Diabetic Complications Research Articles

Changes in urine dipstick proteinuria and its relation to the risk of diabetic retinopathy and neuropathy.

Proteinuria is considered as a predictor for cardiovascular complications in diabetes mellitus (DM). However, no study has examined the association between changes in proteinuria and the risk of diabetic microvascular complications. Study participants were 71,825 DM patients who received urine dipstick test for proteinuria both in 2003-2004 and 2006-2007. They were categorized into four groups according to changes in proteinuria over 3 years (negative: negative → negative, resolved: proteinuria ≥ 1+ → negative, incident: negative → proteinuria ≥ 1+, persistent: proteinuria ≥ 1+ → proteinuria ≥ 1+). Cox-proportional hazard model was used in assessing the adjusted hazard ratios (HR) and 95% confidence interval (CI) for incidence of retinopathy, and neuropathy (adjusted HR [95% CI]). In all of DM patients, risk for comprehensive incidence of retinopathy and neuropathy increased in all types of proteinuria changes. In type 1 DM, HR for retinopathy and neuropathy generally increased in order of negative (reference), resolved (2.175 [1.150-4.114] and 1.335 [0.909-1.961]), incident (2.088 [1.185-3.680] and 1.753 [1.275-2.409]), and persistent proteinuria (1.314 [0.418-4.134] and 2.098 [1.274-3.455]). This pattern of relationship was similarly observed in type 2 DM for retinopathy and neuropathy: negative (reference), resolved (1.490 [1.082-2.051] and 1.164 [0.988-1.371]), incident (1.570 [1.161-2.123] and 1.291 [1.112-1.500]), and persistent proteinuria (2.309 [1.407-3.788] and 1.272 [0.945-1.712]). Risk for diabetic retinopathy and neuropathy generally increased in order of negative, resolved, incident, and persistent proteinuria. Once manifested proteinuria was associated with the increased risk of diabetic retinopathy and neuropathy even after remission of proteinuria.

Unveiling Wide Spectrum Therapeutic Implications and Signaling Mechanisms of Valsartan in Diverse Disorders: A Comprehensive Review.

Valsartan is an orally active non-peptide angiotensin receptor antagonist, an effective and well-tolerated anti-hypertensive drug. Besides its antihypertensive action, it has clinical implications in many other disorders, like heart failure (HF), arrhythmia, chronic kidney disease (CKD), diabetic complications (DM), atherosclerosis, etc. Besides angiotensin receptor blocking activity, valsartan reduces circulating levels of biochemical markers, such as hs-CRP, which is responsible for its anti-inflammatory and anti-oxidant activity. Moreover, valsartan also acts by inhibiting or inducing various signalling pathways, such as inducing autophagy via the AKT/mTOR/S6K pathway or inhibiting the TLR/NF-kB pathway. The current review exhaustively discusses the therapeutic implications of valsartan with specific emphasis on the mechanism of action in various disorders. The article provides a detailed spectrum of the therapeutic profile of valsartan and will likely be very useful to researchers working in the relevant research areas.

Aldose reductase with quinolone antibiotics interaction: In vitro and in silico approach of its relationship with diabetic complications

Aldose reductase (AR, EC1.1.1.21), a member of the aldo-keto reductase family, is critically implicated in the pathogenesis of chronic complications associated with diabetes mellitus, including neuropathy, nephropathy, and retinopathy. Hyperglycemia-induced AR overactivity results in intracellular sorbitol accumulation, NADPH depletion, and oxidative stress. Consequently, AR is recognized as a key mediator of oxidative and inflammatory signaling pathways involved in diverse human pathologies such as cardiovascular diseases, inflammatory disorders, and cancer. This has sparked renewed interest in developing novel AR inhibitors (ARIs) with enhanced therapeutic profiles. In this study, we evaluated the inhibitory potential of five quinolone antibiotics-gatifloxacin, lomefloxacin, nalidixic acid, norfloxacin, and sparfloxacin-as ARIs relevant to various physiological and pathological conditions. Through comprehensive in vitro and in silico analyses, we explored these antibiotics' binding interactions and affinities within the AR active site. Our findings reveal that these quinolones moderately inhibit AR at micromolar concentrations, with inhibition constants (KIs) ranging from 1.03 ± 0.13 μM to 4.12 ± 0.51 μM, compared to the reference drug epalrestat (KI of 0.85 ± 0.06 μM). The combined in vitro and in silico results underscore significant interactions between these drugs and AR, suggesting their potential as therapeutic agents against the aforementioned pathological conditions. Furthermore, these insights will aid in optimizing clinical dosing regimens and mitigating unexpected drug-drug interactions when these antibiotics are co-administered with other treatments.

Identification of key genes in diabetic nephropathy based on lipid metabolism.

