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Background:Epicardial adipose tissue (EAT) contributes to coronary artery disease (CAD). EAT presents a specific lipidomic signature, showing increased ceramides and other proinflammatory lipids content. Besides, LPL (lipoprotein lipase) activity in EAT would contribute to its expansion, supplying fatty acids to the tissue. Our aim was to evaluate the relations between LPL activity, regulators of LPL, and ceramides in EAT from CAD patients.Methods:We studied patients undergoing coronary bypass graft (CAD, n=25) and patients without CAD (no CAD, n=14). EAT and subcutaneous AT (SAT) were obtained, tissue LPL activity and its regulator’s expression (ANGPTL4, GPIHBP1 [glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1], and PPARγ [peroxisomal proliferator–activated receptor γ]) were assessed. Tissue lipidomes were evaluated by UHPLC-MS, in positive and negative ionization modes.Results:LPL activity was higher in EAT from CAD (PPPP=0.01), directly associated with LPL activity, being the strongest association with Cer18:1/24:1 (PP=0.03;Pr=0.63,Pr=0.68,Pr=−0.49,P=0.03). Pairwise partial correlation network showed associations among bioactive lipids and LPL and its regulators (PConclusions:The association between LPL activity, total ceramide, and the atherogenic ceramide ratios highlights the importance of the enzyme and these bioactive lipids contributing to the different metabolic profile of EAT in CAD.

OBJECTIVE:Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD. Approach and Results: Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10-4). Patients with CAD exhibited more ceramides (P=0.01), diglycerides (P=0.004; saturated and nonsaturated), monoglycerides (P=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides; P=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (r=0.45, P=0.019) in EAT and HDL and in EAT and VLDL (r=0.46, P=0.02).CONCLUSIONS:CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome. Fil: Barchuk, Magalí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Dutour, Anne. Aix Marseille Universite; Francia Fil: Ancel, Patricia. Aix Marseille Universite; Francia Fil: Svilar, Ljubica. Aix Marseille Universite; Francia Fil: Miksztowicz, Verónica Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Lopez, Graciela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Rubio Mas, Miguel Angel. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Schreier, Laura Ester. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Nogueira, Juan Patricio. Hospital Central de Formosa; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Valéro, René. Aix Marseille Universite; Francia Fil: Béliard, Sophie. Aix Marseille Universite; Francia Fil: Martin, Jean Charles. Aix Marseille Universite; Francia Fil: Berg, Gabriela Alicia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Gaborit, Bénédicte. Aix Marseille Universite; Francia

Epicardial adipose tissue (EAT) is a small but very biologically active ectopic fat depot that surrounds the heart. Given its rapid metabolism, thermogenic capacity, unique transcriptome, secretory profile, and simply measurability, epicardial fat has drawn increasing attention among researchers attempting to elucidate its putative role in health and cardiovascular diseases. The cellular crosstalk between epicardial adipocytes and cells of the vascular wall or myocytes is high and suggests a local role for this tissue. The balance between protective and proinflammatory/profibrotic cytokines, chemokines, and adipokines released by EAT seem to be a key element in atherogenesis and could represent a future therapeutic target. EAT amount has been found to predict clinical coronary outcomes. EAT can also modulate cardiac structure and function. Its amount has been associated with atrial fibrillation, coronary artery disease, and sleep apnea syndrome. Conversely, a beiging fat profile of EAT has been identified. In this review, we describe the current state of knowledge regarding the anatomy, physiology and pathophysiological role of EAT, and the factors more globally leading to ectopic fat development. We will also highlight the most recent findings on the origin of this ectopic tissue, and its association with cardiac diseases. © 2017 American Physiological Society. Compr Physiol 7:1051-1082, 2017.

This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.

Introduction Le syndrome de Cushing est responsable d’une augmentation de la mortalite cardiovasculaire en partie liee a la modulation de repartition du tissu adipeux (TA) par les glucorticoides. L’impact de l’hypercorticisme sur les depots de graisse ectopique (DGE) n’est pas connu. Objectifs Mesurer les DGE : TA epicardique (TAE), contenu en triglycerides intra-myocardique (CTGM), intra-hepatique (CTGH) et la fonction cardiaque chez 38 patients atteints d’hypercorticisme ACTH-dependant dont 19 actifs et 19 gueris depuis au moins 2 ans, 19 controles apparies sur l’âge et le sexe et 14 sujets obeses apparies sur le TA visceral. Methodes Une imagerie et spectroscopie proton de resonance magnetique sur un aimant 3T ont ete realises. Resultats Le TAE est augmente chez les patients actifs : (93,5 ± 6,1 vs. 55,2 ± 3,6 mL chez les controles, p Conclusion L’hypercorticisme est responsable d’une accumulation specifique ciblee sur le cœur des DGE, le VAT n’explique pas a lui seul le developpement des DGE.

