Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for the treatment of depressive disorders. Recent clinical reports and studies in animal models have suggested that fluoxetine increases the risk of cardiovascular diseases, but the underlying mechanisms remain unknown. Here, we uncover that fluoxetine disrupts lipid and cholesterol metabolism in primary human endothelial cells (ECs). Fluoxetine triggered an upregulation of cholesterol metabolism genes, leading to the accumulation of lipid droplets in ECs. We find higher levels of cholesterol esters, ceramides, sphingolipids and fatty acids in ECs treated with fluoxetine. The disruption of lipid homeostasis was driven by increased cholesterol biosynthesis, as well as low-density lipoprotein (LDL) uptake and transcytosis via the LDL receptor. Fluoxetine accumulated in ECs in the endoplasmic reticulum (ER), caused ER expansion and reduced protein translation, without inducing ER stress markers. Mechanistically, fluoxetine activated the SREBP2 transcription factor in an INSIG-dependent manner. SREBP2 inhibition attenuated the fluoxetine-mediated upregulation of the LDL receptor and lipid accumulation. Our findings reveal that fluoxetine reprograms lipid metabolism and leads to endothelial dysfunction.

Die Behandlung des Typ-1-Diabetes (T1D) entwickelt sich derzeit in 2 Richtungen besonders dynamisch: Einerseits rücken krankheitsmodifizierende und potenziell kurative Ansätze wie Zelltherapien, Transplantationsverfahren und Immuninterventionen stärker in den Vordergrund, andererseits verbessern technologische Innovationen im Bereich der kontinuierlichen Glukosemessung (CGM) und der automatisierten Insulindosierung (AID) die Alltagsversorgung zunehmend auch in bislang unterrepräsentierten Gruppen von Patient:innen. Dabei zeigen aktuelle Daten, dass sowohl hypoimmune allogene Betazellen als auch aus Stammzellen abgeleitete Inselzellen beim Menschen funktionell aktiv sein können und damit das Konzept des Betazellersatzes substanziell stärken. Parallel dazu werden Präventions- und Frühinterventionsstrategien weiter verfeinert, auch wenn sich bislang nur wenige immunologische bzw. gegen Antigene gerichtete Therapien klinisch durchsetzen konnten. Besonders eindrucksvoll ist die technologische Entwicklung im Bereich von CGM- und AID-Systemen. Diese verbessern bei T1D nicht nur die Zeit im Zielbereich und reduzieren Hypoglykämien, sondern zeigten inzwischen auch bei insulinbehandeltem Typ-2-Diabetes (T2D) klinisch relevante Vorteile. Ergänzend werden supportive medikamentöse Strategien wie Natrium-Glukose-Kotransporter-2-Inhibitoren (SGLT2-Inhibitoren) und Glucagon-like-Peptide-1-Rezeptor-Agonisten (GLP-1-Rezeptor-Agonisten) zunehmend auch bei Menschen mit T1D untersucht. Sie eröffnen v. a. bei Patient:innen mit T1D und Adipositas sowie kardiorenalem Risiko neue Optionen, erfordern jedoch wegen potenzieller Risiken weiterhin eine sorgfältige Selektion, Schulung und Überwachung. Insgesamt markieren die aktuellen Studien einen weiteren Schritt weg von der reinen Insulinsubstitution hin zu einer zunehmend personalisierten, technologiegestützten und in Teilen krankheitsmodifizierenden Therapie des T1D.

BACKGROUND AND HYPOTHESIS:The endogenous opioid proenkephalin (PENK) has been identified as an independent risk marker for acute cardiovascular diseases and acute kidney injury. However, its regulation, its association with other cardiometabolic markers and its prognostic role in patients with chronic kidney disease (CKD) have not been thoroughly investigated. METHODS:PENK serum levels were cross-sectionally related to renal and cardiometabolic markers across three large cohorts (total N = 4722), including the Leipzig-CKD cohort (N = 581), as well as the population-based LIFE-Adult (N = 3093) and Sorbs (N = 1048) cohort. Furthermore, a longitudinal analysis was performed in the Leipzig-CKD cohort to assess the association between circulating PENK levels at baseline and a composite 4-point major adverse renal events (4P-MAKE) endpoint comprising incident or worsening kidney disease, development of kidney failure (KF) requiring kidney replacement therapy or kidney transplantation, and renal deaths. RESULTS:In the entire cross-sectional cohort (N = 4722), PENK levels were strongly and inversely correlated with markers of renal function, i.e. estimated glomerular filtration rate (eGFR), creatinine and urinary albumin-creatinine ratio. In multivariable analysis, eGFR was the strongest, independent and inverse predictor of circulating PENK levels after adjustment for age and sex, as well as markers of obesity, glucose intolerance, dyslipidemia and inflammation. Multivariable Cox regression analysis revealed that baseline circulating PENK levels were strongly associated with an increased risk of the 4P-MAKE over a median follow-up of 8.7 years. Each doubling of PENK levels was associated with a >2-fold increase in the risk of developing 4P-MAKE, even after adjusting for various clinical and metabolic variables. PENK provided added value for predicting adverse renal outcomes. CONCLUSIONS:PENK levels are strongly, independently, and inversely associated with renal function in cross-sectional analysis. Furthermore, baseline circulating PENK levels are predictive of a 4P-MAKE in patients and added independent, prognostic value for identification of patients at risk for adverse renal outcomes.

