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The cover image is based on the Research Article Type 2 diabetes albuminuric and non-albuminuric phenotypes have different morphological and functional ultrasound features of diabetic kidney disease by Monia Garofolo et al., https://doi.org/10.1002/dmrr.3585.

Whether different diabetic kidney disease (DKD) phenotypes recognise differences in morphological and vascular properties of the kidney is still unexplored. We evaluated the potential role of kidney ultrasonography in differentiating DKD phenotypes in subjects with type 2 diabetes.This is a cross-sectional, single-centre study. Total (TRV) and parenchymal renal volumes (PRV) were calculated by applying the ellipsoid formula for conventional (2D) ultrasonography and with manual segmentation for 3D ultrasonography, and then adjusted for body surface area (aTRV, aPRV). Renal resistive index (RI) was contextually determined. DKD phenotypes have been defined based on increased urinary albumin-to-creatinine ratio (ACR30 mg/g) and/or reduced eGFR (60 ml/min/1.73 mAmong 256 subjects, 26.2% had No-DKD, 24.6% increased albuminuria only (AlbAs a novel information, we reported that, in type 2 diabetes, the emerging normoalbuminuric DKD phenotype showed reduced TRVs and PRVs even when compared, at similarly reduced eGFR levels, with Alb

Nonalcoholic fatty liver disease (NAFLD) increases overall and CVD mortality. We prospectively observed 774 T1D to assess impact of FLI (based on BMI, waist, GGT and triglycerides) on all-cause death and CVD (MI, stroke, amputation, revascularizations) risk. Over a 11-year follow-up, 57 subjects died (7.4%) and 49 CV events (6.7%) occurred among 736 T1D with retrievable incidence data. FLI was Disclosure M.Garofolo: Employee; Eli Lilly and Company. D.Lucchesi: None. E.Gualdani: None. P.Falcetta: Speaker's Bureau; Abbott Diabetes. M.Giambalvo: None. P.Francesconi: None. S.Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. G.Penno: Advisory Panel; Eli Lilly and Company.

SIRT1 exerts effects on ageing and lifespan, as well cardiovascular (CV) disease risk. SIRT1 gene is very polymorph with a few tagging single nucleotide polymorphisms (SNPs) so far identified. Some SNPs, including rs7896005, were associated with type 2 diabetes (T2DM). We aimed to ascertain whether this SNP may be associated with CV disease at baseline as well with these same outcomes and all-cause mortality over a 13-year follow-up.Genotypes of SIRT1 gene were determined using TaqMan SNP assay.Out of 905 T2DM, 9.1% had the AA genotype, 43.2% the AG, and 47.7% the GG. Hardy-Weinberg Equilibrium was met (minor allele frequency 0.306; p = 0.8899). At baseline, there was no difference across genotypes for sex, age, diabetes duration, CV risk factors, treatments, and microangiopathy. Major CV outcomes, myocardial infarction (MI), any coronary heart disease (CHD), and peripheral artery disease (PAD) were more frequent in GG than in AA/AG (p from 0.013 to 0.027), with no association with cerebrovascular events. By fully adjusted regression, GG remained independently related to major CV outcomes, MI, CHD, and PAD. Over follow-up, we recorded 258 major CV events (28.5%; AA/AG 25.2%, GG 32.2%; p = 0.014) with an adjusted hazard ratio (HR) of GG versus AA/AG of 1.296 (95% CI 1.007-1.668, p = 0.044); 169 coronary events (18.7%; AA/AG 15.4%, GG 22.2%; p = 0.006) with HR 1.522 (1.113-2.080, p = 0.008); 79 (8.7%) hospitalisation for heart failure (AA/AG 7.0%, GG 10.6%; p = 0.045) and HR 1.457 (0.919-2.309, p = 0.109); 36 PAD (4.0%; AA/AG 2.3%, GG 5.8%; p = 0.007) with HR 2.225 (1.057-4.684, p = 0.035). No association was found with cerebrovascular events, end stage renal disease, and all-cause mortality.The rs7896005 SNP of SIRT1 might play a role in cardiovascular disease, mainly CHD risk in T2DM. Results call for larger association studies as well as studies to ascertain mechanisms by which this variant confers increased risk.

Type 1 diabetes (T1D) has higher risk of death and CVD compared with general population. Effective risk stratification is essential to implement preventive strategies. We compare the performance of Steno Type 1 Risk Engine (ST1RE) and EURODIAB PCS Risk Engine (EURO-RE) in 733 T1D (M 52%; age 39.3±11.1; DD 18.5±11.6; A1c 7.8±1.2%) with no prior CVD over a 11-yr follow-up (IQR: 9.9-13.0). Both models include age, A1c and albuminuria; ST1RE includes 7 more variables (sex, DD, SBP, LDL-C, eGFR, smoking and exercise), EURO-RE only 2 more variables (WHR, HDL-C). By ST1RE, 453 T1D (61.8%) had low- ( Disclosure M. Garofolo: Consultant; Self; Eli Lilly and Company. E. Gualdani: None. D. Lucchesi: None. P. Falcetta: None. P. Francesconi: None. S. Del prato: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Sanofi. G. Penno: Advisory Panel; Self; Eli Lilly and Company.

Fibroblast growth factor 23 (FGF23) targets tubular epithelial cells to promote phosphaturia and it has been associated with adverse outcomes in chronic kidney disease (CKD). Emerging data suggest that FGF23 plays a specific role in type 2 diabetes (T2D). We evaluated intact FGF23 (iFGF23) levels (plasma EDTA; chemiluminescence immunoassay) in 182 T2D subjects with no-DKD (n = 46), with albuminuria alone (ACR ≥30 mg/g; DKD stages 1-2, n = 48), with eGFR Disclosure M. Garofolo: Consultant; Self; Eli Lilly and Company. C. Pelosini: None. D. Lucchesi: None. P. Falcetta: None. M. Sessa: None. S. Del prato: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Sanofi. G. Penno: Advisory Panel; Self; Eli Lilly and Company.

