-2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF0.001% (OR=6.34, 95% CI: 1.87-22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01-1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02).Rare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood.

Background and aim: The relationships between uric acid (UA) and prediabetes is poorly explored in youth. We investigated the association between UA, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), insulin resistance (IR) and low insulin sensitivity (IS) in youth with overweight/obesity (OW/OB). Methods and results: A cross-sectional study was performed in 2248 youths with OW/OB (age 5–17 years). The sample was stratified in sex-specific quintiles (Q1 to Q5) of UA and the associations with fasting (FG), 2-h post-load glucose (2H-PG), IR and low IS were investigated. IR and low IS were estimated by assessment model of insulin resistance (HOMA-IR) and whole-body IS index (WBISI), respectively. IFG was defined as FG ≥ 100 < 126 mg/dL, IGT as 2H-PG ≥140 < 200 mg/dL, IR as HOMA-IR ≥75th percentile and low IS as WBISI ≤25th percentile by sex. Age, body mass index z-score, 2H-PG, HOMA-IR and WBISI, increased across sex-quintiles of UA while FG did not. The prevalence of IFG and IR were significantly increased in Q5 vs Q1 (reference quartile, P < 0.025). The prevalence of IGT increased from Q3 to Q5 vs Q1 (P < 0.025–0.0001) and that of low IS from Q2 to Q5 vs Q1 (P < 0.005–0.0001). Conclusions: In youth with OW/OB, rates of IGT and low IS increased progressively across quintiles of UA. On the contrary, IFG and IR were associated only with the highest quintile of UA. Our data suggest that UA is a biomarker of impaired glucose metabolism prevalently in post–challenge condition rather than in fasting state.

Purpose To investigate the relationship between the single-point insulin sensitivity estimator (SPISE) index, an insulin sensitivity indicator validated in adolescents and adults, and metabolic profile in overweight/obese children, and to evaluate whether basal SPISE is predictive of impaired glucose regulation (IGR) development later in life. Methods The SPISE index (= 600 × HDL0.185/Triglycerides0.2 × BMI1.338) was calculated in 909 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy, and in 99 normal-weight, age-, sex-comparable children, selected as a reference group, together with other insulin-derived indicators of insulin sensitivity/resistance. 200 overweight/obese children were followed-up for 6.5 [3.5–10] years, data were used for longitudinal retrospective investigations. Results At baseline, 96/909 (11%) overweight/obese children had IGR; in this subgroup, SPISE was significantly lower than in normo-glycaemic youths (6.3 ± 1.7 vs. 7 ± 1.6, p p values p = 0.002; AUROC: 0.82(0.72–0.92), p Conclusion In children, low SPISE index is significantly associated with metabolic abnormalities and predicts the development of IGR in life.

Aim Biliverdin reductase-A (BVR-A) other than its canonical role in the degradation pathway of heme as partner of heme oxygenase-1 (HO1), has recently drawn attention as a protein with pleiotropic functions involved in insulin-glucose homeostasis. However, whether BVR-A expression is altered in type 2 diabetes (T2D) has never been evaluated. Main methods BVR-A protein levels were evaluated in T2D (n = 44) and non-T2D (n = 29) subjects, who underwent complete clinical workup and routine biochemistry. In parallel, levels HO1, whose expression is regulated by BVR-A as well as levels of tumor necrosis factor α (TNFα), which is a known repressor for BVR-A with pro-inflammatory properties, were also assessed. Key findings BVR-A levels were significantly lower in T2D subjects than in non-T2D subjects. Reduced BVR-A levels were associated with greater body mass, systolic blood pressure, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), triglycerides, transaminases and TNFα, and with lower high-density lipoprotein (HDL) levels. Lower BVR-A levels are associated with reduced HO1 protein levels and the multivariate analysis showed that BVR-A represented the main determinant of HO1 levels in T2D after adjustment. In addition, reduced BVR-A levels were able to predict the presence of T2D with AUROC = 0.69. for potential confounders. Significance Our results demonstrate for the first time that BVR-A protein levels are reduced in T2D individuals, and that this alteration strictly correlates with poor glycometabolic control and a pro-inflammatory state. Hence, these observations reinforce the hypothesis that reduced BVR-A protein levels may represent a key event in the dysregulation of intracellular pathways finally leading to metabolic disorders.