Diabetic nephropathy (DN) is a common systemic microvascular complication of diabetes with a high incidence rate. Notably, the disturbance of lipid metabolism is associated with DN progression. The present study aimed to identify lipid metabolism-related hub genes associated with DN for improved diagnosis of DN. The gene expression profile data of DN and healthy samples (GSE142153) were obtained from the Gene Expression Omnibus database, and the lipid metabolism-related genes were obtained from the Molecular Signatures Database. Differentially expressed genes (DEGs) between DN and healthy samples were analyzed. The weighted gene co-expression network analysis (WGCNA) was performed to examine the relationship between genes and clinical traits to identify the key module genes associated with DN. Next, the Venn Diagram R package was used to identify the lipid metabolism-related genes associated with DN and their protein-protein interaction (PPI) network was constructed. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. The hub genes were identified using machine-learning algorithms. The Gene Set Enrichment Analysis (GSEA) was used to analyze the functions of the hub genes. The present study also investigated the immune infiltration discrepancies between DN and healthy samples, and assessed the correlation between the immune cells and hub genes. Finally, the expression levels of key genes were verified by reverse transcription-quantitative (RT-q)PCR. The present study determined 1,445 DEGs in DN samples. In addition, 694 DN-related genes in MEyellow and MEturquoise modules were identified by WGCNA. Next, the Venn Diagram R package was used to identify 17 lipid metabolism-related genes and to construct a PPI network. GO analysis revealed that these 17 genes were markedly associated with 'phospholipid biosynthetic process' and 'cholesterol biosynthetic process', while the KEGG analysis showed that they were enriched in 'glycerophospholipid metabolism' and 'fatty acid degradation'. In addition, SAMD8 and CYP51A1 were identified through the intersections of two machine-learning algorithms. The results of GSEA revealed that the 'mitochondrial matrix' and 'GTPase activity' were the markedly enriched GO terms in both SAMD8 and CYP51A1. Their KEGG pathways were mainly concentrated in the 'pathways of neurodegeneration-multiple diseases'. Immune infiltration analysis showed that nine types of immune cells had different expression levels in DN (diseased) and healthy samples. Notably, SAMD8 and CYP51A1 were both markedly associated with activated B cells and effector memory CD8 T cells. Finally, RT-qPCR confirmed the high expression of SAMD8 and CYP51A1 in DN. In conclusion, lipid metabolism-related genes SAMD8 and CYP51A1 may play key roles in DN. The present study provides fundamental information on lipid metabolism that may aid the diagnosis and treatment of DN.

Diabetic Retinopathy Leading to Blindness- A Review.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes that damages the retina, leading to blindness. People with type 1 diabetes are at greater risk of developing DR than people with type 2 diabetes. Diabetic retinopathy may be divided into two primary categories: Proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR). There are multiple risk factors for the onset and progression of diabetic retinopathy, such as hypertension, obesity, smoking, duration of diabetes, and genetics. Numerous investigations have evaluated the levels of a wide range of inflammatory chemokines within DR patients' serum, vitreous, and aqueous fluids. In diabetic retinopathy, the vitreous fluid exhibited rises in angiogenic factors like platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) or declines in antiangiogenic factors like pigment epithelium-derived factor (PEDF). For prevention of diabetic retinopathy, more physical activity as well as less sedentary behavior were linked to a reduced likelihood of DR. Supplementing with nutraceuticals containing vitamins (B1, B2, B6, B12, C, D, E, and l-methyl folate) and mineral (zinc) can help decrease or avoid an outbreak of DR. Only laser photocoagulation and Anti-vascular endothelial growth factor (Anti-VEGF) injections are advised as favorable therapies in severe retinopathy. When it comes to treating DR's VEGF levels, inflammation, oxidative stress, apoptosis, and angiogenesis, Traditional Chinese medicine (TCM) has an excellent future.

Development of puerarin-loaded poly(lactic acid) microspheres for sustained ocular delivery: In vitro/vivo evaluation

Diabetic retinopathy, an ocular complication of diabetes, is an important cause of blindness in adults. Puerarin is considered to have promising potential for clinical use in treating diabetic retinopathy. In this study, we designed a novel puerarin-loaded poly(lactic acid) sustained-release microspheres suitable for ocular administration, and we assessed itsin vitro and in vivo properties. The preparation of puerarin-loaded microspheres was optimized by Box-Behnken response surface design. The encapsulation efficiency and drug loading of microspheres were 35.71% and 3.85%, respectively. The microspheres exhibited good dispersion and high safety, making it suitable for ocular drug delivery. In vitro release demonstrated that microspheres had a well-sustained release effectiveness, and its release behavior complied with the zero-order kinetic characteristics. The results of ocular tissue distribution revealed that the CmaxandAUC0-∞ of the microspheres group in the retina and choroid were considerably higher than those of the solution group and the intravenous injection group. This research revealed that intravitreal injection of microspheres can significantly prolong the half-life of puerarin in eye tissues and achieve sustained drug release. Therefore, intravitreal injection of microspheres has positive implications for the treatment of diabetic retinopathy.

