Introduction:Diabetic neuropathy may develop on a background of hyperglycaemia and is associated with increased oxidative stress. Elevated asymmetric dimethylarginine (ADMA) levels are linked to oxidative stress reducing the synthesis of nitric oxide (NO) by uncoupling NO synthase. Oxidative stress induces considerable changes in nerve conduction velocity in diabetic patients. There is strong evidence that α-lipoic acid (ALA) as an antioxidant may improve nerve conduction and relieve neuropathic symptoms. We aimed to investigate the relationship between endothelial dysfunction and NO synthesis in type 2 diabetic patients with peripheral neuropathy after ALA treatment. Material and methods:Fifty-four type 2 diabetic patients with neuropathy were included in the study. Serum ADMA concentration, intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), oxidised low-density lipoprotein (oxLDL), and TNF-α levels were determined with Enzyme-Linked Immunosorbent Assay (ELISA). Nitric oxide concentration was measured by Griess reaction. Peripheral sensory nerve function was assessed by current perception threshold (CPT) testing. Autonomic function was assessed by Ewing's five standard cardiovascular reflex tests composite autonomic score (CAS). Results:Asymmetric dimethylarginine levels were significantly decreased (0.62 ±0.11 vs. 0.53 ±0.11 µmol/l, p < 0.001), as well as TNF-α concentrations (1.21 ±0.42 pg/ml vs. 1.05 ±0.5 pg/ml, p < 0.05), while NO levels were significantly increased (16.78 ±11.1 vs. 21.58 ±8.84 µmol/l, p < 0.05) after 6-months of 600 mg/day ALA treatment. VCAM-1, ICAM-1, and oxLDL levels did not change significantly. The CPT and CAS significantly improved after ALA treatment. The improvement of CPT values was correlated positively with the change of ADMA levels (r = 0.58, p < 0.001). The change in ADMA level was more pronounced in responder patients based on both CPT and CAS. Conclusions:Our results suggest that ALA supplementation improves endothelial function characterised by serum levels of ADMA and TNF-α in patients with diabetic neuropathy. Changes in serum ADMA levels may predict the clinical response to ALA treatment.

Background/Objectives: Diabetic sensorimotor polyneuropathy (DSPN) is a frequent microvascular complication of diabetes mellitus, associated with increased morbidity and reduced quality of life. The existing literature offers a limited understanding of sex-specific cardiovascular risk profiles and their association with DSPN, particularly within Central and Eastern European populations. Methods: A retrospective analysis was conducted using data from 621 individuals with type 1 or type 2 diabetes mellitus who underwent comprehensive neuropathy screening at the University of Debrecen between 2017 and 2021. The diagnosis of DSPN was made in accordance with international criteria, incorporating symptom scores, and electrophysiological measurements. Multivariate logistic regression was applied in order to identify independent predictors. Results: The diagnosis of DSPN was made in 444 individuals (71.5%), of whom 58.2% were female. Despite similar glycemic control (HbA1c: 7.81% in men vs. 7.65% in women, p = 0.297), men had significantly more frequent occurrences of previous myocardial infarction (11.8% vs. 5.0%, p = 0.008), peripheral vascular disease (19.9% vs. 12.7%, p = 0.041) and atherosclerosis (31.7% vs. 22.0%, p = 0.021). Multivariate analysis showed that female gender was independently associated with a lower incidence of DSPN (odds ratio [OR] = 0.592, 95% confidence interval [CI]: 0.369-0.950, p = 0.030), while diabetic retinopathy was a significant predictor (OR = 2.728, 95% CI: 1.300-5.725, p = 0.008). Electrophysiological testing revealed lower nerve conduction amplitudes in females for selected nerves. Conclusions: Our findings highlight sex-specific differences in neuropathy risk and support the implementation of individualized screening strategies in diabetic populations with region-specific risk factors.

