Safety and efficacy of direct oral anticoagulants in geriatric patients with non-valvular atrial fibrillation: A single-center retrospective study.

INTRODUCTION: Direct oral anticoagulants (DOACs) are widely employed for antithrombotic prophylaxis in patients with atrial fibrillation (AF). However, there is still uncertainty about their risk-benefit profile in older patients. Here, we evaluated the efficacy, safety, and dose appropriateness of DOACs in a real-world population of outpatients with non-valvular AF, with a specific focus on subjects aged over 80 years and/or with reduced renal function. MATERIALS AND METHODS: Single-center retrospective study including patients who had been prescribed a DOAC between May 2014 and May 2021 for long-term anticoagulation in non-valvular AF. Patients anticoagulated for <4 weeks were excluded. The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or systemic embolism. The primary safety outcome was major bleeding. RESULTS: A total of 1154 patients (median age 84 yrs., range 57-100 yrs.), among which 862 were 80 years and older, were included. In the subgroup of subjects ≥80 yrs., a subtherapeutic dose of DOAC was associated with an increased incidence of CV mortality, stroke, or systemic embolism (multivariable Cox regression, HR = 2.09, 95 % CI: 1.09-4.02), with no benefit in terms of prevalence of bleeding events (21.5 % vs. 18.6 %, p = 0.428), and the incidence of adverse safety and efficacy outcomes was not increased in patients with a reduced renal function (eGFR ≤30 mL/min). Plasma concentration of DOACs, assessed in a subset of 367 patients, did not increase with advanced age (≥ 80 yrs., two-way ANOVA, p = 0.656) nor with declining eGFR (≤30 mL/min, two-way ANOVA, p = 0.643) and was not associated with adverse safety and efficacy outcomes. CONCLUSIONS: Data from our study support the use of DOACs in populations of older adults and remark on the risks associated with inappropriate prescriptions in terms of CV mortality and adverse events.

The Genetic Variability of Members of the SLC38 Family of Amino Acid Transporters (SLC38A3, SLC38A7 and SLC38A9) Affects Susceptibility to Type 2 Diabetes and Vascular Complications.

Type 2 Diabetes (T2D) is a metabolic disease associated with long-term complications, with a multifactorial pathogenesis related to the interplay between genetic and modifiable risk factors, of which nutrition is the most relevant. In particular, the importance of proteins and constitutive amino acids (AAs) in disease susceptibility is emerging. The ability to sense and respond to changes in AA supplies is mediated by complex networks, of which AA transporters (AATs) are crucial components acting also as sensors of AA availability. This study explored the associations between polymorphisms in selected AATs genes and T2D and vascular complications in 433 patients and 506 healthy controls. Analyses revealed significant association of SLC38A3-rs1858828 with disease risk. Stratification of patients based on presence/absence of vascular complications highlighted significant associations of SLC7A8-rs3783436 and SLC38A7-rs9806843 with diabetic retinopathy. Additionally, the SLC38A9-rs4865615 resulted associated with chronic kidney disease. Notably, these genes function as AAs sensors, specifically glutamine, leucine, and arginine, linked to the main nutrient signaling pathway mammalian target of rapamycin complex 1 (mTORC1). Thus, their genetic variability may contribute to T2D by influencing the ability to properly transduce a signal activating mTORC1 in response to AA availability. In this scenario, the contribution of dietary AAs supply to disease risk may be relevant.

Usefulness of administrative databases in identifying the predictive factors of repeated hospitalizations for heart failure.

OBJECTIVES: to investigate heart failure (HF) hospitalizations, the following one-year follow-up, and any possible connection between rehospitalizations due to HF and patients' characteristics derived from administrative databases. DESIGN: retrospective longitudinal design. SETTING AND PARTICIPANTS: the study was conducted analyzing public hospital records of a district in Abruzzo Region (Central Italy), which counts more than 300,000 inhabitants. Patients hospitalized for HF from 01.01.2016 to 31.12.2017 (index event) were included in the study and followed-up for one year. MAIN OUTCOME MEASURES: frequency of repeated hospital admissions, time intervals from the index HF hospitalizations, and causes of readmissions were investigated. RESULTS: a total of 1,587 patients discharged alive after an index hospitalization for HF were included in the study. The mean age of the patients was 79.6 years and the majority of them were females (53.7%). The mean length of stay (LOS) for the index hospitalizations was 8.8 ±6.8 days. During the follow-up period, 336 (21.2%) patients underwent one to four repeated hospitalizations for HF. The first readmission due to HF occurred after a median time of 106.5 days from the index event discharge, and for 20.0% of all cases it occurred within 31 days; 453 patients (28.6%) were readmitted exclusively for other causes, and 67 (4.2%) died out of hospital without any previous HF re-hospitalization. When the outcome was considered as a composite endpoint (out-of-hospital death/HF re-hospitalization), age >=75 (HR 1.737; 95%CI 1.330-2.267), LOS at the index hospitalization >=8 days (HR 1.302; 95%CI 1.066-1.591), and repeated hospitalizations for other causes (HR 1.789; 95%IC 1.465-2.185) were associated with the risk of repeated hospitalizations for HF. CONCLUSIONS: this study shows that about one HF patient out of five experienced at least one re-hospitalization for HF within one year from index hospitalization. In addition to having a longer index hospitalization, these patients were older and frequently suffered from comorbidities which also led to hospitalizations. The results underline the need for a close and careful follow-up after the discharge of old HF patients with multiple pathologies in order to avoid further HF admissions in a short time.