In spite of being at target for glucose (1) or traditional cardiovascular (CV) risk factors (2), individuals with type 1 diabetes (T1D) still have an excess of CV mortality and morbidity implying a role for other mechanisms including insulin resistance (IR). Impaired insulin action in T1D was established by clamp technique long ago (3). Estimated glucose disposal rate (eGDR) correlates well with the clamp technique (4) and is a risk marker for microangiopathy (5,6), diabetic kidney disease (DKD) (6), CV risk, and mortality (5,7). In this observational single-center study, we investigated to what extent eGDR is a predictor of CV events, coronary artery disease (CAD), and all-cause mortality irrespective of CV risk factors and DKD in 774 subjects with T1D over a 10-year follow-up, as previously described (8). eGDR (mg/kg/min) was calculated at baseline as follows (4): eGDR = 21.158 − (0.09 × WC) − (3.407 × HTN) − (0.551 × HbA1c), where WC is waist circumference (cm), HTN is hypertension (yes = 1, no = 0), and HbA1c is in %. Follow-up data were retrieved from the national and regional health care registers (ICD-9, Clinical Modification, codes) by searching for CV outcomes (primary outcome) up to 31 December 2017 and for all-cause death up to 31 October 2018. Incidence of CV outcomes was available for 736 participants (95.1%), and vital status was available for all individuals (8). We used univariate and multivariate Cox proportional hazards models to …

Scalability is one of the important factors slowing down or even impeding the clinical translation of nanoparticle-based systems. The latter need to be manufactured at a high level of quality, with batch-to-batch reproducibility, and need to be stable after the manufacturing process, during long-term storage and upon clinical administration. In this study, a vesicular formulation intended for cutaneous applications was developed by the easy reconstitution of a commercially available liposomal platform. Resveratrol, a naturally occurring compound with potent antioxidant activity, and Tween80, a hydrophilic non-ionic surfactant, were included in the formulation. The physico-chemical properties of the vesicles were assessed using light scattering and cryogenic transmission electron microscopy. Nanosized (around 80 nm) spherical and elongated, unilamellar vesicles were produced, with remarkable storage stability. The incorporation of resveratrol in the vesicular system did not alter its strong antioxidant activity, as demonstrated by antioxidant colorimetric assays (DPPH and FRAP). Furthermore, the resveratrol liposomes were cytocompatible with fibroblasts and capable of protecting skin cells from oxidative stress by reducing both endogenous and chemically induced reactive oxygen species more effectively than free resveratrol. Therefore, the proposed formulation, based on the use of a commercially available liposomal platform, represents an easy-to-prepare, reproducible, up-scaled and efficient means of delivering resveratrol and potentiating its biological activity in vitro.

Non-albuminuric diabetic kidney disease (Alb-DKD) has been associated with a raised risk of CV outcomes and all-cause mortality in T1D. We report about the association between DKD phenotypes and CV outcomes in a single-centre, prospective, 10.4±2.9 years observation of 774 T1D. Rates of outcomes and vital status were censored on December 2017. Out of 774 T1D, 692 (89.4%) had no-DKD, 53 DKD 1-2 (6.8%), 17 (2.2%) Alb-DKD and 12 (1.6%) Alb+DKD. Incidences of CV outcomes, coronary events and ESRD were available for 736 subjects (95.1%). A CV event occurred in 49 T1D (6.7%; 6.42 events x 1000 PYs), rising from no-DKD (4.2%) to DKD 1-2 (28.6%) and Alb-DKD (35.3%). In Alb+DKD, due to competition with all-cause death, only 1 event occurred. Compared to no-DKD, the adjusted HRs were 4.43 (95%CI 2.27-8.61, p Disclosure M. Garofolo: None. E. Gualdani: None. F. Campi: None. M. Aragona: None. D. Lucchesi: None. C. Bianchi: None. R. Miccoli: None. P. Francesconi: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Takeda Pharmaceutical Company Limited.

Microvascular complications (MC) affect CV risk and mortality in T2D. We explored the association of cumulative burden of retinopathy, nephropathy and peripheral neuropathy with mortality, CV events and ESRD in a single-centre, observational study involving 986 T2D over a 12.9±2.7 yrs follow-up. Vital status and rates of outcomes were censored on December 2017. The cohort included 491 (49.8%), 318 (32.3%), 135 (13.7%) and 42 (4.3%) people with no, 1, 2 or 3 MC. All-cause mortality (23.3%) increased from no-MC (15.3%) to 1 MC (23.3%, HR 1.60; 95%CI 1.16-2.20), 2 MC (41.5%, 3.19; 2.25-4.51) and 3 MC (59.5%, 5.32; 3.38-8.36; p Disclosure M. Garofolo: None. E. Gualdani: None. R. Giannarelli: None. D. Lucchesi: None. R. Miccoli: None. P. Francesconi: None. S. Del Prato: Advisory Panel; Self; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Takeda Pharmaceutical Company Limited. G. Penno: None.

Aims Albuminuric and non-albuminuric phenotypes of chronic kidney disease (CKD) may have different cardiovascular risk and survival in type 1 diabetes (T1DM). Herein we estimated risk of major vascular outcomes by the EURODIAB PCS score and determined all-cause mortality rate in 774 T1DM according to CKD phenotypes. Methods We evaluated the distribution of CKD phenotypes [no CKD, stages 1–2, non-albuminuric stage ≥3 (Alb−CKD), albuminuric stage ≥3 (Alb+CKD)], the EURODIAB risk score for major vascular outcomes [low- (LS), intermediate- (IS), and high- (HS) risk] and all-cause mortality over a follow-up of 8.25 ± 2.34 years. Results Out of 774 subjects, 692 (89.4%) had no CKD, 53 (6.8%) CKD stages 1–2, 17 (2.2%) Alb−CKD and 12 (1.6%) Alb+CKD; 466 (60.2%) had LS, 205 (26.5%) IS and 103 (13.3%) HS. Distribution of HS was: no CKD, 9.1%; CKD stages 1–2, 34.0%; Alb−CKD, 64.7%; Alb+CKD, 91.7% (P Conclusions In our T1DM cohort, one fifth of those with CKDs were non-albuminuric. This phenotype was associated with higher risk of major outcomes and similar rate of mortality as compared to CKD stages 1–2. The greatest risk and highest mortality occur in patients with Alb+CKD.