Recently ANK2, encoding ankyrin-B (AnkB), has been proposed as an obesity susceptibility gene. AnKB negatively regulates the expression of glucose transporter 4 (GLUT4) in adipocytes, and it has been hypothesized that functional alterations of AnkB may determine the persistence of GLUT4 on the cell surface, increasing glucose transport in adipocytes. Adipose tissue-specific AnkB-KO mice develop obesity and progressive pancreatic islet dysfunction with age or high-fat diet. AnkB-deficient adipocytes exhibit increased lipid accumulation associated with increased glucose uptake and impaired endocytosis of GLUT4. Functional alterations have been observed in ANK2 gene in European Americans and African Americans and have been proposed as candidates to contribute to obesity susceptibility in humans. Considering that variants of ANK2 gene were previously observed in subjects of American and African American ethnicity, and that these variants were never studied in association with obesity, we performed a genetic association analysis with obesity in a cohort of Southern European subjects. For this study 1900 Italian subjects with body mass index (BMI) between 16 and 91 were selected. All subjects underwent clinical examination, anthropometric measurements and routine laboratory tests. The SNPs rs45454496 (E1813K) and rs35530544 (L1622I) have been studied in DNAs by Eco TM Real-Time PCR System by Illumina. Among the 1900 subjects we identified 15 (frequency 0.7%) heterozygous subjects for the rs45454496 variant and no homozygous subject. The observed frequency in our population is more than double that observed in other populations of European origin (0.7% vs 0.3%, p = 0.3). We then analysed the association between this polymorphism and clinical and biochemical characteristics. Carriers of the mutation showed no significantly differences compared to wild-type subjects in any of the parameters examined. Population stratification by BMI showed a random distribution of the rs45454496 variant according to weight. Also, population stratification based on glycaemic alterations showed no association of the rs45454496 variant with categories of glucose metabolism. Finally, we analysed the study cohort for the rs35530544, but we did not observe any subject carrying the variant in an initial sample of 840 patients. In conclusion, we observed that the rs45454496 (E1813K) variant of ANK2 gene, although showing a higher frequency in our Southern European population (0.7%) than the frequencies reported in other populations of European origin, in the analysed sample does not seem to have effects on clinical and metabolic alterations.

Objective: To compare the prevalence of mildly reduced estimated glomerular filtration rate (MRGFR) (eGFR .60 and , 90 mL/min/1.73 m2), calculated by two creatinine-based equations, and its association with cardiometabolic risk factors (CMRF) in youth with overweight (OW)/obesity (OB). Methods: This is a multicenter cross-sectional study involving university and non-university hospital pediatrics departments. We enrolled 3,118 youth with OW/OB (5-14 years) and 286 healthy normal weight (NW) youth. eGFR was calculated using bedside Schwartz equation (eGFRBSE) and Full Age Spectrum equation (eGFRFAS). In OW/OB group we analyzed the association between eGFR calculated by both equations and CMRF. Uric acid (UA) and birth weight were available in 2,135 and in 1,460 youth. Results: The prevalence of MRGFR was 3.8% in NW versus 7.8% in OW/OB (P 5 .016) by eGFRBSE, and 8.7% in NW versus 19.4% in OW/OB (P , .0001) by eGFRFAS. eGFRBSE and eGFRFAS identified 242 and 605 young people with OW/OB with MRGFR, respectively. Individuals with MRGFR according with both equations showed lower birth weight, younger age, higher BMI-SDS, non-high-density lipoprotein-cholesterol and UA as compared to those with normal eGFR. To examine whether the eGFRFAS was associated with a worse CMR profile also in the range of normal eGFRBSE, we reclassified young people with normal eGFRBSE (n 5 2,876) according with eGFRFAS. Out of youth with normal eGFRBSE, 366 (12.7%) presented MRGFR by eGFRFAS and had lower age, higher BMI-SDS, BP and UA than the remaining youth reclassified as normal eGFRFAS. Conclusion: MRGFR is associated with an altered CMR profile in a large sample of young people with overweight (OW)/obesity (OB). The eGFRFAS equation identifies a higher prevalence of youth with MRGFR, compared to eGFRBSE equation.