Author Correction: Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes.

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate < 0.1) associated with mortality. Haplotype multivariate analysis revealed that patients carrying the G-C-C haplotype have an increased probability of survival, while an opposite effect was observed among subjects carrying the T-T-A haplotype. Our findings provide evidence that the EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients.

Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants.

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring. Direct oral anticoagulant-specific measurements were performed at trough and peak. Patients who developed bleeding events showed higher DOAC plasma levels at peak. This study suggests the need of a more accurate DOAC dose assessment. BACKGROUND: Direct oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C-trough or C-peak plasma levels and bleeding complications in patients with non-valvular atrial fibrillation (NVAF). METHODS: Five hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C-trough and at C-peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow-up after blood sampling, were recorded. For each DOAC, interval of C-trough and C-peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated. RESULTS: Two hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1-[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C-peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C-peak levels were higher in patients with bleeding than in those without bleeding. CONCLUSIONS: Bleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C-peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C-trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window.

Physical Activity Modulates the Overexpression of the Inflammatory miR-146a-5p in Obese Patients.

Specific microRNAs (miRs), including the "angio-miR-126" and the "inflamma-miR-146a-5p," have been proposed as biomarkers and even therapeutic targets of obesity-associated metabolic diseases. Physical activity, a key measure of prevention for obesity and its complications, is reported to influence the expression of these miRs. In this study, we investigate whether a physical activity program proven to improve metabolic parameters in obese patients can correct the circulating levels of these miRs. Plasma miR-126 and miR-146a-5p were measured in a cohort of obese patients (n = 31, 16F + 15M) before and after the 3-month physical activity program of the CURIAMO trial (registration number for clinical trials: ACTRN12611000255987) and in 37 lean controls (24F + 13M). miR-146a-5p, but not miR-126, was significantly increased in obese patients as compared with lean controls and decreased in approximately two-thirds of the participants post-intervention with a response that positively correlated with pre-intervention levels of this miR. Waist circumference, the inflammatory cytokine IL-8 and lipid parameters, principally total cholesterol, showed the strongest correlation with both the baseline levels and post-intervention correction of miR-146a-5p. Post-hoc analysis of experimental data supports the use of miR-146a-5p as a biomarker and predictor of the clinical response to physical activity in obese patients. Furthermore, miR-146a-5p expression was confirmed to increase together with that of the inflammatory genes TLR4, NF-κB, IL-6, and TNF-α in LPS-stimulated human mononuclear leukocytes. In conclusion, the inflamma-miR-146a-5p can serve as a personalized predictor of clinical outcome in obese patients entering physical activity weight-reduction programs. © 2018 IUBMB Life, 70(10):1012-1022, 2018.

Genes associated with Type 2 Diabetes and vascular complications.

Type 2 Diabetes (T2D) is a chronic disease associated with a number of micro- and macrovascular complications that increase the morbidity and mortality of patients. The risk of diabetic complications has a strong genetic component. To this end, we sought to evaluate the association of 40 single nucleotide polymorphisms (SNPs) in 21 candidate genes with T2D and its vascular complications in 503 T2D patients and 580 healthy controls. The genes were chosen because previously reported to be associated with T2D complications and/or with the aging process. We replicated the association of T2D risk with IGF2BP rs4402960 and detected novel associations with TERT rs2735940 and rs2736098. The addition of these SNPs to a model including traditional risk factors slightly improved risk prediction. After stratification of patients according to the presence/absence of vascular complications, we found significant associations of variants in the CAT, FTO, and UCP1 genes with diabetic retinopathy and nephropathy. Additionally, a variant in the ADIPOQ gene was found associated with macrovascular complications. Notably, these genes are involved in some way in mitochondrial biology and reactive oxygen species regulation. Hence, our findings strongly suggest a potential link between mitochondrial oxidative homeostasis and individual predisposition to diabetic vascular complications.