In a retrospective, observational, cross-sectional, single-centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes. From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 ± 11.7 years, diabetes duration 19.4 ± 12.2 years, HbA1c 7.83 ± 1.17% [62.0 ± 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators. Normo- (ACR

Estimated Glucose Disposal Rate (eGDR), a validated tool to estimate insulin sensitivity (IS) in T1DM [eGDR = 21.158 - (0.09 x WC, cm) - (3.47 x hypertension, yes = 1) - (0.551 x HbA1c, %)], has been associated to all-cause death. The relationship between eGDR and major vascular (CV) events was evaluated in 736 T1DM enrolled in an observational, single-centre study over a 10-year follow-up. Incidence of CV and coronary events were obtained by interrogating hospital discharge registers. Mean eGDR was 7.51±2.26 (M±SD) mg/kg/min (median 8.26; IQR 5.53-9.29). According to the “Swedish National Diabetes Register,” eGDR was stratified in: C1: ≥8.0 (N. 399, 54.2%, ref); C2: 6.0-7.99 (N. 121, 16.4%); C3: 4.0-5.99 (N. 144, 19.6%) and C4: Disclosure M. Garofolo: None. E. Gualdani: None. R. Giannarelli: None. M. Aragona: None. F. Campi: None. D. Lucchesi: None. G. Daniele: None. R. Miccoli: None. P. Francesconi: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. G. Penno: None.

Genetic variants of SIRT1, in particular the G allele of the rs7896005 SNP, are associated with increased risk for T2DM. We recently reported that this SNP was not associated with all-cause mortality over a 13-year follow-up. We are now exploring the association of this SNP with incidence of major CV events in 917 T2DM (98.6% of the original cohort). Incidence data were obtained by interrogating hospital discharge registers. Genotypes distribution was: AA, n. 83 (9.1%), AG, n. 397 (43.3%), GG, n. 437 (47.7%). MAF was 0.307 and Hardy-Weinberg equilibrium met (chi-square 0.2809, p=0.596). There was no difference across genotypes for major CV risk factors and treatments. Over 11.25±4.40 years, 261 major CV events occurred (28.5%): AA/AG n. 121, 25.2%; GG n. 140, 32.0% (K-M logrank 5.798, p=0.016). After adjustment for age, sex, DD, BMI, HbA1c, A/C ratio, eGFR (CKD-EPI), smoking, hypertension, dyslipidemia, retinopathy, peripheral neuropathy and prior CV events, HR of GG vs. AA/AG was 1.28 (95% CI 1.00-1.65, p=0.047). Over 11.81±4.06 years, 176 coronary events occurred (19.2%): AA/AG n. 77, 16.0%; GG n. 99, 22.7% (K-M logrank 7.093, p=0.008). After adjustment, HR vs. AA/AG was 1.47 (1.09-2.00, p=0.013). A total of 81 (8.8%) hospitalization for heart failure (HF) occurred over a follow-up of 12.75±3.11 years: AA/AG n. 33, 6.9%; GG n. 48, 11.0% (K-M logrank 4.999, p=0.025). After correction, HR vs. AA/AG was 1.54 (0.98-2.42, p=0.063). Finally, over 12.92±2.95 years, 36 peripheral vascular events occurred (3.9%): AA/AG n. 11, 2.3%; GG n. 25, 5.7% (K-M logrank 7.320, p=0.007). After adjustment, HR vs. AA/AG was 2.15 (1.02-4.50, p=0.043). No association was found with cerebrovascular events and ESRD. With the limitations of the relatively small sample size, but the strength of the long-term observation, we suggest that in T2DM rs7896005 A/G SNP of SIRT1 is independently associated with incidence of major CV, coronary and peripheral vascular events and also with hospitalization for heart failure. Disclosure G. Penno: None. M. Garofolo: None. E. Gualdani: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. A. Dardano: None. P. Francesconi: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited.

Metabolic Syndrome (MetS) is associated with CV events in T2DM. We assessed over a 13-years follow-up the association between a “MetS severity score”, derived from WC, sBP, HDL and triglycerides (courtesy Dr. Mark DeBoer) and both all-cause death and incident CV events in 986 T2DM. Compared to lowest quartile, Q2-4 showed a steeply worsening CV risk profile. A total of 230 deaths occurred over 12.9±2.7 years (23.3%; 18.0 x 1000 PYs). Death rate was J-shaped: Q1 22.4%; Q2 18.2%; Q3 25.9% and Q4 26.8% (p=0.090). Electing arbitrarily Q2 as reference, and after adjustment for confounders and, finally, for parameters of MetS score, HRs (95% CI) vs. Q2 for death were: Q1 1.46 (0.97-2.19; p=0.070), Q3 1.61 (1.09-2.38; p=0.016) and Q4 1.82 (1.20-2.75, p=0.005). Over 11.3±4.4 years, 276 major CV events occurred in 972 T2DM (28.4%; 25.2 x 1000 PYs); adjusted HRs vs. Q1 were: Q2 1.34 (0.93-1.93; p=0.117), Q3 1.99 (1.40-2.82, p Disclosure M. Garofolo: None. E. Gualdani: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. P. Francesconi: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited.

BackgroundMicrovascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes.MethodsWe recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis.ResultsOut of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59–7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65–15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42–94.57], p ConclusionsIn type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

Background: To which extent the presence of one or more microvascular complication (MC) affects cardiovascular (CV) outcomes and mortality in diabetes is still debated. We evaluated the relationship between MC and incidence of major CV events and all-cause mortality in type 1 diabetes. Methods: We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10*8±2*5 years. Hazard Ratios (HR) for outcomes were determined by unadjusted and adjusted Cox regressions. Findings: Out of 774 individuals, 54·9% had no-MC, 32·3% 1 MC, 9·7% 2 MC and 3·1% 3 MC. A total of 54 deaths occurred. Death rate increased from no-MC 2·1% (Ref) to 1-MC 7·2% (HR 3·54 [95% CI 1·59–7·87]), 2-MC 14·7% (6·41 [2·65–15·49]) and 3-MC 66·7% (41·73 [18·42–94·57]; p

Gonzalez-Clemente et al. (1) claim that a simpler though efficient assessment of cardiovascular risk in people with type 1 diabetes (T1D) is much needed. Since we showed that the estimated glucose disposal rate (eGDR) was an independent predictor of cardiovascular (CVD) and coronary artery disease (CAD) in people with T1D, they evaluated whether cutoff eGDR values could be calculated to be used in clinical practice to stratify CVD risk. They used the Steno Type 1 Risk Engine (ST1RE) (2) in 179 T1D subjects without CVD to identify 10-year risk level for a first CVD event: low (