Background Venous thromboembolism (VTE) is a leading cause of death in obese patients undergoing bariatric surgery (BS), but there is neither consensus nor high-level guidelines yet on VTE prophylaxis in this specific population. Objective We aimed to evaluate patterns of BS perioperative thromboprophylaxis practices. Setting French obesity specialized care centers (CSO), which are tertiary care referral hospitals for the most severe cases of obesity Methods A detailed questionnaire survey (11 opened, 15 closed questions) investigating their prophylactic schemes of anticoagulation (molecule, dose, weight-adjustment, duration, associated measures, follow-up) was sent to the 37 CSO. Results Completion rate was 92%. Over 90% of respondents indicated using low molecular weight heparin. Enoxaparin was the most commonly used molecule (89%), twice daily (71%), started mostly 6 hours after BS (74%), whereas fondaparinux (9%), dalteparin (6%), and tinzaparin (6%) were less often prescribed. Dosing varied significantly according to centers from 4000 to 12,000 IU/d, with the most commonly used dose being 8000 IU once daily, 83%, as well as treatment duration (1 week, 9%; 3 weeks, 47%). Half CSO adjusted low molecular weight heparin dose to weight. Biological monitoring was performed in 88%. Only 1 center followed systematically anti-Xa activity. Associated measures such as elastic stoking or intermittent pneumatic compression were used in 32% and 26%, respectively, and both were used in 39%. Conclusion This study finds significant discrepancies in thromboprophylaxis practices in obese patients undergoing BS, particularly with respect to treatment duration and dose adjustment, highlighting the urgent need for improved implementation of existing clinical practice guidelines in this VTE high-risk population.

International audience; AIM: To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores. METHODS: A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment. RESULTS: The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively). CONCLUSION: Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.

International audience; Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.

2378 www.thelancet.com Vol 387 June 11, 2016 hepatic steatosis is due to weight loss? Previous studies have found a direct eff ect of weight loss on hepatic steatosis. In the LEAN study, the liraglutide effect did not remain signifi cant after adjusting for weight loss. Changes in weight were not signifi cantly diff erent in patients with or without histological response to liraglutide. However, we would have expected that the authors present the eff ect of liraglutide on hepatic steatosis in patients with or without weight loss. If verified, the effect of liraglutide, independent of weight loss, would have been even more convincing. This distinction seems important because in patients with obesity and type 2 diabetes, bariatric surgery has shown benefi cial eff ects on hepatic steatosis, which are sustained in long-term studies, whereas weight stabilisation is often reported in patients chronically treated with glucagon-like peptide-1 receptor agonists. The LEAN study has brought new insight and given a new therapeutic option in non-alcoholic steatohepatitis. Further, larger studies with a longer duration are warranted to confi rm these results.

More than body mass index (BMI), adiposity distribution in visceral area and in ectopic sites likely plays an important role in the obesity-related risk. Ectopic fat accumulation in the heart, the liver, and the pancreas, namely steatosis, could induce accumulation of toxic lipid intermediates

Background Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist). Methods Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 μg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR. Results HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (−57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05). Conclusion CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist. Electronic supplementary material The online version of this article (doi:10.1186/s12968-015-0198-x) contains supplementary material, which is available to authorized users.

International audience; Aims Human epicardial adipose tissue (EAT) is a visceral and perivascular fat that has been shown to act locally on myocardium, atria, and coronary arteries. Its abundance has been linked to coronary artery disease (CAD) and atrial fibrillation. However, its physiological function remains highly debated. The aim of this study was to determine a specific EAT transcriptomic signature, depending on its anatomical peri-atrial (PA), peri-ventricular (PV), or peri-coronary location. Methods and results Samples of EAT and thoracic subcutaneous fat, obtained from 41 patients paired for cardiovascular risk factors, CAD, and atrial fibrillation were analysed using a pangenomic approach. We found 2728 significantly up-regulated genes in the EAT vs. subcutaneous fat with 400 genes being common between PA, PV, and peri-coronary EAT. These common genes were related to extracellular matrix remodelling, inflammation, infection, and thrombosis pathways. Omentin (ITLN1) was the most up-regulated gene and secreted adipokine in EAT (fold-change >12, P