Inflammageing and metaflammation: The yin and yang of type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is characterised by chronic low-grade inflammation, recently referred to as 'metaflammation', a relevant factor contributing to the development of both diabetes and its complications. Nonetheless, 'canonical' anti-inflammatory drugs do not yield satisfactory results in terms of prevention of diabetes progression and of cardiovascular events, suggesting that the causal mechanisms fostering metaflammation deserve further research to identify new druggable targets. Metaflammation resembles ageing-induced low-grade inflammation, previously referred to as inflammageing, in terms of clinical presentation and the molecular profile, pointing to a common aetiology for both conditions. Along with the mechanisms proposed to fuel inflammageing, here we dissect a plethora of pathological cascades triggered by gluco- and lipotoxicity, converging on candidate phenomena possibly explaining the enduring pro-inflammatory program observed in diabetic tissues, i.e. persistent immune-system stimulation, accumulation of senescent cells, epigenetic rearrangements, and alterations in microbiota composition. We discuss the possibility of harnessing these recent discoveries in future therapies for T2DM. Moreover, we review recent evidence regarding the ability of diets and physical exercise to modulate selected inflammatory pathways relevant for the diabetic pathology. Finally, we examine the latest findings showing putative anti-inflammatory mechanisms of anti-hyperglycaemic agents with proven efficacy against T2DM-induced cardiovascular complications, in order to gain insights into quickly translatable therapeutic approaches.

Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages.

Diabetic status is characterized by chronic low-grade inflammation and an increased burden of senescent cells. Recently, the senescence-associated secretory phenotype (SASP) has been suggested as a possible source of inflammatory factors in obesity-induced type 2 diabetes. However, while senescence is a known consequence of hyperglycaemia, evidences of SASP as a result of the glycaemic insult are missing. In addition, few data are available regarding which cell types are the main SASP-spreading cells in vivo. Adopting a four-pronged approach we demonstrated that: i) an archetypal SASP response that was at least partly attributable to endothelial cells and macrophages is induced in mouse kidney after in vivo exposure to sustained hyperglycaemia; ii) reproducing a similar condition in vitro in endothelial cells and macrophages, hyperglycaemic stimulus largely phenocopies the SASP acquired during replicative senescence; iii) in endothelial cells, hyperglycaemia-induced senescence and SASP could be prevented by SOD-1 overexpression; and iiii) ex vivo circulating angiogenic cells derived from peripheral blood mononuclear cells from diabetic patients displayed features consistent with the SASP. Overall, the present findings document a direct link between hyperglycaemia and the SASP in endothelial cells and macrophages, making the SASP a highly likely contributor to the fuelling of low-grade inflammation in diabetes.

Age-related modulation of plasmatic beta-Galactosidase activity in healthy subjects and in patients affected by T2DM.

ß-Galactosidase (ß-Gal) activity has been the most extensively utilized biomarker for the detection of cellular senescence. It can be measured also in plasma, and few recent evidence showed an altered plasmatic ß-Gal activity in patients affected by some age-related diseases (ARDs). Since T2DM is one of the most common ARDs, we aimed to investigate if plasmatic ß-Gal activity is modulated in T2DM patients and if "age" could affect such modulation. To gain mechanistic insights we paralleled this investigation with the evaluation of ß-Gal activity in young and senescent endothelial cells (HUVECs) cultured in normo- and hyper-glycaemic environment. A significant age-related increase of plasmatic ß-Gal activity was observed in healthy subjects (n. 230; 55-87 years), whereas the enzymatic activity was significantly reduced in T2DM patients (n. 230; 55-96 years) compared to healthy subjects. ß-Gal activity detectable both in cells and in the culture medium was significantly increased in senescent cells compared to the younger ones, both under normo- and hyper-glycaemic condition. However, the hyper-glycaemic condition was not associated with an increased ß-Gal activity in milieu compared to normo-glycaemic condition. Overall our data reinforce the notion that plasmatic ß-Gal activity could be a systemic biomarker of aging, whereas T2DM patients are characterized by a different age-releated trend.

Multicenter evaluation of an enzymatic method for glycated albumin.