Abstract Background Polyneuropathy (PN) is a common neurological disorder characterized by sensory, motor, and autonomic dysfunction of peripheral nerves. Its incidence is increasing, especially among the elderly population, making PN a significant and growing public health concern worldwide. Main body This review highlights the key risk factors contributing to the development of PN, with a particular focus on nutritional and metabolic etiologies. These include B-vitamin deficiencies, prediabetes, diabetes mellitus, obesity, and treatment-induced neuropathies. The complex interplay of these factors often exacerbates the progression of PN and complicates management. Current preventive approaches and challenges in early detection are also discussed to provide a comprehensive overview of strategies aimed at reducing the disease burden. Conclusion The rising prevalence and disabling nature of PN necessitate urgent public awareness, better screening, and increased healthcare resources. Advancing prevention strategies targeting modifiable risk factors may significantly reduce the impact of PN on patients and healthcare systems alike.

Treatment of type 1 diabetes (T1D) is currently evolving rapidly in two directions: on the one hand, disease-modifying and potentially curative approaches (e.g., cell therapies, transplantation procedures, and immune interventions) are becoming more important; on the other hand, technological innovations in the field of continuous glucose monitoring (CGM) and automated insulin delivery (AID) are increasingly improving daily care even for underrepresented patients groups. Current data show that both hypoimmune allogeneic beta cells and islet cells derived from stem cells can be functionally active in humans, thereby, substantially strengthening the concept of beta cell replacement. Furthermore, prevention and early intervention strategies are also being further refined, despite only a few immunological or antigen-targeted therapies having been clinically implemented. Technological developments in the field of CGM and AID systems are especially remarkable. In T1D, these not only increase time in target range and reduce hypoglycemia, but clinically relevant benefits in insulin-treated type 2 diabetes (T2D) are also reported. Supportive pharmacologic strategies such as sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) and glucagon-like-peptide-1 receptor agonists (GLP-1 receptor agonists) are also increasingly being investigated in people with T1D. This opens up new options, especially for patients with T1D and obesity or cardiorenal risks; however, due to potential risks, they still require careful patient selection, training, and monitoring. Overall, the current studies illustrate the continued shift from simple insulin replacement toward increasingly personalized, technology-supported and, in some aspects, disease-modifying treatment for T1D.

BACKGROUND:With decreasing estimated glomerular filtration rate (eGFR) and increasing albuminuria, the risk of cardiovascular events and overall mortality increases in chronic kidney disease (CKD). Established clinical renal endpoints often correspond to the late stage of CKD. Early stages are often initially asymptomatic. OBJECTIVE:This article classifies the eGFR progression and changes in albuminuria as early markers and possible surrogate endpoints in CKD studies and describes key aspects for their clinical and methodological use in studies and benefit assessment. RESULTS:The eGFR and the urine albumin-creatinine ratio (UACR) are complementary for risk stratification and progress monitoring, including in the cardiorenal context. Variability and influencing factors such as volume status, infections and blood pressure necessitate repeated measurements and contextual interpretation, especially in heart failure and after initiation of treatment with acute effects. For the eGFR Slope, a distinction is made between total Slope over several years and chronic Slope after the early acute phase. A meta-analysis of randomized studies reported a strong association between the total Slope averaged over 3 years and renal endpoints with a median R2 of 0.97, while the predictive accuracy of the chronic eGFR Slope was lower. Concerning albuminuria, it has been shown that higher UACR values are independently associated with cardiovascular mortality and that a reduction in UACR is associated with a more favorable renal prognosis. CONCLUSION:The progression of the eGFR and albuminuria can improve the practicality of studies in early stages of CKD, lead to faster results and facilitate interdisciplinary classification if validation, time window, acute phase, standard treatment and competing risks are reported in a comprehensible manner.