Epicardial adipose tissue is a novel cardiovascular risk factor. It plays a role in the progression of coronary artery disease, heart failure and atrial fibrillation. Given its rapid metabolism, clinical measurability, and modifiability, epicardial fat works well as therapeutic target of drugs modulating the adipose tissue. Epicardial fat responds to glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). GLP-1A and SGLT2i provide weight loss and cardiovascular protective effects beyond diabetes control, as recently demonstrated. The potential of modulating the epicardial fat morphology and genetic profile with targeted pharmacological agents can open new avenues in the pharmacotherapy of diabetes and obesity, with particular focus on cardiovascular risk reduction.

Aims Neurotensin (NT) is a gut hormone that promotes lipids absorption and controls appetite. Elevated circulating pro-NT, the stable precursor of NT, is associated with cardiovascular (CV) disease, metabolic syndrome (MS) and type 2 diabetes (T2D). Features of MS and insulin resistance are reported also in type 1 diabetes (T1D), with detrimental impact on the overall CV risk profile. Aims of the study were to evaluate plasma pro-NT in T1D patients and to test whether its levels are associated with and/or predictive of CV risk factors and overall risk profile. Methods For this longitudinal retrospective study, we analyzed clinical data from 41 T1D individuals referring to the diabetes outpatient clinics at Sapienza University of Rome, Italy, collected at the baseline and after 10 years. Fasting plasma pro-NT levels were measured in T1D subjects at the baseline and in 34 age-, sex-, BMI-comparable healthy individuals recruited in the same period. Results Pro-NT did not differ significantly between patients and controls (median[range] pro-NT: 156.3 [96.6–198.2] vs. 179.4 [139.7–230.7] pmol/L, p = 0.26). In T1D, greater fasting pro-NT associated with poor glycemic control at baseline and predicted increased waist circumference, reduced insulin sensitivity, dyslipidemia and hypertension at 10-year follow-up. High pro-NT predicted 10-year very-high CV risk with adjusted OR = 11 (95%C.I.: 1.4–94.5; p = 0.029). Conclusions In T1D individuals, elevated pro-NT levels predict the development of adverse metabolic profile, which translates in higher CV risk profile at 10-year follow-up. Pro-NT represents a novel predictor/marker of CV risk factors in adults with T1D.

Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes&rsquo, size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02&ndash, 1.9, &chi, 2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76&ndash, 1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

Neurotensin (NT) is an intestinal peptide released after fat ingestion, which regulates appetite and facilitates lipid absorption. Elevated plasma levels of its stable precursor pro-neurotensin (pro-NT) are associated with type 2 diabetes, obesity and cardiovascular mortality in adult populations; no data on pro-NT and metabolic disease are available in children. Aim of the study was to evaluate plasma pro-NT in relation to the presence of obesity in children, and to test if high pro-NT associates with the development of metabolic impairment later in life.For this longitudinal retrospective study, we studied 151 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy. Pro-NT was also assessed in 46 normal-weight, age-, sex-comparable normal-weight children, selected as a reference group. At the baseline, pro-NT was comparable between overweight/obese and normal-weight children and correlated positively with age (p 0.001), triglycerides (p 0.001) and inversely with HDL levels (p = 0.008). Plasma pro-NT associated with high triglycerides with OR = 5.9 (95%CI: 1.24-28.1; p = 0.026) after adjustment for multiple confounders. At the 6.5-year follow-up, high basal pro-NT associated with impaired β-cell function to compensate for insulin-resistance (disposition index: r = -0.19, p = 0.035) and predicted bodyweight increase, as indicated by percentage change of standard deviation score BMI (median(95%CI) = +20.8(+4.9-+27.5)% in the highest tertile), independently from age, sex, triglycerides and insulin-resistance (standardized β = 0.24; p = 0.036).Elevated pro-NT levels in children are significantly associated with weight gain later in life and may represent a marker of susceptibility to metabolic impairment in presence of obesity.