Recent studies have demonstrated the efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in enhancing glycemic control, regulating body weight, and modulating lipid metabolism. However, their effects on lipoprotein subfractions have not been clarified. The objective of this 52-week, single-center, randomized trial was to compare the effects of subcutaneous semaglutide administered once weekly and oral sitagliptin administered once daily on anthropometric measurements and lipoprotein subfractions measured by Lipoprint gelelectrophoresis in patients with type 2 diabetes mellitus (T2DM). A total of 34 obese individuals with T2DM were enrolled in the study and randomly assigned to receive semaglutide (n = 18) or sitagliptin (n = 16). Thirty-one age- and body weight-matched non-diabetic obese individuals served as controls. Semaglutide treatment resulted in significant reductions in body mass index (BMI), waist circumference, and HbA1c, along with improvements in lipid parameters, including reductions in LDL cholesterol and non-HDL cholesterol levels, and redistribution of LDL and HDL subfractions toward a less atherogenic profile. Conversely, sitagliptin elicited modest glycemic improvements without substantial alterations in lipid composition. Multivariate regression analysis demonstrated that fluctuations in lipoprotein subfractions were not influenced by changes in BMI or HbA1c. These results support the pleiotropic metabolic benefits of semaglutide and its potential role in managing the cardiometabolic risk of T2DM.

Background/Objectives: Type 2 diabetes mellitus (T2DM) and its macro- and microvascular complications are major health concerns with multiple factors, like advanced end glycation products (AGEs), in the background. AGEs induce long-lasting functional modification of the proteins and collagen in the vascular wall and nerve tissue. We investigated the effect of alpha-lipoic acid (ALA) treatment on AGEs, soluble AGE receptor (sRAGE), the AGE/sRAGE ratio, and the parameters of endothelial dysfunction and their correlations. Methods: In our 6-month intervention study, 54 T2DM patients with neuropathy treated according to the actual therapeutic guidelines with unchanged oral antidiabetic drugs were included and treated by daily oral administration of 600 mg ALA. A total of 24 gender and age-matched T2DM patients without neuropathy served as controls. Results: In our work, we first demonstrated the attenuating effect of alpha lipoic acid therapy on AGEs in humans (11.89 (9.44–12.88) to 10.95 (9.81–12.82) AU/μg (p = 0.017)). sRAGE levels or the AGEs/sRAGE ratio were not affected by ALA treatment or by the presence of neuropathy. We found a correlation between the changes of AGEs and the improvement of current perception threshold and progranulin levels, and an inverse correlation with the change of asymmetric dimethylarginine. Conclusions: According to our results, ALA decreases AGEs, which may contribute to the clinically well-known beneficial effect in diabetic neuropathy and improvement of endothelial function.

Distal sensorimotor polyneuropathy (DSPN) is the earliest detectable and the most frequent microvascular complication in diabetes mellitus. Several studies have previously demonstrated correlations between cardiovascular risk factors in diabetic patients and independent risk factors for diabetic neuropathy. Our objective was to retrospectively analyze data from diabetic patients in the North-East region of Hungary who underwent neuropathy screening at the Diabetic Neuropathy Center, University of Debrecen, between 2017 and 2021. We aimed to investigate the correlations between cardiovascular risk factors and microvascular complications among patients with DSPN. The median age of the patients was 67 years, 59,6% were female, and 91,1% had type 2 diabetes. The prevalence of DSPN among the study subjects was 71.7%. A significantly longer duration of diabetes (p<0.01) was noted in patients with DSPN. Those with DSPN demonstrated a significantly higher HbA1c level (p<0.001) and a greater frequency of insulin use (p = 0.001). We observed a significantly elevated albumin/creatinine ratio (p<0.001) and a significantly lower eGFR (p<0.001) in patients with DSPN. Diabetic retinopathy exhibited a significantly higher prevalence in patients with DSPN (p<0.001). A higher prevalence of myocardial infarction (p<0.05), ischemic heart disease (p<0.001), peripheral arterial disease (p<0.05) and a history of atherosclerosis (p<0.05) was observed in patients with DSPN. In a multivariate logistic regression analysis, the following factors were independently associated with the presence of DSPN: higher HbA1c (OR:2.58, 95% CI:1.89-3.52, p<0.001), age (OR:1.03, 95% CI:1.01-1.05, p = 0.006), albumin/creatinine ratio above 3 mg/mmol (OR:1.23, 95% CI:1.06-1.45, p = 0.008), retinopathy (OR:6.06, 95% CI:1.33-27.53, p = 0.02), and composite cardiovascular endpoint (OR:1.95, 95% CI:1.19-3.19, p = 0.008). Our study revealed that age, elevated HbA1c levels, significant albuminuria, retinopathy, and cardiovascular complications may increase the risk of DSPN. Further investigation of these associations is necessary to understand the impact of patient characteristics during the treatment of diabetic neuropathy.