Lipoedema is a chronic adipose tissue disorder often misdiagnosed as obesity due to overlapping symptoms and a lack of biomarkers. In this study, we analysed 13 adipocytokines in 79 women and identified chemerin, FGF21 and adiponectin as key biomarkers for distinguishing lipoedema. Decision tree models achieved up to 95% sensitivity, supporting the potential of these biomarkers for improving diagnostic accuracy, particularly in women with overweight or obesity.

Mit sinkender eGFR und zunehmender Albuminurie steigen bei chronischer Nierenkrankheit (CKD) das Risiko für kardiovaskuläre Ereignisse und die Gesamtmortalität. Etablierte klinisch-renale Endpunkte sind häufig das Endstadium der CKD. Frühe Stadien bleiben zunächst häufig asymptomatisch. Der Beitrag ordnet den eGFR-Verlauf und Veränderungen der Albuminurie als frühe Marker und mögliche Surrogatendpunkte in CKD-Studien ein und beschreibt wesentliche Aspekte für ihre klinische und methodische Nutzung in Studien und Nutzenbewertung. Estimated glomerular filtration rate und UACR ergänzen sich für Risikostratifizierung und Verlaufsmonitoring, u. a. im kardiorenalen Kontext. Variabilität und Einflussfaktoren wie Volumenstatus, Infektionen und Blutdruck machen wiederholte Messungen und Kontextinterpretation nötig, besonders bei Herzinsuffizienz und nach Therapiebeginn mit Akuteffekten. Für den eGFR Slope wird zwischen Total Slope über mehrere Jahre und Chronic Slope nach der frühen Akutphase unterschieden. Eine Metaanalyse randomisierter Studien berichtet für den über 3 Jahre gemittelten Total Slope eine starke Assoziation mit renalen Endpunkten mit medianem R2 von 0,97, während die Vorhersagegüte des Chronic eGFR Slope geringer war. Für die Albuminurie wurde gezeigt, dass höhere UACR-Werte unabhängig mit kardiovaskulärer Mortalität assoziiert sind und eine Reduktion der UACR mit einer günstigeren renalen Prognose einhergeht. Verlauf der eGFR und Albuminurie können Studien in frühen CKD-Stadien praktikabler machen, zu rascheren Ergebnissen führen und die interdisziplinäre Einordnung erleichtern, wenn Validierung, Zeitfenster, Akutphase, Standardtherapie und konkurrierende Risiken nachvollziehbar berichtet werden.

Abstract Background This study examined the associations of estimated glucose disposal rate (eGDR), a surrogate of insulin sensitivity, and the insulin resistance indices TG/HDL-C and TyG with gastrointestinal (GI) cancer mortality in the UK Biobank. Methods We included 369,447 participants without cancer at baseline and recorded 4,305 GI cancer-related deaths over a mean follow-up of 13.5 years. Fine-Gray models assessed associations of eGDR, TG/HDL-C, and TyG with GI cancer mortality. Results Higher eGDR was associated with lower pooled GI cancer mortality (sHR, 0.67; 95% CI, 0.61–0.74; P < 0.001); associations with EC, ESCC, CRC, LC, and PC mortality remained significant after false discovery rate (FDR) correction. TyG, but not TG/HDL-C, remained associated with pooled GI cancer mortality, and both markers remained associated with LC mortality. Subgroup analyses were exploratory. Conclusions Higher eGDR was associated with lower pooled and several site-specific GI cancer mortality outcomes, whereas TG/HDL-C and TyG associations were modest and site-specific. These findings do not establish clinical utility.