Issue The world is rapidly urbanizing, causing alarming health problems to their citizens. The Cities Changing Diabetes program aims to address the social factors and cultural determinants that can increase type 2 diabetes vulnerability among people living in cities. Rome joined the program in 2017, and a series of initiatives was launched with the aim of mapping the problem, sharing the learnings, and designing interventions. Description of the Problem The first phase of the project documented that a wide variation exists in the prevalence of diabetes among the districts of Rome, associated with social and cultural determinants. A linear correlation exists between the prevalence of diabetes in the districts, unemployment rate and use of private transportation rate, while an inverse correlation is present with aging index, school education level, and slow mobility rate. These findings were the base for the development of an action plan to be implemented in the next three years. A structured, multi-stakeholder approach was adopted to prioritize the areas of intervention. Politicians, healthcare policy makers, healthcare providers, epidemiologists, social scientists, and patient association representatives were involved. Results The following actions have been identified: To potentiate healthcare resources to meet the increasing needs associated with urban development and improve accessibility;To create and strengthen support networks in the territory, to meet the needs of elderly, fragile people, often living alone;To support sustainable mobility and improve the usability of shared and public transport networks;To increase information available to the most vulnerable subjects;To create a uniform network of specialist care through innovative solutions and increase the access to specialist care in suburban, underserved areas;To support the development of information and telemedicine systems, to promote integrated care. Key messages The aim of the initiative is triggering a virtuous circle in which prevention, access to care/innovation and sustainability of healthy lifestyles are the result of integrated actions in the territory. The experience of Rome can inspire other metropolitan areas in implementing effective strategies to reduce the burden of diabetes.

Background To understand the presence and impact of social and cultural factors on health vulnerability it is important for improving diabetes care and management. In fact, through the social dimension, it is possible to identify the priorities and attitudes towards diabetes and diabetes care among those living with the condition. Methods The study was carried out as part of the global Cities Changing Diabetes programme, involved a sample of individuals living with diabetes in the Rome metropolitan area and employed mixed-method and qualitative approaches to data collection and analysis (survey, sorting procedure and focus group). Results Four specific sub-groups of participants have been identified, each with distinct but shared priorities and attitudes towards diabetes: Health conscious thanks to the context; Medicalized elderly people; Fatalistic citizens; Worried but undisciplined young people. The connection between the place where you live and the possibility to adopt a healthier lifestyle was confirmed. For these patients, the disease is mainly characterized by its relationship with food and its connections with psychological aspects are also relevant. Conclusions An important issue concerns information and the different understandings of diabetes. A clear need emerged for further elaboration of the various aspects of a disease that tends to be underestimated also by those who have it. Another aspect concerns the importance of the living environment and consequently of the actions on its urban planning, mobility, but also in everyday life organization, as factors that can make a difference in properly managing the disease. These results are very important to promote a joint action, that have to involve public and private stakeholders, in order to improve treatment opportunities and quality of life of people facing diabetes every day in the Rome metropolitan area. Key messages An important issue concerns information. A clear need emerged for further elaboration of the various aspects of a disease that tends to be underestimated also by those who have it. The living environment in important too and the actions on its urban planning, mobility, in everyday life organization, as factors that can make a difference in properly managing the disease.