The aim of this paper is to study the wintertime physical properties of atmospheric aerosol particles on the basis of data observed at the K-puszta regional background station in Hungary. In Hungary wintertime smog episodes are linked to strong stable air (high pressure blocking events) with thermal inversion. These atmospheric conditions are frequently formed during winter months (November–February) due to the special geographical location of the country. The formation of smog events is highly probable in cases of thermal inversion periods sustaining for at least 4 days. We discuss in the paper the role of high-pressure blocking events in aerosol properties in terms of PM10 concentrations, aerosol size distributions, new particle formation and optical properties. We found that high-pressure blocking events have significant impacts on the size distribution and particle formation processes. At K-puszta the aerosol is in highly aged state with size distribution dominated by the accumulation mode. This is further supported by the optical properties, e.g., by high scattering Ångstrom exponent and by relatively weak absorption. The most significant effect of extreme episodes is manifested in the changes in PM10 concentrations and, consequently, in aerosol optical properties. The PM10 concentrations, scattering coefficients and absorption coefficients considerably increase to extreme values that are characteristic of a heavily polluted atmosphere rather than rural air. Our results indicate that in winter, the air quality at K-puszta is often influenced by regional air pollution as shown by spatial distribution of PM10 concentration. It is found that PM10 had almost the same concentration in regional background air and in different types of urban environments. The special meteorological conditions and the role of regional-scale transport can explain why local abatements in cities cannot lead to significant improvement of the air quality during smog events.

Abstract In aortic stenosis (AS) patients, assessment of left ventricular (LV) systolic function is complicated due to the significant impact of increased afterload on conventional parameters. Myocardial work (MW) analysis, a novel echocardiographic method adjusts myocardial deformation to instantaneous LV pressure which may better reflect the LV contractile state. Importantly, long-term LV pressure overload has marked backward effects beyond the LV: classification of this extravalvular cardiac damage effectively represents the involvement of the cardiopulmonary system in AS. Both MW and cardiac damage staging could hold remarkable prognostic power in the clinically complex population of transcatheter aortic valve replacement (TAVR) candidates. Accordingly, our aim was to assess the prognostic value of MW analysis and cardiac damage staging in patients undergoing TAVR. We enrolled 289 patients (79±6 years, 41% female) prior to TAVR. Echocardiographic measurements were performed one day before the procedure. We calculated LV ejection fraction (EF) and by speckle-tracking echocardiography global longitudinal strain (GLS), as well. Global constructive work (GCW) was quantified with dedicated software and LV pressure was estimated using transaortic mean gradient and systolic blood pressure. Based on the echocardiographic data, we also determined the extent of cardiac damage associated with AS: patients were classified as Stage 0 (no cardiac damage), Stage 1 (LV damage), Stage 2 (mitral valve or left atrial damage), Stage 3 (pulmonary artery vasculature or tricuspid valve damage), or Stage 4 (right ventricular damage). Our primary outcome was all-cause mortality, reached by 68 patients (median follow-up: 26 months). In our cohort, preprocedural EF was 47±13 %, GLS was -12.3±4 %, while GCW was 2043±791 mmHg%. 