Introduction:Kallikrein-related peptidase 7 (KLK7) is a protease implicated in metabolic disease and obesity. Patients with chronic kidney disease (CKD) exhibit several cardio-metabolic comorbidities and increased mortality. The goal of this study was to investigate the associations of KLK7 levels with renal function and clinical outcomes in patients with CKD. Methods:Baseline KLK7 serum levels were cross-sectionally related to renal and cardiometabolic markers in the Leipzig-CKD cohort (n=542). Longitudinal Cox Regression analyses (n=472) were performed to associate baseline circulating KLK7 concentrations and risk of major adverse renal (MARE) and cardiovascular (MACE) events, as well as all-cause mortality. Additionally, mRNA expression of Klk7 and related genes was examined in CKD versus control mice using bulk RNA sequencing. Results:KLK7 levels were inversely associated with markers of renal function, i.e. estimated glomerular filtration rate (eGFR), and inflammation, i.e. C-reactive protein, in multivariable regression. Longitudinal analyses associated higher baseline KLK7 with lower all-cause (adjusted HR [95% CI]: 0.65 [0.49-0.86], p=0.003) and non-cardiovascular (adjusted HR [95% CI]: 0.56 [0.40-0.78], p=0.001) mortality over a median follow-up of 7.6 years. A KLK7 threshold of 1383.6 pg/ml stratified patients into low- and high-risk groups for mortality. No associations were found for MARE or MACE. In tissues of CKD and control mice, no significant changes in Klk7 mRNA expression were found. Discussion:Circulating KLK7 associates inversely with renal function and inflammation, likely reflecting reduced renal clearance. Higher circulating KLK7 independently predicts lower all-cause mortality, whereas baseline KLK7 was not related to composite renal and CV outcomes.

Chronic kidney disease (CKD) is a strong risk factor for cardiovascular mortality and morbidity. We hypothesized that a senescent phenotype instigated by uremic toxins could account for early vascular aging (EVA) and vascular dysfunctions of microvasculature in end stage kidney disease (ESKD) patients which ultimately lead to increased cardiovascular complication. To test this hypothesis, we utilized both in vivo, and ex vivo approaches to study endothelial and smooth muscle function and structure, and characterized markers related to EVA in 82 ESKD patients (eGFR <15 ml/min) and 70 non-CKD controls. In vivo measurement revealed no major difference in endothelial function between ESKD and control group, aside from higher stiffness detected in the microcirculation of ESKD participants. In contrast, ex vivo measurements revealed a notable change in the contribution of endothelium-derived factors and increased stiffness in ESKD patients vs. controls. In support, we demonstrated that ex vivo exposure of arteries to uremic toxins such as Trimethylamine N-oxide, Phenylacetylglutamine, or extracellular vesicles from CKD patients impaired endothelial function via diminishing the contribution of endothelium-derived relaxing factors such as nitric oxide and endothelium derived hyperpolarizing factor. Uremic arteries displayed elevated expression of senescence markers (p21CIP1, p16INK4a, and SA-β-gal), calcification marker (RUNX2), and reduced expression of Ki67, sirtuin1, Nrf2, and MHY11 markers, indicating the accumulation of senescent cells and EVA phenotype. Correspondingly, treating uremic vessel rings ex vivo with senolytic agents (Dasatinib + Quercetin) effectively reduced the senescence-associated secretory phenotype and changed the origin of extracellular vesicles. Notably, sex differences exist for certain abnormalities suggesting the importance of biological sex in the pathogenesis of vascular complications. In conclusion, the uremic microvasculature is characterized by a "senescence signature", which may contribute to EVA and cardiovascular complications in ESKD patients and could be alleviated by treatment with senolytic agents.

Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.