Investigating the Mechanism of Banxia Xiexin Decoction in Treating Gastritis and Diabetes Mellitus through Network Pharmacology and Molecular Docking Analysis

Background: Banxia Xiexin decoration (BXD), a complex prescription in Traditional Chinese Medicine (TCM), clinically acts as a treatment for gastritis and diabetes while its mechanism of treatment remains unknown. Objection: This study aimed to explore the common mechanism of BXD in treating gastritis and diabetes based on network pharmacology and molecular docking technology. Methods: The seven Chinese herbal components and drug targets were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) for gastritis and diabetes using GeneCards, DisGeNET, Comparative Toxicogenomics Database (CTD), and Online Mendelian Inheritance in Man (OMIM) databases. Common drug and disease targets were imported into the STRING data platform for protein-protein interaction (PPI) analysis, and Cytoscape 3.7.2 software for network topology analysis, and core targets were filtered. Results: There were 124 components, 249 targets, 449 targets for gastritis, and 4005 targets for diabetes. After mapping, 83 BXD targets for gastritis and diabetes were obtained, and the targets with high correlation were STAT 3, JUN, TNF, IL-6, etc. More relevant targets were involved in the cancer pathway, AGE-RAGE signaling pathway of diabetic complications, fluid shear stress, and atherosclerosis pathway. Conclusion: This study preliminarily reveals that BXD may play a role in the treatment of gastritis and diabetes mellitus through multi-components, multi-targets, and multi-pathways, and proposes some potential "component-target-pathway" hypotheses in light of previous reports.

Radish red protects against early diabetic kidney disease through inhibiting inflammation, pyroptosis and insulin resistance via IRAK1 signaling suppression

Diabetic kidney disease (DKD) is a major diabetic complication and a leading cause of end-stage renal disease (ESRD), but the therapeutic strategies for DKD are still limited. Red radishes (Raphanus sativus L.) are a rich source of natural anthocyanins that have antioxidant, anti-apoptotic and anti-inflammatory activities. In this study, we attempted to explore the effects of natural pigment anthocyanin called radish red (RR) extracted from red radishes on DKD progression and the underlying molecular mechanisms. RR dose-dependently reduced the tubular cell injury, indicated by the decreased expression of kidney injury molecule 1 (KIM1). Furthermore, releases of pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) stimulated by HF were strongly relieved by RR. Inflammatory response and pyroptosis were also identified to be induced by HF stimulation but were mitigated by RR in HK2 cells through repressing nuclear factor-κB (NF-κB) activation and NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. IR and lipogenesis due to HF exposure were also significantly ameliorated by RR in HK2 cells. Mechanistically, RNA-Seq analysis showed that RR strongly depressed interleukin-1 receptor-associated kinase-1 (IRAK1)-mediated NLRP3 inflammasome, pyroptosis, IR and lipid deposition. Importantly, IRAK1 overexpression almost diminished the beneficial effects of RR, while being rescued upon NLRP3 knockdown in HF-treated HK2 cells, revealing that RR performed its nephroprotective functions in diabetic kidney via inactivating the IRAK1-NLRP3 signaling pathway. Similarly, animal studies confirmed that RR supplementation efficiently ameliorated HFF-caused metabolic disturbance, IR, renal dysfunctions in mice and improved structural kidney damage. Consistently, RR consumption dramatically reduced lipid accumulation, inflammatory response and pyroptosis in kidney tissues of HFF-challenged mice mainly through repressing IRAK1-NLRP3 axis. Our results demonstrated that dietary supplementation with RR may serve as an IRAK1-NLRP3 inhibitor for preventing and treating diabetic nephropathy.

Homoplantaginin alleviates high glucose-induced vascular endothelial senescence by inhibiting mtDNA-cGAS-STING pathway via blunting DRP1-mitochondrial fission-VDAC1 axis.

Vascular endothelial senescence is a major risk factor for diabetic vascular complications. Abnormal mitochondrial fission by dynamically related protein 1 (DRP1) accelerates vascular endothelial cell senescence. Homoplantaginin (Hom) is a flavonoid in Salvia plebeia R. Br. with protecting mitochondrial and repairing vascular properties. However, the relevant mechanism of Hom against diabetic vascular endothelial cell senescence remains unclear. Here, we used db/db mice and high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs) to assess the anti-vascular endothelial cell senescence of Hom. We found that Hom inhibited senescence-associated β-galactosidase activity, decreased the levels of senescence markers, and senescence-associated secretory phenotype factors. Additionally, Hom inhibited the expression of cGAS-STING pathway and downstream inflammatory factors. STING inhibitor H-151 delayed endothelial senescence, whereas STING overexpression attenuated the anti-endothelial senescence effect of Hom. Furthermore, we observed that Hom reduced mitochondrial fragmentation and inhibited abnormal mitochondrial fission using transmission electron microscopy. Importantly, Hom has a stronger effect on mitochondrial fission protein than mitochondrial fusion protein, especially downregulated the expression of DRP1. DRP1 inhibitor Mdivi-1 suppressed cGAS-STING pathway and vascular endothelial senescence, yet DRP1 agonist FCCP attenuated the effect of Hom. Surprisingly, Hom blunted abnormal mitochondrial fission mediated by DRP1 mitochondrial localization, suppressed interaction of DRP1 with VDAC1 and prevented VDAC1 oligomerization, which was necessary for mtDNA escape and subsequent cGAS-STING pathway activation. These results revealed a previously unrecognized mechanism that Hom alleviated vascular endothelial senescence by inhibited mtDNA-cGAS-STING signaling pathway via blunting DRP1-mitochondrial fission-VDAC1 axis.