14 (5%) patients were classified as Stage 0, 61 (21%) as Stage 1, 128 (44%) as Stage 2, 15 (5%) as Stage 3, and 71 (25%) as Stage 4. GCW showed a continuous decline through the AS Stages (from Stage 0-4: 2963±652 vs. 2154±652 vs. 2168±718 vs. 1988±969 vs. 1552±772 mmHg%; p<0.001). Using univariate Cox analysis GCW (HR 0.968 [95% CI 0.938-0.998] per 100 unit change; p=0.034) and AS Staging (HR 1.236 [95% CI 1.015-1.505]; p=0.035) were both associated with all-cause mortality, while EF (HR 0.984 [95% CI 0.966-1.002]; p=0.085) and GLS (HR 1.042 [95% CI 0.984-1.103]; p=0.160) were not. In multivariate Cox regression models, both GCW (HR 0.957 [95% CI 0.922-0.992] per 100 unit change; p=0.018) and AS cardiac damage staging (HR 1.263 [95% CI 1.029-1.549]; p=0.025) were proven to be significant independent predictors of all-cause mortality. In TAVR patients, preoperative GCW values exhibited a persistent decrease across AS Stages. As opposed to EF and GLS, GCW and AS Staging both showed strong association with all-cause mortality in our cohort. Moreover, GCW had higher prognostic value than any other conventional or advanced measure of LV function.

Diabetic sensorimotor neuropathy (DSPN) is strongly associated with the extent of cellular oxidative stress and endothelial dysfunction in type 2 diabetes (T2DM). Alpha-lipoic acid (ALA) attenuates the progression of DSPN through its antioxidant and vasculoprotective effects. Kallistatin has antioxidant and anti-inflammatory properties. We aimed to evaluate changes in kallistatin levels and markers of endothelial dysfunction in patients with T2DM and DSPN following six months of treatment with 600 mg/day of ALA. A total of 54 patients with T2DM and DSPN and 24 control patients with T2DM but without neuropathy participated in this study. The serum concentrations of kallistatin, ICAM-1, VCAM-1, oxLDL, VEGF, ADMA, and TNF-alpha were measured by an ELISA. Peripheral sensory neuropathy was assessed with neuropathy symptom questionnaires and determination of the current perception threshold. After ALA treatment, the level of kallistatin significantly decreased, as well as the levels of TNF-alpha and ADMA. Changes in kallistatin levels were positively correlated with changes in oxLDL. The improvement in DSPN symptoms following ALA treatment showed a positive correlation with changes in kallistatin, VEGF, oxLDL, and ADMA levels. Based on our results, kallistatin could represent a potential new biomarker for assessing therapeutic response during ALA treatment in patients with DSPN.

The present meta-analytic study examined the association between alexithymia and psychoactive substance use. Studies published from 1988 to August 20, 2022 were identified by a systematic search and 168 eligible studies were included in five meta-analyses. Results showed that (1) the correlation between substance use and alexithymia is small but significant (r = 0.177); (2) substance users have substantially higher alexithymia than nonusers (g = 0.545); (3) alexithymic participants have significantly but slightly higher levels of substance use than non-alexithymics (g = 0.242); (4) substance users are significantly but only slightly more likely to be alexithymic than nonusers (OR = 2.392); and (5) alexithymic individuals are not more likely to be substance users than non-alexithymics. Larger effects were observed among samples diagnosed with substance use disorder (SUD), and the use of depressants, alcohol, opiates, and illicit stimulants had stronger relation to alexithymia. We found a tendency for a larger association with problematic use as compared to other indicators (e.g., frequency and duration) of substance use. Among the components of alexithymia, difficulties in identifying feelings has the strongest association with substance use. Our findings support clinical practice by suggesting the improvement of emotion regulation in SUD.