Type II diabetes is highly prevalent in people with kidney failure on peritoneal dialysis, with a proportion requiring insulin therapy. Compared to human insulin, analogue (genetically altered) insulin has been associated with superior survival in hemodialysis. Inferior glycemic stability can increase thirst, reduce ultrafiltrate, therefore require higher daily dialysate glucose load (DDGL) which have been associated with worse outcomes in peritoneal dialysis. How analogue insulin associates with prescribed dialysate glucose, body mass index (BMI) and patient survival is unknown. People with kidney failure and type 2 diabetes receiving peritoneal dialysis and recruited into PDOPPS (2014–2022) who received insulin treatment at the start or during follow-up were identified from seven countries. Cox proportional hazards models with inverse probability weighting adjustment for country, study phase and patient characteristics including BMI and HBA1c estimated the hazard for mortality by insulin type over two years. The relationship between insulin type and the variables of BMI and DDGL, estimated using dialysate prescribed glucose strength and volume, was assessed longitudinally using mixed effects linear regression. 13,146 people with type 2 diabetes receiving peritoneal dialysis were identified, of whom 3,387 (26%) received a purely analogue or human insulin, either before recruitment into the study (2,789) or during follow-up (628). 355 received analogue and 3,032 received human insulin. The proportion of type 2 diabetics receiving an insulin, and the proportion on insulin who received a human insulin varied by country but patient characteristics by insulin type were similar. Crude survival at two years in those receiving analogue insulin was 77% compared with 68% in human insulin users (HR 0.71, 95% CI 0.54 to 0.94), and in adjusted models was 77% and 65% respectively (HR 0.66, 95% CI 0.48 to 0.92). Similar effect sizes were obtained when stratifying by incident or prevalent peritoneal dialysis use. While in incident cohorts DDGL did not vary over time or by insulin type, in prevalent cohorts mixed effects models estimated that DDGL increased by 1.0 g/month of peritoneal dialysis in the human insulin group. This increase with time was significantly slower in the analogue insulin group (difference −0.9 g/month, 95% CI −1.2 to −0.5) but DDGL was 23 g higher in the analogue insulin group at baseline. In prevalent cohorts BMI did not statistically change with time (0.1/month, −0.2 to 0.4) in human insulin group and in analogue users was not higher at baseline (1.4, 95% CI −1.6 to 4.4) or increase more quickly (−0.1/month, 95% CI −0.4 to 0.2). Analogue insulin was associated with superior patient survival in people with kidney failure and type 2 diabetes receiving peritoneal dialysis. DDGL was statistically higher in analogue insulin at baseline, however the absence of insulin-specific changes in DDGL over time or in BMI measures generally suggest the metabolic impact of analogue insulin is limited. Although residual confounding may be present, this is reassuring given recent announcements from insulin manufacturers regarding halting human insulin production.

Vielversprechende Studienergebnisse aus dem letzten Jahr deuten auf neue therapeutische Ansätze sowohl im medikamentösen als auch im technologischen Bereich bei Typ-1-Diabetes (T1D) hin. So wird auf dem Gebiet der immunologischen Therapieoptionen der Einsatz von Antikörpern erforscht. Neben Teplizumab zeigte u. a. Ustekinumab in einer Phase-2-Studie eine Verbesserung der Betazellfunktion. Daneben führte eine Inselzelltransplantation bei einer Patientin mit T1D zu einer beeindruckenden Remission der Erkrankung bis hin zur Insulinunabhängigkeit. Darüber hinaus wurde der Einsatz neuartiger Wocheninsuline bei T1D untersucht, und erste Studienergebnisse dokumentieren eine erhöhte Hypoglykämierate bei deren Anwendung in PatientInnen mit T1D. Auch ein inhalatives Insulin wurde als neue Therapiemodalität untersucht, wies allerdings keine Verbesserung der postprandialen Hyperglykämierate bei NutzerInnen von AID-Systemen (AID: automatisierte Insulindosierung) im Vergleich zur gewöhnlichen subkutanen Insulininjektion auf. Zudem zeigt der Einsatz von AID-Systemen weiterhin großes Potenzial, die glykämische Kontrolle bei T1D zu optimieren. Besonders in älteren PatientInnengruppen können sie zur Reduktion von Hypoglykämien beitragen und so die Lebensqualität verbessern. Ergänzende medikamentöse Optionen wie GLP-1-RA (Agonisten des Rezeptors [RA] des glukagonähnlichen Peptids) und SGLT2-Inhibitoren (SGLT: Natrium-Glukose-Kotransporter) werden ebenfalls intensiv erforscht, um diabetesbedingte Komplikationen bei Menschen mit T1D zukünftig reduzieren zu können. Der Einsatz beider Medikamentengruppen nahm in den letzten Jahren auch bei T1D zu und zeigte positive Effekte, insbesondere in Bezug auf Gewichtskontrolle und kardiovaskuläre sowie renale Auswirkungen. Dennoch sind länger angelegte Studien zur Evaluation der Sicherheit und Effektivität der bisher nicht bei T1D zugelassenen Medikamente notwendig.

Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2D) are associated with inflammation and the accumulation of macrophages in peripheral nerves, which increases the risk of developing peripheral neuropathy (PN). We have previously investigated that macrophage infiltration in the peripheral nerves of animals with T2D (leptin-deficient ob/ob mice, leptin receptor-deficient db/db) correlated with PN, whereas this process in animals with MetS (Wistar Ottawa Karlsburg W (RT1u) WOKW rat) did not lead to neuropathic changes. Additional data presented in this study suggest an association between increased mRNA expression of the anti-inflammatory marker IL-10 and autophagy in the prevention of neuropathy.