Introduction Les maladies de l’obesite, comme le diabete, sont associes a l’accumulation de tissu adipeux dans la region intra-abdominale. Les mecanismes moleculaires et cellulaires qui influencent l’obesite viscerale sont mal compris. Il y a un interet croissant dans la capacite des macrophages des tissus adipeux a controler l’inflammation vers une reponse pathologique favorisant le developpement du diabete. Interferon regulatory factor 5 (IRF5) est decrit comme un important regulateur de la polarisation des macrophages vers un phenotype pathologique (pro-inflammatoire). Son role est bien connu dans les pathologies auto-immunes comme l’arthrite rhumatoide ou le lupus. Cependant, les fonctions immuno-metaboliques de IRF5 sont encore meconnues. Nous emettons l’hypothese que l’alteration de l’activite de IRF5 va limiter la pathogenicite de l’obesite visceral et le developpement du diabete. Materiels et methodes Etude in vivo : Afin de decrire le role de IRF5 dans l’obesite viscerale et le developpement de l’insulinoresistance. Nous avons utilise deux modeles murins presentant une invalidation de IRF5 dans toutes les cellules (KO Total) et specifiquement dans les cellules myeloides (macrophages). Les souris ont ete soumises a un regime standard et riche en graisse (60 % de gras) pendant 12 semaines. Les souris ont ete ensuite caracterisees sur le plan metabolique, immunitaire et moleculaire. Etude humaine : Afin de transposer nos observations sur nos modeles murins, nous avons analyse l’expression de IRF5 dans le tissu adipeux visceral de sujets minces (n = 15), en surpoids (n = 15), obese (n = 14) et super obeses (n = 36). Nous avons pu ensuite determiner les relations entre l’expression de IRF5 avec les parametres anthropometriques et metaboliques de ces differents groupes de sujets. Resultats Dans cette etude nous demontrons que l’invalidation de IRF5 limite l’accumulation du tissu adipeux intra-abdominal et favorise l’accumulation dans les regions plus superficielles comme la region inguinale. Cette modification a pour effet de proteger les souris contre l’insulino-resistance et l’intolerance au glucose. De maniere surprenante, le tissu adipeux intra-abdominal des souris invalidees pour IRF5 est caracterise par une augmentation de nombre de macrophages et par l’accumulation des depots de collagene. Le changement de polarisation des macrophages entraine un remodelage adaptatif du tissu adipeux qui permet de le maintenir dans un etat sain. Les fonctions pathologiques de IRF5 ont egalement ete observees dans nos populations humaines ou l’expression de IRF5 est fortement associee a l’obesite viscerale et a l’insulinoresistance peripherique. Discussion Nos resultats demontrent pour la premiere fois une fonction metabolique deletere de IRF5 dans le l’obesite viscerale et le developpement du diabete. IRF5 pourrait etre utilise a des fins therapeutiques (inhibition de son activite) et a des fins diagnostics permettant une meilleure stratification du statut inflammatoire des patients diabetiques et proposer un traitement plus adaptes (immunotherapie). Declaration d’interet Les auteurs declarent ne pas avoir d’interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Low-grade chronic inflammation is a major characteristic of obesity and results from deregulated white adipose tissue function. Consequently, there is interest in identifying the underlying regulatory mechanisms and components that drive adipocyte inflammation. Here, we report that expression of the transcriptional corepressor complex subunits GPS2 and SMRT was significantly reduced in obese adipose tissue, inversely correlated to inflammatory status, and was restored upon gastric bypass surgery-induced weight loss in morbid obesity. These alterations correlated with reduced occupancy of the corepressor complex at inflammatory promoters, providing a mechanistic explanation for elevated inflammatory transcription. In support of these correlations, RNAi-mediated depletion of GPS2 and SMRT from cultured human adipocytes promoted derepression of inflammatory transcription and elevation of obesity-associated inflammatory markers, such as IL-6 and MCP-1. Furthermore, we identified a regulatory cascade containing PPARγ and TWIST1 that controlled the expression of GPS2 and SMRT in human adipocytes. These findings were clinically relevant, because treatment of diabetic obese patients with pioglitazone, an antidiabetic and antiinflammatory PPARγ agonist, restored expression of TWIST1, GPS2, and SMRT in adipose tissue. Collectively, our findings identify alterations in a regulatory transcriptional network in adipocytes involving the dysregulation of a specific corepressor complex as among the initiating events promoting adipose tissue inflammation in human obesity.

Introduction En chirurgie bariatrique (CB), les accidents thromboemboliques, mais aussi les accidents hemorragiques, sont des complications post-operatoires potentiellement graves et redoutees par toutes les equipes. Actuellement, les recommandations concernant la thromboprophylaxie peri-operatoire sont de bas grade. L’objectif de cette etude etait d’evaluer les pratiques dans les centres specialises d’obesite (CSO). Methodes Un questionnaire portant sur la thromboprophylaxie veineuse encadrant la CB comportant 25 questions a ete envoye par courriel aux 37 CSO. L’heure et le jour de debut de l’anticoagulation, la dose, l’adaptation au poids, la duree, et la surveillance ont ete evaluees. Resultats 92 % des CSO ont repondu. L’anticoagulant le plus utilise etait l’enoxaparine (89 %), en 2 injections/j (71 %), debutee pour la majorite 6 h apres l’intervention (74 %). Les doses variaient selon les equipes (de 4 000 a 12 000 unites/J), de meme que la duree de l’anticoagulation (7j, 9 % ; 21j, 4 7 %). La moitie des equipes realisait une adaptation posologique au poids. Une surveillance biologique etait effectuee dans 5 9 % des c as ; une seule equipe dosait l’activite anti-Xa (4 %). Une prophylaxie mecanique intermittente etait associee dans 40 % des cas. Conclusion Cette enquete montre une grande heterogeneite des pratiques dans les CSO, notamment pour l’adaptation posologique et la duree du traitement prophylactique, soulignant la necessite d’etablir des recommandations specifiques. Declaration d’interet Les auteurs n’ont pas transmis de conflits d’interets.

AimsRecent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models.MethodsWe performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs.We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice.ResultsIn the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization.ConclusionsThe AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.