Metabolic Syndrome (MetS) is identified by dichotomous criteria thus masking MetS-related risk exists as a continuum. We assessed the association of a “MetS severity score” (MSs; courtesy Dr. M. DeBoer) with all-cause death in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) over a 10.6±2.5 year follow-up. MSs was derived from WC, sBP, HDL and triglycerides (no glucose). Mean MSs was -0.5046±0.6717 (median -0.5820; IQR -0.9556 to -0.1529). MSs was stratified by quartiles. Compared to Q1, Q2-4 had a worse CV risk profile with increasing age, BMI, dBP, fasting glucose, HbA1c, total-, LDL- and nonHDL-Ch, uric acid and fibrinogen (p Disclosure G. Penno: None. M. Garofolo: None. R. Giannarelli: None. F. Campi: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. A. Dardano: None. G. Daniele: None. R. Miccoli: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Insulin resistance (IR) was described in type 1 diabetes (T1D) and is related to higher risk of complications. The association of estimated Glucose Disposal Rate (eGDR), a proxy of IR, to all-cause mortality was assessed in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a follow-up of 10.6±2.5 years. Mean eGDR was 7.52±2.28 mg/kg/min (median 8.29; IQR 5.54-9.31). In agreement with the “Swedish National Diabetes Register” eGDR was stratified in 4 categories: C1: ≥8.0 (n. 424, 54.8%); C2: 6.0-7.99 (n. 125, 16.1%); C3: 4.0-5.99 (n. 149, 19.3%) and C4: Disclosure M. Garofolo: None. A. Bertolotto: None. F. Campi: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. A. Dardano: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Type 1 diabetes (T1D) is associated with a sustantially increased risk of cardiovascular (CV) events and premature death. The effect of the microvascular disease (MD) burden, i.e., the cumulative burden of retinopathy, nephropathy and peripheral neuropathy on all-cause mortality was evaluated in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a mean follow-up of 10.6±2.5 years. Distribution of MD was: no-MD: n. 425 (54.9%); MD1: 250 (32.3%); MD2: 75 (9.7%); MD3: 24 (3.1%). Distribution was unchanged after esclusion of 41 T1D (5.3%) with previous CV events (CV+; 57.0%, 32.2%, 8.5% and 2.3%, respectively). Compared to no-MD, MD1-3 groups showed an adverse CV risk profile with steeply increase in age, DD, BMI, WHR, BP, HbA1c, uric acid and EURODIAB PCS risk score for major vascular outcomes (p Disclosure M. Garofolo: None. R. Giannarelli: None. M. Aragona: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Background High-density lipoproteins (HDLs) can exert anti-atherogenic effects. On top of removing excess cholesterol through reverse cholesterol transport, HDLs play beneficial actions on endothelial function and integrity. In particular, HDLs are strong determinant of endothelial progenitor cells (EPCs) number and function. To gain further insights into such an effect we characterized in vitro functionality of circulating “early” EPCs obtained from 60 type 2 diabetes individuals with low HDL-cholesterol (HDL-C) and 59 with high HDL-C levels. Methods After an overnight fast, venous blood was drawn in EDTA tubes and processed within 2-h from sampling. Peripheral blood mononuclear cells were isolated and plated on fibronectin coated culture dishes; after 3 days culture, adherent cells positive for Dil-ac-LDL/Lectin dual fluorescent staining were identified as monocytic angiogenic cells (MACs). After 5–7 days culture in EBM-2 medium, adherent cells were evaluated for viability/proliferation (MTT assay), senescence (beta-galactosidase activity detection), migration (modified Boyden chamber using VEGF as chemoattractant), adhesion capacity (on fibronectin-coated culture dishes) and ROS production (ROS-sensitive fluorescent probe CM-H2DCFDA). Results MACs obtained from diabetic individuals with high HDL-C had 23% higher viability compared to low HDL-C (111.6 ± 32.7% vs. 90.5 ± 28.6% optical density; p = 0.002). H2O2 exposure impaired MACs viability to a similar extent in both groups (109.2 ± 31.7% vs. 74.5 ± 40.8% in high HDL-C, p

Background and aims An intra-islet incretin system has been recently suggested to operate through modulation of the expression and activity of proconvertase 1/3 and 2 (PC1/3, PC2) in pancreatic alpha-cell accounting for local release of GLP-1. Little is known, whether this alpha-cell activity can be affected by the metabolic alterations occurring in type 2 diabetes, such as hyperglycemia, hyperlipidemia or hyperglucagonemia. Materials and methods AlphaTC1/6 cells from a mice pancreatic cell line were incubated in the presence of two glucose (G) concentration (5.5 and 16.7 mM) for 16 h with or without free fatty acid, IL6 or glucagon. GLP-1 secretion was measured by ELISA and expression of PC1/3 and PC2 by RT-PCR and western blot; cell viability was determined by MTT method, Reactive Oxygen Species generation (ROS) by H2DCFDA fluorescence and apoptosis by Annexin staining and Propidium Iodine (PI) fluorescence. Results Upon 16.7G incubation, GLP-1 secretion (total and active) was significantly increased in parallel with a significant increment in PC1/3 expression, a slight increase in cell viability and ROS generation and by a decrement in PC2 expression with no change in cell apoptosis. When cells were incubated at 5.5mM glucose with FFA, also an increment in GLP-1 secretion and PC1/3 expression was observed together an increment in ROS generation, a decrement in cell viability, and a modest increment in apoptosis. When incubated with 16.7mM glucose with FFA, the increment in GLP-1 secretion was reduced to basal, accompanied by an increment in apoptosis and ROS generation. This was also observed with IL-6, but in this case, no modification in ROS generation or apoptosis was observed when compared to 16.7mM glucose. The presence of glucagon did not modify any of the parameters studied. Conclusion These data suggest that under hyperglycemic, hyperlipidemia or inflammatory conditions, alpha cells can increase expression PC1/3 and activate GLP-1 secretion, which may contribute protecting both alpha and beta-cells from glucose and lipotoxicity, while this effect seems to be lost in the presence of both pathophysiological conditions.