Novel markers of vascular disease in diabetes could help identify new disease pathways and enhance risk stratification. Osteoprotegerin (OPG) and osteopontin (OPN) are key molecules involved in bone and vascular calcification processes, both compromised in diabetes. To evaluate whether OPG and/or OPN are associated with diabetic vascular complications, we measured their serum concentrations in 995 type 2 diabetes subjects enrolled in the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study. Any association with history of cardiovascular disease (CVD), diabetic retinopathy (DR) and reduced eGFR were examined with ANOVA, correcting for age, gender, HbA1c and lipid profile. Among the population, 15.7% had CVD, 18.4% had DR, 12.0% had an eGFR between 45-59 ml/min/1.73m2 and 7.5% had an eGFR Disclosure E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. K. Park: None. M. Di Guida: None. L. Coraggio: None. C. Luordi: None. L. D’Onofrio: None. M.G. Baroni: None. M.G. Cavallo: None. P. D’Angelo: None. S. De Cosmo: None. F. Leonetti: None. S. Morano: None. L. Morviducci: None. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. S. Prudente: None. G. Pugliese: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma International, Sanofi-Aventis, Sigma-tau, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Laboratori Guidotti. V. Trischitta: None. R.R. Holman: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. R. Buzzetti: Advisory Panel; Self; Sanofi. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Merck Sharp & Dohme Corp. Funding European Foundation for the Study of Diabetes; AstraZeneca (MS 2017_2); Società Italiana di Diabetologia

The risk of cardiovascular disease (CVD) (myocardial infarction, stroke, peripheral vascular disease) is twice in type 2 diabetes (T2D) patients compared to non-diabetic subjects. Furthermore, cardiovascular disease (CV) is the leading cause of death in patients with T2D.In the last years several clinical intervention studies with new anti-hyperglycaemic drugs have been published, and they have shown a positive effect on the reduction of mortality and cardiovascular risk in T2D patients. In particular, these studies evaluated sodium/glucose-2 cotransporter inhibitors (SGLT2i) and Glucagon-like peptide-1 receptor agonists (GLP-1RA).In secondary prevention, it was clearly demonstrated that SGLT2i and GLP-1RA drugs reduce CV events and mortality, and new guidelines consider now these drugs as first choice (after metformin) in the treatment of T2D; there are also some signs that they may be effective also in primary prevention of CVD. However, the mechanisms involved in cardiovascular protection are not yet fully understood, but they appear to be both "glycaemic" and "extra-glycaemic".In this review, we will examine the fundamental results of the clinical trials on SGLT2i and GLP-1RA, their clinical relevance in term of treatment of T2D, and we will discuss the mechanisms that may explain how these drugs exert their cardiovascular protective effects.

Obesity in youth is associated with increased risk of metabolic disorders. Adipose tissue hormones are involved in body-weight regulation. Among these, apelin is recognized as an insulin-sensitizer adipokine. Data on apelin levels in obese children and its relation to insulin-sensitivity are limited.We aimed to evaluate apelin levels in relation to obesity and insulin sensitivity in a large cohort of overweight/obese children and adolescents. Furthermore, these youths were reevaluated after a median 6.5 years of follow-up, thus allowing assessing changes in apelin levels in relation to increasing age and weight changes.Clinical data in 909 children and adolescents were collected between 2007 and 2010. Two hundred and one were reexamined at a median 6.5 years of follow-up. All subjects at baseline and at follow-up underwent an OGTT. Apelin levels were measured on sera by ELISA method.At baseline, lower apelin levels were associated with increasing age and puberty (Tanner ≥II 0.67 ± 0.96 ng/mL vs. Tanner I 0.89 ± 1.13 ng/mL,Apelin levels decrease significantly with pubertal development, whilst body-weight in children and adolescents did not determine changes in apelin. Reduced levels of apelin in children and adolescents may therefore represent a necessary response to maintain the "physiological" insulin resistance of puberty.

