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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.

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 …

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.

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.

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.

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.

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.