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin–angiotensin–aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima–media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Abstract Global myocardial work index is a novel echocardiographic parameter of the left ventricular (LV) function, which may overcome the load-sensitvity of the traditional functional measures by measuring LV deformation in the context of simultaneous pressures. This approach may gain particular importance in pressure overload states, such as patients with severe aortic stenosis. However, the longitudinal changes of this recently introduced measure are scarcely investigated in this population, and data are also lacking about its association with functional improvement following transcatheter aortic valve replacement (TAVR). Accordingly, our aim was to investigate the clinical determinants of preoperative and also postoperative GMWI in patients undergoing TAVR. Eighty-four patients (54%% male, age: 79±6 years) were enrolled. Prior to the procedure, subjects underwent echocardiographic investigation and the detailed medical history was also recorded. Serum NT-proBNP levels were also measured. We calculated LV ejection fraction and LV end-diastolic volume (EDV), and speckle-tracking analysis was performed to measure global longitudinal strain (GLS). As an accepted method of its estimation, LV pressure curve was generated by adding the mean aortic valve gradient to the systolic blood pressure. Using these measures, global myocardial work index (GMWI) was quantified by commercially available software. 12 months after the procedure, the patients underwent a follow-up echocardiographic examination, and at that time point we determined the same measures. At follow-up, GLS has significantly increased (-13.5±4.5 vs. -15.2±3.6%; p<0.001), while GMWI was significantly lower at the follow-up assessment (1913±786 vs. 1666±594 mmHg%, p<0.01). Compared to the preoperative values, LVEDV also showed a significant decrease at follow-up (115±46 vs. 105±41 mL, p<0.01). Using multivariable analysis, atrial fibrillation (β=0.36; p<0.001) ischemic heart disease (β=0.20; p<0.05) and also GMWI (β=-0.22; p<0.05) were found to be independent predictors of the postoperative NT-proBNP (R2=0.36; overall p<0.001). Importantly, by replacing GMWI to GLS, the latter did not enter the model as a predictor (β=0.17, p=0.11). TAVR significantly alters LV functional and morphological measures. Regarding the functional outcome of the patients, different clinical factors influence NT-proBNP after the procedure. Possibly due to its significant load dependency, preoperative GLS failed to predict NT-proBNP at follow-up, while GMWI was an independent precictor of NT-proBNP at follow up along with atrial fibrillation and ischemic heart disease. GMWI may serve as a useful imaging marker of preprocedural patient assessment before TAVR.

Bevezetés: A súlyos férfi terheléses inkontinencia a radikális prostatectomia után kialakult leggyakoribb szövődmény, sebészi kezelésében „gold standard” a művi záróizom-beültetés. A készüléket dr. Brantley Scott fejlesztette ki és ültette be először 1972-ben, majd az évtizedek során számos fejlesztésen ment keresztül. A ma is használt formája 1982-ben került forgalomba AMS 800 néven, amely azóta több, mint 250 ezer esetben került beültetésre. Az irodalmi adatok alapján a leggyakoribb szövődmény magának az eszköznek a meghibásodása, uroinfekció, húgycsőlézió, illetve hibás méretválasztás. Ezekben az esetekben a műsphincter cseréje, illetve eltávolítása szükséges. A relatíve magas szövődményráta ellenére is a súlyos esetekben elsőként választandó műtéti terápiás megoldás, mivel a betegek 79%-ánál a kontinencia jelentős javulása érhető el. Betegek és módszerek: Munkacsoportunk által 2010 és 2022 között 21 betegnél került beültetésre AMS 800 műsphincter. Összefoglalónk célja az volt, hogy az általunk végzett beavatkozások szövődményeit összehasonlítsuk az irodalmi adatokkal. Eredmények: 21 beteg nyomon követését végeztük, 16 esetben radikális prostatectomia, míg 5 esetben transurethralis prosztatareszekció után történt AMS 800 beültetése. 6 beteg adjuváns irradiációban is részesült. Az esetek 9%-ában infekciós szövődményt észleltünk, emellett 9-9%-ban húgycsőatrófia, illetve húgycsőerózió került felismerésre. A készülék meghibásodását az esetek 19%-ában észleltük. Az adjuváns irradiáción átesett betegeknél a sebészei reintervenció szignifikánsan gyakrabban vált szükségessé. Következtetés: A jelentős és tartós kontinenciajavulás miatt a gyakori szövődmények ellenére a súlyos férfi terheléses inkontinencia kezelésében a műsphincter-implantáció a „gold standard” megoldás. A gyakori szövődményarány miatt ezen betegek rendszeres utánkövetése alapvető fontosságú.