Subphenotypes of adult-onset diabetes: Data-driven clustering in the population-based KORA cohort.

A data-driven cluster analysis in a cohort of European individuals with type 2 diabetes (T2D) has previously identified four subgroups based on clinical characteristics. In the current study, we performed a comprehensive statistical assessment to (1) replicate the above-mentioned original clusters; (2) derive de novo T2D subphenotypes in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) cohort and (3) describe underlying genetic risk and diabetes complications. We used data from n = 301 individuals with T2D from KORA FF4 study (Southern Germany). Original cluster replication was assessed forcing k = 4 clusters using three different hyperparameter combinations. De novo clusters were derived by open k-means analysis. Stability of de novo clusters was assessed by assignment congruence over different variable sets and Jaccard indices. Distribution of polygenic risk scores and diabetes complications in the respective clusters were described as an indication of underlying heterogeneity. Original clusters did not replicate well, indicated by substantially different assignment frequencies and cluster characteristics between the original and current sample. De novo clustering using k = 3 clusters and including high sensitivity C-reactive protein in the variable set showed high stability (all Jaccard indices >0.75). The three de novo clusters (n = 96, n = 172, n = 33, respectively) adequately captured heterogeneity within the sample and showed different distributions of polygenic risk scores and diabetes complications, that is, cluster 1 was characterized by insulin resistance with high neuropathy prevalence, cluster 2 was defined as age-related diabetes and cluster 3 showed highest risk of genetic and obesity-related diabetes. T2D subphenotyping based on its sample's own clinical characteristics leads to stable categorization and adequately reflects T2D heterogeneity.

Novel mitochondria-targeted therapy AP39 limits mitochondrial dysregulation and diastolic dysfunction in 2D & 3D human models of diabetic cardiomyopathy

Abstract Introduction Mitochondrial dysregulation has been implicated in many complications of diabetes. Mitochondrial-targeted therapies AP39 and SS31 are renoprotective, but their cardioprotective potential in diabetes has not been fully resolved. Purpose We investigated AP39 and SS31 in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-hCM) and endothelial cells (iPSC-hEC) independently in 2D culture, as well as collectively in a 3D cardiac organoid (iPSC-hCO) model also comprising fibroblasts (iPSC-hFB), under type 2 diabetes (T2D)-like conditions. Methods Cells (iPSC-hCM, iPSC-hEC, iPSC-hFB; foreskin-2 cell line) were exposed to either 5.55mM glucose (control) or T2D conditions (20mM glucose plus fatty acids, endothelin-1 and cortisol) ± AP39 (50nM) or SS31 (1µM) for 48h. Cardiac organoids were subjected to 5.55mM glucose (control) or T2D for 4 days, with AP39 (50nM) or SS31 (1µM) added on day 2. Data are expressed as mean±SEM (fold) with n=4-6 from 2-3 independent experiments. One-way ANOVA with Dunnett`s post hoc analysis was performed with P<0.05 considered significant. Results 2D human cells: After 48h, T2D increased mitochondrial superoxide in iPSC-hCM (2.4±0.1 fold vs control) and iPSC-hEC (3.2±0.29 fold vs control), both P<0.05 (measured by MitoSOX). This was blunted by both AP39 (to 1.1±0.17) and SS31 (to 1.5±0.17) in T2D iPSC-hCM (P<0.05), with similar impact in iPSC-hEC, to 2.9±0.26 and 1.3±0.16 fold, both P<0.05. T2D increased cell death in both iPSC-hCM (1.6±0.09 fold vs control) and iPSC-hEC (1.6±0.12 fold, both P<0.05 measured by propidium iodide staining. Interestingly, AP39 selectively blunted cell death in T2D iPSC-hCM (to 1.1±0.06, P<0.05), mimicked by SS31 in T2D iPSC-hEC only (to 1.0±0.10, P<0.05). Further, T2D-induced mitochondrial hyperpolarisation in iPSC-hCM (1.5±0.09 fold vs control, assessed using TMRM), was only protected by AP39 (1.2±0.06 fold, P<0.05), but not SS31. 3D human cardiac organoids: After 4 days, T2D increased total contraction duration (1.6±0.10 fold control), time to peak (1.7±0.11) and relaxation duration (1.5±0.13, indicative of diastolic dysfunction), assessed by Olympus IX71 with a DP72 camera. All 3 contractile parameters were attenuated with AP39 (to 1.5±0.06, 1.3±0.09 and 1.0±0.04 fold, respectively) or SS31 (to 1.1±0.05, 1.2±0.15 and 1.2±0.12 fold, respectively), all P<0.05. T2D increased mitochondrial superoxide (2.7±0.16 fold control), blunted by AP39 (to 1.8±0.16) and SS31 (to 1.9±0.17), both P<0.05. Cellular injury measured by LDH was evident in T2D iPSC-hCO (2.1±0.23 fold control) was limited by AP39 (to 1.2±0.09) and SS31 (to 1.1±0.07), both P<0.05. Conclusion Our results highlight the cardioprotective potential of AP39 and SS31 to limit mitochondrial dysregulation, cell death and contractile dysfunction in human in vitro models of T2D. These findings may facilitate their clinical progression as therapeutic options for diabetic cardiomyopathy.