Endogenous and exogenous signals derived by the gut microbiota such as lipopolysaccharides (LPS) orchestrate inflammatory responses contributing to development of the endothelial dysfunction associated with atherosclerosis in obesity, metabolic syndrome, and diabetes. Endothelial progenitor cells (EPCs), bone marrow derived stem cells, promote recovery of damaged endothelium playing a pivotal role in cardiovascular repair. Since healthy nutrition improves EPCs functions, we evaluated the effect of a fermented grain, Lisosan G (LG), on early EPCs exposed to LPS. The potential protective effect of LG against LPS-induced alterations was evaluated as cell viability, adhesiveness, ROS production, gene expression, and NF-kB signaling pathway activation. Our results showed that LPS treatment did not affect EPCs viability and adhesiveness but induced endothelial alterations via activation of NF-kB signaling. LG protects EPCs from inflammation as well as from LPS-induced oxidative and endoplasmic reticulum (ER) stress reducing ROS levels, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defense. Moreover, LG pretreatment prevented NF-kB translocation from the cytoplasm into the nucleus caused by LPS exposure. In human EPCs, LPS increases ROS and upregulates proinflammatory tone, proapoptotic factors, and antioxidants. LG protects EPCs exposed to LPS reducing ROS, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defenses possibly by inhibiting NF-κB nuclear translocation.

BACKGROUND: In Mexican Americans, the IRS1 G972R polymorphism (rs1801278) has been associated to such a marked reduction in glomerular filtration rate (GFR) (i.e. β = −8.3 mL/min/1.73 m(2)) to be considered a major determinant of kidney function. METHODS: This was a cross-sectional study to investigate whether a similarly strong effect can also be observed among individuals of European ancestry. We investigated a total of 3973 White patients with type 2 diabetes. Standardized serum creatinine was measured by the modified kinetic Jaffè reaction and estimated GFR (eGFR) calculated by the modification diet renal disease (MDRD) formula; rs1801278 was genotyped by TaqMan assay. RESULTS: No significant association was observed, with R972 carriers showing only a modestly, not significant, lower eGFR level as compared with other subjects (β = −1.82 mL/min/1.73 m(2), P = 0.086). CONCLUSIONS: Our data indicate that IRS1 G972R is not a strong determinant of GFR in diabetic patients of European ancestry as in Mexican Americans. Since we had 100% power to detect the previously reported association, the risk our finding is a false negative one is minimal.

This study focused on an extract from fermented flour from the Lady Joy variety of the common bean Phaseolus vulgaris. The extract, Lady Joy lysate (Lys LJ), is enriched in antioxidant compounds during the fermentation. We assessed it for its protective effect on endothelial cells treated with oxidized-LDL (ox-LDL). The oxidative stress was determined by measuring the contents of thiobarbituric acid-reactive substances and reactive oxygen metabolites. ICAM-1, ET-1 and IL-6 concentrations were assessed using ELISA. LOX-1 and CHOP expression were analyzed using both quantitative RT-PCR and ELISA or western blotting. Ox-LDL treatment induced significant oxidative stress, which was strongly reduced by pre-treatment with the extract. The ox-LDL exposure significantly enhanced ICAM-1, IL-6 and ET-1 levels over basal levels. Lys LJ pre-treatment exerted an inhibitory effect on ox-LDL-induced endothelial activation with ICAM-1 levels comparable to those for the untreated cells. IL-6 and ET-1 production, although reduced, was still significantly higher than for the control. Both LOX-1 and CHOP expression were upregulated after ox-LDL exposure, but this effect was significantly decreased after Lys LJ pre-treatment. Lys LJ alone did not alter the ICAM-1, IL-6 and ET-1 concentrations or CHOP expression, but it did significantly lower the LOX-1 protein level. Our data suggest that Lys LJ is an effective antioxidant that is able to inhibit the oxidation process, but that it is only marginally active against inflammation and ET-1 production in HMEC-1 exposed to ox-LDL.

Endothelial cells and endothelial progenitor cells (EPCs) play a key role in the pathogenesis of vascular disease. Both cell types are affected by the oxidative stress but their susceptibility may be different. This study aimed to investigate the antioxidative enzymes activated in EPCs after high constant glucose exposure as compared to endothelial cells (HUVECs). Both cells were incubated in the presence of normal (5mM) and high constant (25mM) d-glucose, as well as l-glucose as osmotic control for 48 and 96h. After a 48-hour exposure to high d-glucose, cell viability was significantly decreased both in EPCs and HUVECs as compared with normal d-glucose (p

BACKGROUND Polymorphisms within the gene for transforming growth factor (TGF)-beta-1, a pro-fibrogenic cytokine pathophysiologically involved in hypertension and hypertensive target damage, might modulate the biological activity of the encoded protein. Through that mechanism, they might contribute to microalbuminuria, a marker of subclinical renal damage and a correlate of systemic inflammation and endothelial dysfunction in hypertension, a possibility never before tested. For this reason, we assessed the association of four TGF-beta-1 polymorphic variants (C-509T, Leu(10)-->Pro, Arg(25)-->Pro, Thr(263)-->Ile) with albuminuria in uncomplicated essential hypertensive men, using (circulating active + acid-activatable latent) TGF-beta-1 levels as an indirect index of their in vivo biological activity. Because of the close pathophysiological link of TGF-beta-1 with the renin-angiotensin system, we also tested the behaviour of the angiotensin converting enzyme (ACE) deletion/insertion (D/I) polymorphism. METHODS Albuminuria (three overnight collections), office and 24-h BP, left ventricular mass index (LVMI), BMI, renal function, glucose, lipids, plasma TGF-beta-1 (n = 162, ELISA) were measured in 222 genetically unrelated, never-treated, uncomplicated Caucasian hypertensive men. ACE D/I polymorphisms were analysed by the polymerase chain reaction technique or a 5' nuclease assay with further restriction analysis when required. RESULTS Urine albumin levels or microalbuminuria (albuminuria > or =15 microg/min) did not differ by TGF-beta-1 genotypes, but both parameters were more frequent in ACE D/D homozygotes. Plasma TGF-beta-1 was similar across genetic backgrounds and was unrelated to albuminuria. Cardiovascular, renal, metabolic parameters were homogeneously distributed across genotypes. CONCLUSIONS In contrast to its link with the ACE D/I genotype, microalbuminuria was independent of TGF-beta-1 polymorphism in this group of never-treated, uncomplicated essential hypertensive men.