Background and Aims : There are strong associations between obesity, cardiovascular complications, and lipid abnormalities in type 2 diabetes (T2DM). Once-weekly administration of semaglutide lowers the blood glucose level in a glucose-dependent manner and has a beneficial effect on lipid levels. Small and dense LDL particles play a pivotal role in the development of atherosclerosis and cardiovascular diseases. Chemerin, a previously described adipokine, is associated with insulin resistance associated with obesity and lipoprotein abnormalities. To date, the effect of semaglutide treatment on chemerin and lipoprotein subfraction levels are currently unclear.Methods: We enrolled 11 T2DM patients on metformin monotherapy who received 1 mg semaglutide per week add-on therapy. We assessed the changes in body weight, lipoprotein subfractions, adiponectin, leptin and chemerin levels after six months. LDL and HDL subfractions were detected using non-gradient polyacrylamide gel electrophoresis.Results: Body mass index and HbA1c were significantly reduced. Among the lipid subfractions, a significant decrease in small dense LDL ratio and concentration were found (p<0.001 and p<0.01, respectively). Serum chemerin levels were significantly lower in T2DM patients after six months of semaglutide treatment (p<0.01). We found a positive correlation between the change in the ratio of small dense LDL subfraction and the change in the level of chemerin (p<0.05).Conclusions: Semaglutide treatment reduces body weight in obese T2DM patients and may have a beneficial effect on lipid parameters. Chemerin may be involved in the regulation of lipoprotein metabolism in T2DM patients treated with semaglutide. Background and Aims : There are strong associations between obesity, cardiovascular complications, and lipid abnormalities in type 2 diabetes (T2DM). Once-weekly administration of semaglutide lowers the blood glucose level in a glucose-dependent manner and has a beneficial effect on lipid levels. Small and dense LDL particles play a pivotal role in the development of atherosclerosis and cardiovascular diseases. Chemerin, a previously described adipokine, is associated with insulin resistance associated with obesity and lipoprotein abnormalities. To date, the effect of semaglutide treatment on chemerin and lipoprotein subfraction levels are currently unclear. Methods: We enrolled 11 T2DM patients on metformin monotherapy who received 1 mg semaglutide per week add-on therapy. We assessed the changes in body weight, lipoprotein subfractions, adiponectin, leptin and chemerin levels after six months. LDL and HDL subfractions were detected using non-gradient polyacrylamide gel electrophoresis. Results: Body mass index and HbA1c were significantly reduced. Among the lipid subfractions, a significant decrease in small dense LDL ratio and concentration were found (p<0.001 and p<0.01, respectively). Serum chemerin levels were significantly lower in T2DM patients after six months of semaglutide treatment (p<0.01). We found a positive correlation between the change in the ratio of small dense LDL subfraction and the change in the level of chemerin (p<0.05). Conclusions: Semaglutide treatment reduces body weight in obese T2DM patients and may have a beneficial effect on lipid parameters. Chemerin may be involved in the regulation of lipoprotein metabolism in T2DM patients treated with semaglutide.