Angiopoietin-like protein 4 (ANGPTL4) regulates lipid partitioning by inhibiting circulating and tissue lipoprotein lipase (LPL), ANGPTL4 loss-of-function variants improve insulin sensitivity and reduce type 2 diabetes (T2D) risk with mechanisms partially unknown. This study was designed to explore metabolic implications of differential ANGPTL4 and LPL expression in human adipose tissue (AT). We recruited eighty-eight obese individuals, with and without abnormal glucose metabolism (AGM), undergoing bariatric surgery, visceral AT (VAT) fragments were obtained intra-operatively and analyzed by immunohistochemistry and mRNA by rt-PCR. Data on hepatic ANGPTL4 mRNA were available for 40 participants. VAT ANGPTL4 expression was higher in AGM individuals than in those with normal glucose tolerance (NGT) and associated with VAT inflammation, insulin resistance, and presence of adipocyte size heterogeneity. Increased ANGPTL4 was associated with AGM with OR = 5.1 (95% C.I.: 1.2&ndash, 23, p = 0.02) and AUROC = 0.76 (95% C.I.: 1.2&ndash, p &lt, 0.001). High LPL was associated with the detection of homogeneous adipocyte size, reduced microvessel density, and higher HIF-1&alpha, levels and inversely correlated to blood transaminases. In conclusion, in obese individuals, VAT ANGPTL4 levels are increased in the presence of local inflammation and AGM. Conversely, higher LPL expression describes a condition of increased lipid storage in adipocytes, which may serve as a protective mechanism against ectopic fat accumulation and related metabolic disease in obesity.

AIMS Experimental data suggest that visceral adipose tissue (VAT) dysfunction contributes to non-alcoholic fatty liver disease (NAFLD) development in obesity, however, data on humans are limited. Aims of this study were to investigate the relationship between NAFLD and VAT morphofunctional impairment and to determine whether the extent of VAT remodelling is associated with liver damage and metabolic alterations in obesity. METHODS We analysed data from 40 obese individuals candidate to bariatric surgery in whom paired intraoperative liver and omental biopsies were performed for diagnosing NAFLD and VAT inflammation by immunohistochemistry and mRNA expression studies. RESULTS Within our study population, NAFLD was significantly associated with greater VAT CD68+ macrophages infiltration (P = .04), fibrosis (P = .04) and impaired microvascular density (P = .03) as well as increased expression of markers of local hypoxia, apoptosis and inflammation (UNC5B, CASP7, HIF1-α, IL-8, MIP2, WISP-1, all P

The risk of cardiovascular disease (CVD) (myocardial infarction, stroke, peripheral vascular disease) is twice in type 2 diabetes (T2D) patients compared to non-diabetic subjects. Furthermore, cardiovascular disease (CV) is the leading cause of death in patients with T2D.

OBJECTIVE: To evaluate the association between high uric acid (UA), reduced estimated glomerular filtration rate (eGFR), and non-alcoholic fatty liver disease (NAFLD) in outpatient children and adolescents with overweight (OW) or obesity (OB). METHODS: Anthropometric, biochemical, hepatic ultrasound and eGFR data were available from 2565 young people with OW/OB (age 5-18 years). eGFR was calculated using the Schwartz's bedside formula and reduced eGFR (ReGFR+) was defined by a value < 90 mL/min/1.73 m2. High UA was defined as >= 75th percentile by sex in children and adolescents. RESULTS: The population was stratified in four categories: (1) normal eGFR and absence of NAFLD (ReGFR-/NAFLD-) (n = 1,236); (2) ReGFR+ and absence of NAFLD (ReGFR+/NAFLD- (n = 155); (3) normal eGFR and presence of NAFLD (ReGFR-/NAFLD+) (n = 1019); (4) presence of both conditions (ReGFR+/NAFLD+) (n = 155). Proportions of youth with high UA across the four categories were 17%, 30%, 33% and 46%, respectively (P < 0.0001). Young people with high levels of UA had odds ratio (95% CI) of 2.11 (1.43-3.11) for ReGFR+; 2.82 (2.26-3.45) for NAFLD+; and 5.04 (3.45-7.39) for both conditions (P < 0.0001 for all), independently of major confounders. CONCLUSIONS: High levels of UA were independently associated with ReGFR, NAFLD and the combination of both conditions in young people with OW/OB. The strength of this association was the highest in cases presenting both reduced eGFR and NAFLD. UA may serve as marker to identify patients at risk for these conditions.