Background: Early identification of impairment in renal function is crucial in diabetic patients. Serum cystatin C may be the most sensitive indicator of glomerular filtration rate (GFR) in the clinical setting. Methods: We compared cystatin C with creatinine, the Cockcroft-Gault (C-G) formula, and the Modification of Diet in Renal Disease (MDRD) study equation for the assessment of early decreased renal function in 288 diabetic patients (125 type 1, 163 type 2) with renal impairment [GFR: 4–222 mL · min−1 · (1.73 m2)−1]. Relationships of cystatin C, creatinine, and iohexol clearance were linearized by plotting their reciprocals in a simple regression model. Diagnostic efficiency was calculated from ROC curves. Results: In this study population, cystatin C (P = 0.0013) was better correlated with GFR (r = 0.857) than were creatinine (r = 0.772), C-G (r = 0.750), and MDRD (r = 0.806), a result replicated in patients with normal renal function (P = 0.023, type 1; P = 0.011, type 2), but not in those with decreased GFR. Mean cystatin C concentrations showed step-by-step statistically significant increases as GFR decreased, allowing very early detection of reduction in renal function. At 90 mL · min−1 · (1.73 m2)−1 and 75 mL · min−1 · (1.73 m2)−1 cut-points, diagnostic efficiencies of cystatin C (89% and 92%) were better than those of the other variables (79%–82% and 85%–86%, respectively; P = 0.01). Conclusions: All data supported the value of serum cystatin C compared with conventional estimates based on serum creatinine measurement for detecting very early reduction of renal function. Use of cystatin C to measure renal function will optimize early detection, prevention, and treatment strategies for diabetic nephropathy.

According to WHO cardiovascular diseases (CVDs) are the first cause of death in the world: more people die annually from CVDs than from any other cause. Vascular endothelium plays a pivotal role in the onset and the progression of these pathologies and cardiovascular risk factors are frequently associated to the levels of endothelial progenitor cells (EPCs), bone marrow-derived circulating progenitors for the endothelial lineage. Since EPCs not only preserve vascular endothelium homeostasis, but directly participate to re-endothelization and neovascularization, these cells represent an emerging actor in vascular competence and thus a cell model of great interest. An unhealthy diet is one of the main cardiovascular risk factor; there is indeed a great interest in the potential protective effects of "nutraceuticals,", food-derived compounds that exert beneficial effects on human and animal health. The characterization of the endothelial effects of different nutraceuticals may provide fresh insights into their potential role in CVDs prevention. Several studies have already showed the protective effects of natural antioxidants on EPCs levels and functionality; some examples are resveratrol, catechin and folic acid. Fermentation has recently shown interesting roles in cardiovascular prevention since this process created a new class of food, rich in bioactive compounds, the fermented food. Consumption of fermented legumes and cereals, but also fermented beverages (such as beer and wine) was found to protect endothelial function through lipid-lowering, anti-inflammatory and antioxidative mechanisms. Little is known about the effects of fermentation-derived nutraceuticals on EPCs and given the important role of this cardiovascular biomarker, further analysis in this field can improve CVDs prevention and treatment.

A D/D (deletion/deletion) polymorphism within the ACE (angiotensin 1-converting enzyme) gene increases the risk of microalbuminuria, a predictor of atherosclerotic vascular disease, in essential hypertension. It is unknown, however, whether this genetic profile is accompanied by disturbed macromolecular permeability of systemic capillary endothelium, possibly in the context of generalized endothelial dysfunction. In the present study, the ACE gene polymorphism was determined by PCR in 79 never-treated uncomplicated hypertensive men and 16 normotensive men as controls. Evaluation variables were TERalb (transcapillary escape rate of albumin; the 1-h decline rate of intravenous 125I-albumin, a measure of integrity of systemic capillary endothelium), albuminuria and forearm vasodilation to intra-arterial acetylcholine, an index of NO (nitric oxide)-mediated vasomotion, in addition to a series of sensitive parameters of albumin permeation (blood pressure, metabolic status and smoking habits). Analyses were done by comparing D/D homozygotes with grouped I/D (insertion/deletion) and I/I (insertion/insertion) subjects. TERalb was higher in D/D hypertensives, who had higher albuminuria, more frequent microalbuminuria and comparable forearm responsiveness to intra-arterial acetylcholine. Fasting glucose and insulin, insulin sensitivity, 24-h blood pressure, smoking habits and metabolic parameters did not differ between the two groups. TERalb and urine albumin values were positively associated in the hypertensive subjects. In conclusion, ACE D/D homozygosis, independently of several confounding factors, associates with higher TERalb in men with essential hypertension. This may reflect noxious genetic influences on systemic vascular permeability, a critical control mechanism for atherogenesis in the absence of grossly impaired NO-mediated arteriolar responsiveness. The parallel behaviour of TERalb and albuminuria suggests some shared genetically mediated determinant of renal and systemic microvascular abnormalities in hypertension.

Background A single-nucleotide polymorphism (Gly460Trp) within the alpha-adducin gene (ADD1) may influence several renal phenotypes, including salt sensitivity, susceptibility to renal failure, the renal haemodynamics and confer a worse cardiovascular risks profile. However, its relationship with microalbuminuria, a marker of early renal and cardiovascular damage and an independent predictor of morbid events in hypertension, is unknown. For this reason, we related the ADD1 genetic polymorphism to urine albumin levels and other clinical variables in essential hypertensive men. The angiotensin-converting enzyme (ACE) insertion/deletion (ID) polymorphism was also evaluated because of its interactive potential with the ADD1 genotype. Methods Albuminuria (three overnight collections), echocardiographic left ventricular mass index, blood pressure, body mass index, renal function, glucose and lipids were measured in 238 genetically unrelated, never treated, uncomplicated Caucasian essential hypertensive men. Polymerase chain reaction or a 5' nuclease assay were used to characterize the ACE ID and ADD1 Gly460Trp variants, respectively. Results Microalbuminuria (albuminuria >or= 15 microg/min) was more frequent in patients with the ACE DD variant, but only in those with a ADD1 Gly460Gly background. In contrast, urine albumin did not differ by ACE ID genotype in the presence of mutated ADD1 Trp alleles. ADD1 polymorphisms per se were not associated with albuminuria. Cardiovascular, renal, metabolic parameters were homogeneously distributed among different genetic backgrounds. Conclusions ACE DD and ADD1 Gly460Gly polymorphisms may jointly influence albuminuria in hypertensive men, 460Gly homozygosis facilitating or, possibly, the 460Trp allele mitigating the noxious renal impact of the ACE DD genotype. The data highlight further the complex pathophysiological implications of microalbuminuria in hypertension.