STING-mediated DNA damage response in diabetes-induced vascular complications

Abstract Background Hyperglycemia drives endothelial dysfunction, a key factor in the development of diabetes vascular complications. The stimulator of interferon genes (STING) signal, plays a crucial role in the immune system and is implicated in the pathogenesis of inflammatory diseases. Therefore we investigated the role of STING in endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Methods and Results Diabetes was induced by single-dose administration of STZ in 8-week-old C57BL/6 and Sting-/- mice. STZ injection promoted the expression of STING and DNA damage markers in the aorta of C57BL/6 mice. Genetic deletion of STING ameliorated endothelial dysfunction as determined by vascular reactivity assay (P < 0.001) and increased aortic eNOS phosphorylation (P < 0.05) in STZ-injected mice. Stimulation of STING agonist (cGAMP), or mtDNA increased inflammatory molecules expression (e.g., VCAM1 and IFNB) and decreased eNOS phosphorylation in HUVECs. In ex-vivo experiments, cGAMP significantly impaired endothelial function which was ameliorated in the presence of an STING inhibitor or a neutralizing IFN-β antibody. Furthermore, the administration of STING inhibitor ameliorated endothelial dysfunction in STZ-induced diabetic mice (P < 0.01). Conclusion The DNA damage response regulated by STING aggravated diabetes-induced endothelial dysfunction. STING signaling may be a potential therapeutic target for diabetic vascular complications.

Circadian heart rate fluctuations predict 21-year cardiovascular and all-cause mortality in type 2 and type 1 diabetes

Abstract Background Alterations in circadian heart rate (HR) fluctuations have been associated with cardiovascular events in the general population. This study aimed at defining their long-term prognostic value for cardiovascular and all-cause mortality in patients with diabetes. Methods We examined a cohort of 349 patients with type 2 or type 1 diabetes (52% women, age 57.1±11.9 years, BMI 29.4±5.9 kg/m2, HbA1c 8.6±2.1%, 81% type 2 diabetes) who underwent 24h ambulatory blood pressure and HR monitoring (ABPM) and assessment of diabetic microvascular complications. The median standard deviation (SD) value of ABPM-derived HR measurements was used to define patients with low daily HR fluctuations (low 24h-HR SD), while a <10% decline in average night-time vs day-time HR identified patients with blunted nocturnal HR dip (n=107, 31%). The clinical features and time-dependent prognostic impact of these conditions were evaluated over a 21-year observational follow-up. Results Low 24h-HR SD and blunted nocturnal HR dip were associated with an adverse cardiometabolic risk profile and high prevalence of cardiac autonomic neuropathy and nephropathy. After 6,251 person-years of follow-up (21.0 [14.0-21.0] years), a total of 136 (39%) deaths occurred, of which 100 (68%) of cardiovascular cause. After adjustment for potential confounders, the low 24h-HR SD group had a higher risk for both cardiovascular (hazard ratio 1.99, 95% CI 1.29–3.06, p=0.002) and all-cause mortality (hazard ratio 1.50, 95% CI 1.03–2.18, p=0.033), compared with high 24h-HR SD. Consistently, patients with blunted nocturnal HR dip had a higher adjusted risk for cardiovascular (1.61, 95% CI 1.07–2.43, p=0.023) and all-cause mortality (1.61, 95% CI 1.11–2.34, p=0.012), compared with those with preserved nocturnal HR dip. Conclusions Impaired circadian HR fluctuations are frequent in patients with long-standing diabetes and are associated with microvascular disease and increased long-term cardiovascular and all-cause mortality. Identifying these conditions via 24h-ABPM may provide a cost-effective risk stratification tool in this high-risk population.Kaplan-Meier curves

Reference values of normal fetal ductus venosus Doppler flow measurements at 11-14 weeks of gestation.