Objective ANGPTL4 inhibits lipoprotein lipase in adipose tissue, regulating plasma triglycerides levels. In persons with obesity plasma ANGPTL4 levels have been positively correlated with body fat mass, TG levels and low HDL. A loss-of-function E40K mutation in ANGPTL4 prevents LPL inhibition, resulting in lower TGs and higher HDLc in the general population. Since obesity determines metabolic alterations and consequently is a major risk factor for cardiovascular disease, the aim was to explore if obesity-related metabolic abnormalities are modified by the ANGPTL4-E40K mutation. Methods ANGPTL4-E40K was screened in 1206 Italian participants, of which 863 (71.5%) with obesity. All subjects without diabetes underwent OGTT with calculation of indices of insulin-sensitivity. Results Participants with obesity carrying the E40K variant had significantly lower TG (p = 0.001) and higher HDLc levels (p = 0.024). Also in the whole population low TGs and high HDLc were confirmed in E40K carriers. In the obese subpopulation it was observed that almost all E40K carriers were within the lowest quartile of TGs (p = 1.1 × 10-9). E40K had no substantial effect of on glucose metabolism. Finally, none of the obese E40K carriers had T2D, and together with the favourable lipid profile, they resemble a metabolically healthy obese (MHO) phenotype, compared to 38% of E40E wild-type obese that had diabetes and/or dyslipidaemia (p = 0.0106). Conclusions In participants with obesity the ANGPTL4-E40K variant protects against dyslipidemia. The phenotype of obese E40K carriers is that of a patient with obesity without metabolic alterations, similar to the phenotype described as metabolic healthy obesity.

Gestational diabetes mellitus (GDM) is the most frequent complication of pregnancy; around 10% of GDM cases may be determined by autoimmunity, and our aims were to establish the role of autoimmunity in a population of Sardinian women affected by GDM, to find predictive factors for autoimmune GDM, and to determine type 1 diabetes (T1D) auto-antibodies (Aabs) together with glucose tolerance after a mean 21.2 months of follow-up. We consecutively recruited 143 women affected by GDM and 60 without GDM; clinical data and pregnancy outcomes were obtained by outpatient visit or phone recall. T1D auto-antibodies GADA, IA2-A, IAA, ZnT8-A were measured in the whole population at baseline, and in the Aab-positive women at follow-up. The overall prevalence of autoimmunity was 6.4% (13/203). No significant difference was found in the prevalence of auto-antibodies between GDM (5.6%) and control (8.3%) women, neither in antibody titres. Highest titres for GADA and ZnT8-A were observed in the control group; no phenotypic factors were predictive for autoimmune GDM. Diabetes-related autoantibodies were still present in all the GDM women at follow-up, and their presence was associated with a 2.65 (p

Vitamin D acts through the binding to the vitamin D receptor (VDR). Several polymorphisms in VDR gene have been studied. Among these, the rs2228570 CT (FokI) variant has been demonstrated to be functional, leading to a protein with a different size and activity. So far, genetic studies on the association between VDR gene rs2228570 single nucleotide polymorphism (SNP) and type 2 diabetes mellitus (T2DM) showed contradictory results. Thus, we performed an association study in a large cohort of adult Italian subjects with T2DM and in nondiabetic controls.For this study, 1713 subjects, 883 T2DM patients and 830 controls, were genotyped for the polymorphism. All participants without a diagnosis of diabetes underwent oral glucose tolerance test (OGTT), with measurement of glucose and insulin levels. Indices of insulin resistance (Homeostatic model assessment of insulin resistance, insulin sensitivity index), secretion (homeostatic model assessment for beta-cell, corrected insulin response at 30 minutes) and disposition index were calculated.Genotype distributions and allele frequencies did not show difference between T2DM subjects and controls. We did not find significant differences among the three genotypes regarding gender, age, BMI, waist, hip, waist-to-hip ratio, and blood pressure. There were also no significant differences in lipid parameters, aspartate aminotransferase, and alanine aminotransferase levels. We tested for association with OGTT-derived data and surrogate indices of insulin resistance and secretion. We did not find significant differences among the genotypes in any of above-mentioned parameters. Furthermore, vitamin D levels were measured in a subgroup of subjects. We did not find significant differences among the genotypes.Our study does not provide evidence for the association of the rs2228570 polymorphism with T2DM in a Caucasian population.