Introduction Cardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications. Methods Type 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip .) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po .). Results DAPA decreased blood glucose levels (D: 37±2.7 vs . D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment. Conclusions These data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Hungarian National Research, Development and Innovation Fund Introduction Smoke-induced diseases cause 20% of global mortality. The toxic agents of cigarette smoke have notorious destructive effects on the cardiovascular system. Therefore, many people use e-cigarettes instead of traditional tobacco products; yet, nicotine content remains the cause of addiction. Purpose Human induced pluripotent stem cells (hiPSC) provide a useful personalised link between clinical and in vitro cardiovascular models. Here we generated hiPSC lines from a pair of identical twins with diabetes to test long and short-term effects of nicotine. Methods Blood samples were used to reprogram mononuclear cell fractions into hiPSC via Sendai viral transduction of the Yamanaka factors (Cytotune 2.0). Genotype and pluripotency of the iPSC were checked with FACS, PCR, immunocytochemistry and embryoid body formation. hiPSC line from non-diabetic healthy control ("GM") was used as control. The hiPSC lines were differentiated into endothelial cells and used in a toxicology and phenotypic assays. hiPSC-derived endothelial cells and control HUVEC were treated with e-cigarette liquid with (nicotine 0.225 mg/ml, ECL18) and without nicotine (ECL0) or nicotine in culture medium (0.225 mg/ml). The cells were analysed with high content microscopy (HCS, Opera), using Hoechst, apoptotic marker caspase3/7, mitochondrial TMRM and endothelial CD31 labelling. Results On the clinical side, one of the diabetic twins was a smoker ("C") and diagnosed and treated with a severe coronary disease, whilst the other ("D") was a non-smoker and no coronary artery disease. For the reprogrammed twin clones (normal, 46XX chromosomes), no differences in exome sequence were found. Cells were positive for pluripotency marker SSEA4 (>90%, FACS); Oct4 and Nanog were also positive, embryoid body formation and PCR were positive for all the three germ layers. The phenotypic fidelity of hiPSC-derived endothelial cells (hiPSC-EC) were different from the twin lines. C cell line showed a higher endothelial-to-mesenchymal transition rate and non-endothelial drift as compared to D line at 3 passages FACS after CD31 isolation (9% CD31+ vs 37% and 41%, for C, D and non-diabetic control, respectively). Nicotine did not change TMRM or caspase 3/7 activation in "C" hiPSC-EC, in turn it induced apoptosis in "D" cells (p=0.01 vs ECL18 and p=0.02 vs EGM2+nicotine, n=3). In GM and HUVEC endothelial cells, TMRM intensity increased after e-cigarette liquid treatment (all p<0.05, n=3) and caspase was higher group with ECL containing nicotine (p = 0.0178, n=3). "D" line endothelial cells showed higher cell loss to the nicotine diluted in EGM2, than in ECL (p = 0.0091, n=6). Conclusions Our developed a novel patient-specific hiPSC model where and in vitro toxicology assay showed alteration in endothelial phenotype associated with nicotine exposure. A scalable platform can provide further cohort level information on toxic agent like nicotine to the cardiovascular system.

Background: Diabetic neuropathy (DN) is a very frequent microvascular complication of type 2 diabetes mellitus (T2DM). Obesity and physical inactivity are well-known risk factors for T2DM. Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone with several beneficial effects on obesity-related metabolic disorders. We aimed to investigate the effect of short-term physical activity on the levels of FGF21, and its correlation with the severity of peripheral sensory polyneuropathy in T2DM patients. Methods: Thirty patients with DN were enrolled in the study, compared to age- and gender-matched controls. We conducted a six-week aerobic training program, which meant treadmill and cycle ergometers three times a week. Anthropometric and laboratory parameters were measured for each patient before and after intervention. Serum levels of FGF21, TNF-alpha, irisin, leptin and adiponectin were measured by ELISA. The sensory perception threshold (CPT) was quantitatively measured using Neurometer®. Results: We found significant decreases in BMI, waist circumference, HbA1c and TNF-alpha levels. From baseline to six-week follow-up, FGF21 levels were significantly increased in DN patients. Significant negative correlations were shown between the changes in FGF21 levels and BMI, between changes in FGF21 and the improvement of CPT values, and between the changes in FGF21 and TNF-alpha levels. There was no difference in irisin, adiponectin and leptin levels in DN patients after aerobic training program. Conclusions: The physical activity may increase the level of FGF21 in T2DM patients with neuropathy. Our results highlight the importance of regular physical activity in the treatment of diabetic neuropathy.