To establish the reference range of normal fetal ductus venosus pulsatility index (DV PI) and ductus venosus (DV) blood flow velocity at 11-14 weeks of gestation. Fetal ductus venosus Doppler flow was measured in singleton pregnancies attending our hospital for early pregnancy nuchal translucency (NT) screening between June 2021 and May 2022. All fetuses were followed up for pregnancy outcome using the following inclusion criteria: Singleton pregnancy; no maternal underlying diseases such as diabetes, hypertension, rheumatism, or other pregnancy complications; fetal crown-rump length (CRL) of 45 to 84 mm; normal NT screening ultrasound; no absent or reversed ductus venosus a-wave; no fetal structural abnormalities; no chromosomal abnormalities during follow-up; and good pregnancy outcome. DV PI, peak ventricular systolic velocity (S-wave), atrial systolic flow velocity (a-wave) and time-averaged maximum velocity (TAMXV) were recorded. The ductus venosus Doppler parameters of 224 fetuses which met the inclusion criteria were analysed. DV PI P5 and P95 ranged from 1.0007 and 1.3415 for a CRL of 45 mm to 0.9734 and 1.2115 for a CRL of 84 mm, indicating a statistically significant correlation with CRL. DV S-wave, a-wave, and TAMXV all increased as CRL increased, demonstrating a statistically significant correlation with CRL values. A reference range of normal fetal ductus venosus Doppler spectral parameters at 11-14 weeks was established to provide a basis for further research into the clinical value of normal and abnormal DV PI values in relation to adverse pregnancy outcomes.

Preliminary data on short-term outcomes within the cardio-obstetrics registry

Abstract Background Pregnancy leads to physiological changes within the cardiovascular system such as increased plasma volume and cardiac output or hypercoagulability. These changes can be challenging for women with pre-existing cardiovascular disease with higher risks of complications. The guidelines of the European Society of Cardiology recommend treating high-risk patients in specialized centres by an interdisciplinary pregnancy heart team. In a team-based approach, the Pregnancy Heart Team was founded at our university hospital, in order to establish specific structures of communication and responsibility. Methods A prospective registry of all patients treated by the Pregnancy Heart Team between November 2022 and March 2024 was established. Patients consisted of women with pre-existing cardiovascular disease undergoing pregnancy as well as women who developed pregnancy-associated cardiovascular disease. Patients were evaluated throughout pregnancy by lab work and echocardiography during each trimester as well as in the postpartum period. Results In total 39 women (mean age 34±5 years) were prospectively included in the registry. 17 patients (43.5%) were classified as mWHO ≥ III. 17 patients (43.5 %) with pre-existing (pregnancy-associated) cardiovascular disease were managed throughout pregnancy and delivery. 9 patients (18.4 %) developed pregnancy-associated cardiovascular diseases such as peripartum cardiomyopathy or spontaneous coronary artery dissection. Preliminary data shows that mean left-ventricular ejection fraction remained stable during pregnancy with a non-significant trend towards lower values postpartum. Cardiac biomarkers such as high-sensitivity troponin T and NT-pro-BNP showed a non-significant trend towards increased values in the third trimester and postpartum. Adverse maternal outcomes occurred in 14 patients (35.9 %), including preterm premature rupture of membranes (12.2%), gestational hypertension (7.6%), gestational diabetes (5.1%), preeclampsia/eclampsia (7.6%) and delivery-associated complications (10.2%). Fetal complications included macrosomia (10.2%) or intrauterine growth retardation (5.1%). Discussion These preliminary data of a real-world patient collectivedemonstrate that a significant number of patients experienced adverse pregnancy outcomes which was associated with a trend towards increased cardiac biomarkers throughout pregnancy and postpartum. As recent studies have shown, interpretation of standard parameters such as cardiac biomarkers is not fully understood during pregnancy, especially in women with pre-existing cardiovascular disease. Our data may aid to understand prognostic implications of cardiac biomarkers during pregnancy.

Blockade of endothelial to mesenchymal transition (EndMT) by an inhibitor of histone methyltransferase EZH2 attenuates atherosclerosis in diabetes