Adipose tissue (AT) is one of the largest endocrine organs contributing to metabolic homeostasis. The functional pleiotropism of AT depends on its ability to secrete a large number of hormones, cytokines, extracellular matrix proteins and growth factors, all influencing many local and systemic physiological and pathophysiological processes. In condition of chronic positive energy balance, adipocyte expansion, hypoxia, apoptosis and stress all lead to AT inflammation and dysfunction, and it has been demonstrated that this sick fat is a main risk factor for many metabolic disorders, such as type 2 diabetes mellitus, fatty liver, cardiovascular disease and cancer. AT dysfunction is tightly associated with aberrant secretion of bioactive peptides, the adipocytokines, and their blood concentrations often reflect the expression in the AT. Despite the existence of an association between AT dysfunction and systemic pro-inflammatory state, most of the circulating molecules detectable in obese and dysmetabolic individuals do not identify specifically the condition of sick fat. Based on this premise, this review provides a concise overview of “classic” and novel promising adipocytokines associated with AT inflammation and discusses possible critical approaches to their interpretation in clinical practice.

Biliverdin reductase-A (BVR-A) is a serine/threonine/tyrosine kinase involved in the regulation of insulin signaling. In vitro studies have demonstrated that BVR-A is a substrate of the insulin receptor and regulates IRS1 by avoiding its aberrant activation, and in animal model of obesity the loss of hepatic BVR-A has been associated with glucose/insulin alterations and fatty liver disease. However, no studies exist in humans. Here, we evaluated BVR-A expression levels and activation in peripheral blood mononuclear cells (PBMC) from obese subjects and matched lean controls and we investigated the related molecular alterations of the insulin along with clinical correlates. We showed that BVR-A levels are significantly reduced in obese subjects and associated with a hyper-activation of the IR/IRS1/Akt/GSK-3β/AS160/GLUT4 pathway. Low BVR-A levels also associate with the presence of obesity, metabolic syndrome, NASH and visceral adipose tissue inflammation. These data suggest that the reduction of BVR-A may be responsible for early alterations of the insulin signaling pathway in obesity and in this context may represent a novel molecular target to be investigated for the comprehension of the process of insulin resistance development in obesity.

Dipeptidyl peptidase 4 (DPP4) is a key enzyme involved in the regulation of the incretin system exerted by cleaving the glucagon-like peptide 1 (GLP-1); the blockage of DPP4, exerted by the antidiabetic agents DPP4-inhibitors (DPP4-I), results in greater GLP-1 concentration and improved glycaemic control. DPP4 acts also as a pro-inflammatory molecule and mediates vascular damage in experimental models. The relationship between DPP4 activity and endothelial function in diabetes has not been explored yet. Aim of this study was to investigate systemic plasma DPP4 activity in relation to endothelial function in patients with type 2 diabetes mellitus (T2DM).Sixty-two T2DM individuals were recruited in our Diabetes outpatient clinics, Sapienza University, Rome, Italy. All participants underwent complete clinical work-up; endothelial function was evaluated by flow-mediated dilatation (FMD) test; plasma DPP4 activity was assessed by measuring the 7-amino-4-methylcoumarin (AMC) cleavage rate from the synthetic substrate H-glycyl-prolyl-AMC and compared with DPP4 activity measured in sixty-two age-, sex-, BMI-matched non-diabetic subjects. Patients with T2DM had significantly higher DPP4 activity than non-diabetic individuals (211,466 ± 87657 vs 158,087 ± 60267 nmol/min/ml, p 0.001); in T2DM patients, greater DPP4 activity significantly correlated with lower FMD whereas was not associated with BMI and metabolic control. Greater systemic DPP4 activity was an independent predictor of reduced FMD after adjusting for age, gender and other confounders.Circulating DPP4 activity is increased in individuals with T2DM and associated with signs of endothelial dysfunction such as impaired FMD. DPP4 may negatively affect endothelial function through mechanisms beyond glucose homeostasis and metabolic control.