BACKGROUND: The use of glycated albumin (GA) has been proposed as an additional glycemic control marker particularly useful in intermediate-term monitoring and in situation when HbA1c test is not reliable. METHODS: We have performed the first multicenter evaluation of the analytical performance of the enzymatic method quantILab Glycated Albumin assay implemented on the most widely used clinical chemistry analyzers (i.e. Abbott Architect C8000, Beckman Coulter AU 480 and 680, Roche Cobas C6000, Siemens ADVIA 2400 and 2400 XPT). RESULTS: The repeatability of the GA measurement (expressed as CV, %) implemented in the participating centers ranged between 0.9% and 1.2%. The within-laboratory CVs ranged between 1.2% and 1.6%. A good alignment between laboratories was found, with correlation coefficients from 0.996 to 0.998. Linearity was confirmed in the range from 7.6 to 84.7%. CONCLUSION: The new enzymatic method for glycated albumin evaluated by our investigation is suitable for clinical use.

The "Metabolic Memory" Theory and the Early Treatment of Hyperglycemia in Prevention of Diabetic Complications.

Several epidemiological and prospective studies suggest that an early intensive control of hyperglycaemia is able to decrease the risk of diabetic micro- and macro-vascular complications. A growing body of experimental evidence supports the concept that the risk for diabetes complications may be linked to oxidative stress, non-enzymatic glycation of proteins, epigenetic changes, and chronic inflammation, laying the foundation for the "metabolic memory" theory. From a clinical point of view, this theory supports the need for a very early aggressive treatment, with the goal of normalizing metabolic control as soon as possible. It may also prove beneficial to introduce therapeutic agents that are able to reduce reactive species and glycation, in addition to presenting better control of glucose levels in patients with diabetes, in order to minimize long-term diabetes complications. In this review, we evaluate the effect of glucose intake and metabolism in the light of this theory.

The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin functions as antioxidant on human endothelial cells exposed to chronic hyperglycemia and metabolic high-glucose memory.

Dipeptidyl peptidase-4 inhibitors are widely used in type 2 diabetes. Endothelium plays a crucial role maintaining vascular integrity and function. Chronic exposure to high glucose drives to endothelial dysfunction generating oxidative stress. Teneligliptin is a novel dipeptidyl peptidase-4 inhibitor with antioxidant properties. This study is aimed to verify a potential protective action of teneligliptin in endothelial cells exposed to high glucose. Human umbilical vein endothelial cells were cultured under normal (5 mmol/L) or high glucose (25 mmol/L) during 21 days, or at high glucose during 14 days followed by 7 days at normal glucose, to reproduce the high-metabolic memory state. During this period, different concentrations of teneligliptin (0.1, 1.0 and 3.0 µmol/L) or sitagliptin (0.5 µmol/L) were added to cells. Ribonucleic acid and protein expression were assessed for antioxidant response, proliferation, apoptosis and endoplasmic reticulum stress markers. Teneligliptin promotes the antioxidant response in human umbilical vein endothelial cells, reducing ROS levels and inducing Nrf2-target genes messenger ribonucleic acid expression. Teneligliptin, but not sitagliptin, reduces the expression of the nicotine amide adenine dinucleotide phosphate oxidase regulatory subunit P22 -phox , however, both blunt the high glucose-induced increase of TXNIP. Teneligliptin improves proliferation rates in human umbilical vein endothelial cells exposed to high glucose, regulating the expression of cell-cycle inhibitors markers (P53, P21 and P27), and reducing proapoptotic genes (BAX and CASP3), while promotes BCL2 expression. Teneligliptin ameliorates high glucose-induced endoplasmic reticulum stress reducing the expression of several markers (BIP, PERK, ATF4, CHOP, IRE1a and ATF6). Teneligliptin has antioxidant properties, ameliorates oxidative stress and apoptotic phenotype and it can overcome the metabolic memory effect, induced by chronic exposure to high glucose in human endothelial cells.

Leukocyte telomere length and mortality risk in patients with type 2 diabetes.

Leukocyte telomere length (LTL) shortening is found in a number of age-related diseases, including type 2 diabetes (T2DM). In this study its possible association with mortality was analyzed in a sample of 568 T2DM patients (mean age 65.9 ± 9 years), who were followed for a median of 10.2 years (interquartile range 2.2). A number of demographic, laboratory and clinical parameters determined at baseline were evaluated as mortality risk factors. LTL was measured by quantitative real-time PCR and reported as T/S (telomere-to-single copy gene ratio). Age, gender, creatinine, diabetes duration at baseline, and LTL were significantly different between T2DM patients who were dead and alive at follow-up. In the Cox regression analysis adjusted for the confounding variables, shorter LTL, older age, and longer disease duration significantly increased the risk of all-cause mortality (HR = 3.45, 95%CI 1.02-12.5, p = 0.004). Kaplan-Maier analysis also found a different cumulative mortality risk for patients having an LTL shorter than the median (T/S ≤0.04) and disease duration longer than the median (>10 years) (log-rank = 11.02, p = 0.011). Time-dependent mortality risk stratification showed that T2DM duration and LTL combined was a fairly good predictor of mortality over the first 76 months of follow-up.In conclusion, LTL combined with clinical parameters can provide additive prognostic information on mortality risk in T2DM patients.