Abstract Background Atherosclerosis is a major contributor to cardiovascular disease (CVD) related deaths in individuals with diabetes. Persistent endothelial cell activation caused by factors such as hyperglycaemia induces endothelial to mesenchymal transition (EndMT), which promotes both initiation as well as progression of atherosclerosis. Gene expression changes that occur during EndMT, are regulated by multiple factors including epigenetic modifiers such as the histone methyltransferase EZH2 (Enhancer of zest homolog 2). Recent studies have implicated the role of EndMT in cardiovascular complications of diabetes including atherosclerosis. However, the role of EZH2 in induction of EndMT in diabetes associated atherosclerosis is not known. Methods Aortae of atheroprone diabetic Apoe-/- mice were subjected to single cell RNA sequencing (scRNA-seq) analysis using 10X Genomics platform. In vitro model mimicking diabetes-induced EndMT was established in human aortic endothelial cells (HAECs) using high glucose (25mM) and TNF-α containing media for 72 hrs ± a small molecule inhibitor of EZH2, GSK126. RNA and Chromatin Immunoprecipitation (ChIP) sequencing was performed to identify EZH2-mediated epigenomic and corresponding transcriptomic changes in this setting. Complementary in vitro EZH2 knockdown experiments using shRNA were also performed. Moreover, Apoe-/- mice made diabetic with streptozotocin, were treated with GSK126 (50 mg/kg BW daily for 5 weeks) in an intervention study design. Aortic sections from treated and control mice were subjected to immunofluorescent staining specific for the EndMT pathway. Results scRNA-seq analysis identified an EndMT+ve endothelial cell sub-population with a diabetes specific proatherogenic transcriptomic profile. Comparison with the ENCODE dataset for EZH2 target genes using Harmonizome showed that indeed multiple repressed genes in diabetes were targets of EZH2. Methyltransferase activity of EZH2 was elevated in in vitro settings of EndMT. Interestingly, EZH2 inhibition by GSK126 attenuated EndMT. Gene expression analysis showed that GSK126 treatment rescued 76 of 242 differentially expressed genes in HAECs exposed to EndMT conditions. Several differentially expressed genes including COL1A2, MMP2, NOS3, COL4A1, and TGFB2 (FDR <0.05, Log2 fold change (2x)) were targets of EZH2 validating integrated analysis of our scRNA-seq with the ENCODE dataset. EZH2 knockdown experiments validated experimental findings of EZH2 inhibition studies using GSK126 in HAECs. Importantly, GSK126 treatment blocked EndMT resulting in reduced atherosclerosis in diabetic Apoe-/- mice in intervention studies. Conclusion This study showed that the inhibition of EZH2 with GSK126 is a potential vasculoprotective treatment for the diabetes induced EndMT and associated atherosclerosis.

Association of MnSOD (rs4880) and GPx1 (rs1050450) with diabetic nephropathy: a meta-analysis

Abstract Background Microvascular complications of diabetes including retinopathy, nephropathy, and neuropathy are those long-term complications that affect small blood vessels. Diabetic nephropathy (DN) is characterized by persistent microalbuminuria. A meta-analysis of case–control studies aims to examine the relationship between MnSOD (rs4880) and GPx1 (rs1050450) and the risk of DN. Methods Various databases such as Web of Science, PubMed, Springer Link, Cochrane Library, Science Direct, Embase, and Google Scholar were utilized to extract relevant studies. The statistical software MedCalc version 22.009 was acquired to accomplish the meta-analysis of the included studies. Results A significant association was found between two SNPs (rs4880 and rs1050450) and DN in the homozygous recessive model [95% confidence interval (CI) 0.97–2.41, odds ratio (OR) TT vs CC = 1.53, P = 0.06] and heterozygous model [95% CI 0.92–1.97, OR CT vs CC = 1.35, P = 0.12], while there was no association with the other genetic models. A significant association between rs4880 and DN was perceived in the Asian population [95% CI 1.24–2.03, OR = 1.6, P < 0.001], meanwhile the studies among Caucasian group showed insignificant association [95% CI 0.87–1.32, OR = 1.07, P = 0.5]. On the other hand, the association between rs1050450 and DN was significant [95% CI 3.80–13.01, OR = 7.04, P < 0.001] and insignificant [95% CI 0.96–2.28, OR = 1.48, P = 0.07] among Asian and Caucasian population, respectively. Conclusion To date, this meta-analysis could be the first to contribute a panoramic exploration of the MnSOD and GPx1 polymorphic association with DN. The results of the study contemplate the data presently accessible from the literature and can be employed as an influential lead for future research.

Associations of the TyG index with albuminuria and chronic kidney disease in patients with type 2 diabetes.