This study tried to replicate in a large sample of white patients with type 2 diabetes (T2D) from Italy a previously reported association of the IRS1 G972R polymorphism with failure to oral antidiabetes drugs (OAD). A total of 2,409 patients from four independent studies were investigated. Case subjects (n = 1,193) were patients in whom, because of uncontrolled diabetes (i.e., HbA1c >8%), insulin therapy had been added either on, or instead of, maximal or near-maximal doses of OAD, mostly metformin and sulfonylureas; control subjects (n = 1,216) were patients with HbA1c

Background UMOD variability has been associated at a genome-wide level of statistical significance with glomerular filtration rate (GFR) in Swedish individuals with type 2 diabetes (T2D; n = 4888). Whether this finding is extensible also to diabetic patients from other populations deserves further study. Our aim was to investigate the relationship between UMOD variability and GFR in patients with T2D from Italy. Methods Genotyping of the single nucleotide polymorphism (SNP) rs12917707 at the UMOD locus has been carried out in 3087 individuals from four independent Italian cohorts of patients with T2D by TaqMan allele discrimination. Results In none of the four study cohorts was rs12917707 significantly associated with GFR (P > 0.05 for all). Similar results were obtained when the four samples were pooled and analyzed together (β = 0.83, P = 0.19). Such effect was strikingly smaller than that previously reported in Swedish patients (P for heterogeneity = 1.21 × 10-7). Conclusions The previously reported strong association between rs12917707 and GFR in diabetic patients from Sweden is not observed in Italian diabetic patients, thus clearly pointing to a heterogeneous effect across the two different samples. This suggests that UMOD is a strong genetic determinant of kidney function in patients with T2D in some, but not all, populations.

La ricerca scientifica biomedica, nel settore della nutrizione e dell'alimentazione, si interessa fortemente a definire i composti più attivi della dieta ed a comprenderne i meccanismi d' azione a livello molecolare e cellulare. E' stato attribuito un ruolo positivo ad estratti di sostanze naturali in termini di aumento delle difese endogene antiossidanti, grazie alla regolazione dell' espressione di geni codificanti per enzimi chiave del sistema antiossidante. Il Lisosan G, un lisato di grano, registrato presso il Ministero della Salute come integratore alimentare, nasce da una particolare lavorazione di cruschello e germe di grano biologico. Tra le principali componenti del lisato c'è una consistente presenza di antiossidanti quali vitamina B, tocoferoli ed oligoelementi; Lisosan G ha mostrato un'azione protettiva nella tossicità indotta da un agente chemioterapico quale il cisplatino1. I fagioli, alimenti ad elevato contenuto di fibre e di proteine, rappresentano una ricca fonte di antiossidanti e possono fornire benefici alla salute simili a quelli della frutta quale uva, mele e mirtilli, come recentemente dimostrato2. I fagioli presentano alte dosi di flavonoidi, in particolare antociani responsabili dell'effetto benefico descritto. Asahara et coll. hanno dimostrato un subset di cellule circolanti in grado di differenziarsi in cellule endoteliali mature, attive nella vasculogenesi3 e denominate cellule progenitrici endoteliali (EPCs). Sono state descritti due tipi di EPCs: precoci (early EPCs) e tardive (late EPCs)4. Le EPCs precoci compaiono in 4-7 giorni di coltura e esprimono markers endoteliali e monocitari e rilasciano fattori di crescita angiogenica5. Scopo di questo lavoro è stato valutare l'effetto protettivo di Lisosan G e di lisato di un fagiolo privo di fitoemoagglutinina ed arricchito in faseolamina, inibitore dell'?-amilasi (denominato Lady Joy), su EPCs precoci, esposte a stress ossidativo indotto da H2O2. Le EPCs sono state isolate da cellule mononucleari di sangue periferico (PBMCs). Brevemente, le PBMCs, isolate da sangue eparinato, sono state piastrate su fibronectina. Dopo 3 giorni di coltura le cellule non aderenti sono state rimosse; le cellule aderenti, al giorno 5 sono state incubate con i rispettivi lisati, quindi esposte ad H2O2. Nelle cellule condizionate con i lisati (Lisosan G e Lady Joy) abbiamo valutato i livelli di vitalità, mediante saggio MTT, e l'espressione genica di superossido dismutasi (SOD2), catalasi (CAT) e glutatione perossidasi (GPx), mediante real-time PCR. In presenza di stress ossidativo la vitalità è risultata maggiore in cellule condizionate con gli estratti Lady Joy e Lisosan G. I risultati preliminari del nostro lavoro rilevano una maggior espressione di GPx e CAT in EPCs pretrattate con Lisosan G, e successivamente esposte a H2O2, rispetto alle cellule pretrattate con il lisato di fagiolo. Quest'ultime mostrano un'induzione di enzimi antiossidanti rispetto alle colture di controllo, sebbene la differenza non risulti statisticamente significativa.

Background. We investigated whether the coronary artery disease (CAD) locus on chromosome 9p21 (as represented by single nucleotide polymorphism rs2383206) is associated with low estimated glomerular filtration rate (eGFR) or increased urinary albumin excretion in patients with Type 2 diabetes mellitus (T2DM). Methods. Four samples, including a total of 3167 patients, were studied. The presence of low eGFR (