Oscillating glucose induces microRNA-185 and impairs an efficient antioxidant response in human endothelial cells.

BACKGROUND: Intracellular antioxidant response to high glucose is mediated by Cu/Mn-superoxide dismutases (SOD-1/SOD-2), catalase (CAT) and glutathione peroxidases (GPx), particularly glutathione peroxidase-1 (GPx-1). Although oscillating glucose can induce a more deleterious effect than high glucose on endothelial cells, the mechanism by which oscillating glucose exerts its dangerous effects is incompletely understood; however, the involvement of oxidative damage has been generally accepted. In this study we sought to determine whether oscillating glucose differentially modulates antioxidant response, and to elucidate the potential regulatory mechanisms exerted by the microRNA-185 (miR-185). METHODS: Human endothelial cells were exposed for 1 week to constant and oscillating high glucose. SOD-1, SOD-2, CAT and GPx-1, as well as two markers of oxidative stress [8-hydroxy-2'-deoxyguanosine (8-OHdG) and the phosphorylated form of H2AX (γ-H2AX)] were measured at the end of the experiment. Intracellular miR-185 was measured and loss-of function assays were performed in HUVEC. Bioinformatic tool was used to predict the link between miR-185 on 3'UTR of GPx-1 gene. Luciferase assay was performed to confirm the binding on HUVEC. RESULTS: After exposure to constant high glucose SOD-1 and GPx-1 increased, while in oscillating glucose SOD-1 increased and GPx-1 did not. SOD-2 and CAT remained unchanged under both conditions. A critical involvement of oscillating glucose-induced miR-185 in the dysregulation of endogenous GPx-1 was found. Computational analyses predict GPx-1 as miR-185's target. HUVEC cultures were used to confirm glucose's causal role on the expression of miR-185, its target mRNA and protein and finally the activation of antioxidant response. In vitro luciferase assays confirmed computational predictions targeting of miR-185 on 3'-UTR of GPx-1 mRNA. Knockdown of miR-185, using anti-miR-185 inhibitor, was accompanied by a significant upregulation of GPx-1 in oscillating glucose. 8-OHdG and γ-H2AX increased more in oscillating glucose than in constant high glucose. CONCLUSIONS: Glucose oscillations may exert more deleterious effects on the endothelium than high glucose, likely due to an impaired response of GPx-1, coupled by the upregulation of miR-185.

The Possible Role of Flavonoids in the Prevention of Diabetic Complications.

Type 2 diabetes mellitus is a disease that affects many metabolic pathways. It is associated with insulin resistance, impaired insulin signaling, ß-cell dysfunction, abnormal glucose levels, altered lipid metabolism, sub-clinical inflammation and increased oxidative stress. These and other unknown mechanisms lead to micro- and macro-complications, such as neuropathy, retinopathy, nephropathy and cardiovascular disease. Based on several in vitro animal models and some human studies, flavonoids appear to play a role in many of the metabolic processes involved in type 2 diabetes mellitus. In this review, we seek to highlight the most recent papers focusing on the relationship between flavonoids and main diabetic complications.

The simultaneous control of hyperglycemia and GLP-1 infusion normalize endothelial function in type 1 diabetes.

BACKGROUND: To test the effect of normoglycemia and glucagon-like peptide-1 (GLP-1), alone or in combination, on the possible normalization of endothelial function in type 1 diabetes. METHODS: Fifteen people with type 1 diabetes participated in three experiments: reaching and maintaining normoglycemia for 4h; reaching and maintaining hyperglycemia plus GLP-1 infusion for 4h; and reaching and maintaining normoglycemia for 4h with simultaneous infusion of GLP-1. RESULTS: Both normoglycemia and GLP-1 infusion restored endothelial function and decreased and plasma 8-iso prostaglandin F2α levels. However, only the combination of normoglycemia and GLP-1 was able to normalize endothelial function. CONCLUSIONS: This study confirms that long-lasting hyperglycemia in type 1 diabetes induces a permanent alteration which contributes to maintaining endothelial dysfunction even when glycemia is normalized, and that in the presence of normoglycemia, GLP-1 can contribute to normalizing endothelial function.