Diabetes-related kidney disease reduces patients' quality of life, increases the risk of death, and is associated with insulin resistance (IR). The triglyceride-glucose (TyG) index is a simple and inexpensive alternative to IR measurement. Furthermore, the relationship between albuminuria and chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) remains unclear. Therefore, we aimed to investigate the association of TyG index with albuminuria and CKD in patients with T2DM. Data from 01/2013-12/2017 period were obtained from the Population Health Data Archive's Diabetes Complications Data Set. A total of 1048 patients with T2DM were included in this study. CKD is defined as an estimated glomerular filtration rate < 60 ml/min-1.1.73 m-2 or a urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. Albuminuria is defined as a UACR ≥ 30 mg/g. The TyG index is calculated by measuring the triglyceride and fasting blood glucose levels. Logistic regression models were used to analyze the association between albuminuria, CKD with T2DM and TyG index. We identified 1048 subjects, 63.03% of whom were men. The mean age was 46.21 years, and the mean body mass index was 26.742 kg/m2. CKD and albuminuria detection rates showed an increasing trend in the different TyG subgroups. (p = 0.008, p = 0.006). Using the Q1 group as a baseline, the risk of albuminuria and CKD was significantly greater in the group Q3 (OR = 1.514, 95% CI 1.121-2.047 P = 0.05), and the same result was obtained after adjusting for covariates (OR = 2.241, 95% CI 1.245-4.034, P = 0.007). Subgroup analyses revealed a significant increase in the incidence of albuminuria and CKD in the group Q3 compared to that in the Q1 group. The TyG index is positively associated with albuminuria and CKD in patients with T2DM and may be a marker for predicting the occurrence of early kidney injury in patients with T2DM. Clinicians should test this indicator early to detect lesions and improve patient prognosis.

Three decades of lipid-lowering therapy in type 2 diabetic patients with angiographically proven stable coronary artery disease

Abstract Lipid-lowering therapy (LLT) is key to reducing the burden of macrovascular diabetes complications. Here, we aim to assess long-term trends in LLT and LDL-C levels among patients with type 2 diabetes (T2DM) with angiographically proven coronary artery disease (CAD). We investigated T2DM patients (n=590), who were referred to elective coronary angiography and were diagnosed with CAD in one of three observational cohort studies (OS) spanning 25 years: OS1: 1999-2000 (n=190); OS2: 2005-2008 (n=241); OS3: 2022-2023 (n=159). These studies were conducted at the same cardiology unit of a tertiary care hospital in Central Europe. The proportion of patients receiving statin therapy (C10AA and C10AB) increased significantly from 57.9% in OS1 to 64.3% in OS2 and 78.6% in OS3 (ptrend&amp;lt;0.001). Further, there was an increase in patients receiving high-intensity statin therapy, rising from none in OS1 to 8.5% in OS2 and 73.4% in OS3 (ptrend&amp;lt;0.001). The proportion of patients receiving more than one LLT compound also increased (OS1: 2.1%; OS2: 2.1%; OS3: 35.2%; ptrend&amp;lt;0.001). Use of ezetimibe (C10AX09) increased (OS1: 0.0%; OS2: 1.2%; OS3: 39.0%; ptrend&amp;lt;0.001) and fibrate use (C10AB) decreased (OS1: 5.3%; OS2: 3.3%; OS3: 0.6%; ptrend=0.015). Newly approved compounds (C10AX13 - C10AX16) were prescribed for 3.8% of patients in OS3. Among statin combination therapies, ezetimibe was predominantly used (93.5%). Mean LDL-C levels declined significantly from 123±38 mg/dL (OS1) to 115±39 mg/dL (OS2) and 77±38 mg/dL (OS3; ptrend&amp;lt;0.001). However, only 2.2% of patients in OS1, 2.5% in OS2 and 32.1% in OS3 reached an LDL-C target of &amp;lt;55 mg/dL (ptrend&amp;lt;0.001). This analysis suggests an upward trend in treatment intensity and a substantial improvement in LDL-C levels among T2DM patients with CAD. However, the majority of these patients still does not reach their LDL-C target.

Dietary potassium intake and its interaction with sodium intake on risk of developing cardiovascular disease in persons with type 2 diabetes: The Japan Diabetes Complication and its Prevention Prospective study (JDCP study 12).

Many guidelines recommend increases in potassium intake. However, the relationship of dietary potassium intake with incident cardiovascular disease (CVD) has not been examined in those with type 2 diabetes (T2DM), including sodium acting antagonistically with potassium. We investigated these relationships in Japanese patients with T2DM. The investigation was part of the JDCP study, a nationwide prospective study begun in 2007. Analysed were 1477 persons with T2DM, 40-75 years of age, who completed a brief-type, self-administered Diet History Questionnaire at baseline. Primary outcome was a CVD event during the follow-up median 7 years (3.9-8.1 years). Hazard ratios (HRs) for CVD were estimated by Cox regression adjusted for confounders of daily potassium intake categorized by tertiles. Tertiles of sodium intake were also analysed. Mean daily potassium intake in tertiles was 1877, 2627 and 3532 mg, respectively, and significant associations were not shown between potassium intake and incidence of CVD. When HRs for CVD were stratified for potassium intake in tertiles (reference group, bottom tertile) and sodium intake (reference group, bottom tertile), potassium intake in the bottom tertile and sodium intake in the second and top tertiles were associated with significantly elevated HR for CVD (2.79 [1.02-7.63] and 3.92 [1.30-11.79], respectively). Low potassium intake in conjunction with high sodium intake was significantly associated with increased incident CVD in persons with T2DM. However, CVD incidence was not related to high potassium intake, regardless of sodium intake.