Endothelium-derived factors are thought to be physiological modulators of large artery stiffness. The aim of the study was to investigate whether endothelial function could be a determinant of arterial stiffness in essential hypertensive patients, in relation with the concomitant presence of type 2 diabetes mellitus.The study included 341 participants (84 hypertensive patients with and 175 without type 2 diabetes mellitus, 82 matched controls). Brachial artery endothelium-dependent flow-mediated dilation (FMD) was determined by high-resolution ultrasound and computerised edge detection system. Applanation tonometry was used to measure carotid-femoral pulse wave velocity (PWV).Hypertensive patients with diabetes had higher PWV (10.1 ± 2.3 m/s vs 8.6 ± 1.4 m/s, p0.001) and lower FMD (3.51 ± 2.07 vs 5.16 ± 2.96%, p0.001) than non-diabetic hypertensive patients, who showed impaired vascular function when compared with healthy participants (7.9 ± 1.6 m/s and 6.68 ± 3.67%). FMD was significantly and negatively correlated to PWV only in hypertensive diabetic patients (r = -0.456, p0.001), but not in hypertensive normoglycaemic patients (r = -0.088, p = 0.248) or in healthy participants (r = 0.008, p = 0.946). Multivariate analysis demonstrated that, in the diabetic group, FMD remained an independent predictor of PWV after adjustment for confounders (r(2) = 0.083, p = 0.003). Subgroup analysis performed in non-diabetic hypertensive patients revealed that neither obesity nor the metabolic syndrome affected the relationship between FMD and PWV.Endothelial dysfunction is a determinant of aortic stiffness in hypertensive diabetic patients but not in hypertensive patients without diabetes. These results suggest that type 2 diabetes mellitus on top of hypertension might worsen arterial compliance by endothelium-related mechanisms.

Endothelial progenitor cells (EPCs) play a role in angiogenesis during pregnancy. The aim of this study was to evaluate circulating EPCs in pregnant women with gestational alterations of glucose tolerance. Glucose tolerance, insulin sensitivity and β-cell function were derived from oral glucose tolerance tests in 23 women with normal glucose tolerance (NGT), 18 with gestational impaired glucose tolerance (GIGT) and 24 with gestational diabetes mellitus (GDM). Circulating cells expressing CD34 in combination with CD133, kinase insert domain receptor (KDR) or both were quantified by flow cytometry. Women with GIGT and GDM had lower CD34+KDR+ and CD34+CD133 +KDR+ cells at 27±3.2 weeks’ gestation compared with NGT (ANOVA p+KDR+ and CD34+CD133+KDR+ cells were inversely correlated with the area-under-the-glucose-curve ( p

Aim. To investigate the association between V281L CYP21 polymorphism and the hyperandrogenic phenotype of polycystic ovary syndrome (PCOS), in a cohort of 110 Italian women. Methods. The CYP21 genotype distribution was evaluated in 50 women with PCOS and 60 control subjects. Genotypes were detected using restriction fragment length polymorphism (RFLP) analysis performed on polymerase chain reaction templates from genomic DNA. Genotypes distribution was compared between groups and we considered a p-value less than 0.05 as statistically significant. Results. The frequency of VV, VL and LL was in agreement with other populations. Nevertheless no significant association was observed between CYP21 polymorphism and the presence of PCOS in an Italian cohort of women. Conclusion. Although CYP21 gene, involved in steroidogenesis, is a candidate gene for pathogenesis of PCOS, our data suggest that V281L polymorphism is not associated with PCOS in Italian women; a larger study is needed to confirm this result.

BACKGROUND Elevated levels of the proinflammatory cytokine soluble CD40 ligand (sCD40L) were reported in subjects with diabetes, impaired glucose tolerance, metabolic syndrome (MS), obesity, and insulin resistance. Metabolic abnormalities might also account for increased sCD40L in subjects with essential hypertension. METHODS Several metabolic and vascular correlates of sCD40L levels have been investigated in 90 nondiabetic never-treated essential hypertensive men. RESULTS Median sCD40L level was 8.7 ng/ml (interquartile range: 4.9-11.7). On the basis of sCD40L, subjects were divided by tertiles (thresholds at 6.6 and 11.0 ng/ml). The three groups did not differ for age, body mass index (BMI), smokers, blood pressure (BP), prevalence of nondippers, lipids and lipoproteins, renal function, and albuminuria. Carotid intima-media thickness (IMT: 0.79 +/- 0.22, 0.83 +/- 0.29, and 0.85 +/- 0.30 mm) and percentage of subjects with wall thickening (IMT >0.9 to

The Glu298Asp, T786C and 4a/4b genetic polymorphisms within the endothelial nitric oxide synthase (e-NOS) gene may predispose to hypertension, ischaemic heart disease and renal damage, possibly by reducing the generation of nitric oxide (NO), a fundamental substance in renal and cardiovascular biology. That same mechanism may contribute to raise albuminuria, a correlate of endothelial dysfunction and a marker of early kidney damage and poor cardiovascular prognosis in patients with hypertension. To assess that hypothesis, we evaluated the association of albuminuria with eNOS genotypes and their interacting potential with the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism. We also tested their impact on systemic NO availability, as reflected by endothelial-mediated forearm vasodilatation.Albuminuria (three overnight collections), blood pressure, body mass index, renal function, glucose, lipids and prevalence of the metabolic syndrome were measured in 235 genetically unrelated, never-treated, uncomplicated white men with essential hypertension. Endothelial function was assessed in a patient subgroup (n = 94) by measuring plethysmographic forearm blood flow vasodilatation in response to intra-arterial acetylcholine with sodium nitroprusside as a control. Polymerase chain reaction or a 5' nuclease assay were used to characterize the eNOS and ACE I/D variants.Albuminuria or microalbuminuria (albuminuriaor = 15 microg/min) showed no association with eNOS polymorphisms either per se or after accounting for the co-existing ACE I/D genetic configuration. Forearm responses to acetylcholine did not differ by eNOS polymorphisms. Cardiovascular, renal, metabolic parameters were homogeneously distributed across different genetic backgrounds.eNOS polymorphisms apparently play no role in promoting hypertensive renal damage, and do not influence endothelial-mediated vasodilatation in never-treated men with essential hypertension.

P450 cytochromes (CYPs) enzymes play a major role in variability of drug response and cancer susceptibility. In particular, up to 60-fold interindividual variation has been detected in the activity of CYP1A2, which is involved in the metabolism of caffeine, several drugs and various toxic and carcinogenic compounds. Aim of this study is to assess the frequency of CYP1A2 F21L and F186L polymorphisms (formerly CYP1A2(*)2 and (*)11 alleles), up to now found in Asiatic populations only. These variants were absent in 500 Italian healthy subjects. Therefore it can be suggested that the variation of CYP1A2-dependent metabolism in the Caucasian population is not related to these two CYP1A2 polymorphisms. Thus, this study supports the view that ethnicity is a relevant factor to be carefully considered in pharmacogenetic studies.