Search

Abstract Background Metabolic clusters can stratify subgroups of individuals at risk for type 2 diabetes mellitus and related complications. Since obesity and insulin resistance are closely linked to alterations in hemostasis, we investigated the association between plasmatic coagulation and metabolic clusters including the impact on survival. Methods Utilizing data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, we assigned 917 participants without diabetes to prediabetes clusters, using oGTT-derived glucose and insulin, high-density lipoprotein cholesterol, triglycerides, and anthropometric data. We performed a comprehensive analysis of plasmatic coagulation parameters and analyzed their associations with mortality using proportional hazards models. Mediation analysis was performed to assess the effect of coagulation factors on all-cause mortality in prediabetes clusters. Results Prediabetes clusters were assigned using published tools, and grouped into low-risk (clusters 1,2,4; n = 643) and high-risk (clusters 3,5,6; n = 274) clusters. Individuals in the high-risk clusters had a significantly increased risk of death (HR = 1.30; CI: 1.01 to 1.67) and showed significantly elevated levels of procoagulant factors (fibrinogen, FVII/VIII/IX), D-dimers, von-Willebrand factor, and PAI-1, compared to individuals in the low-risk clusters. In proportional hazards models adjusted for relevant confounders, elevated levels of fibrinogen, D-dimers, FVIII, and vWF were found to be associated with an increased risk of death. Multiple mediation analysis indicated that vWF significantly mediates the cluster-specific risk of death. Conclusions High-risk prediabetes clusters are associated with prothrombotic changes in the coagulation system that likely contribute to the increased mortality in those individuals at cardiometabolic risk. The hypercoagulable state observed in the high-risk clusters indicates an increased risk for cardiovascular and thrombotic diseases that should be considered in future risk stratification and therapeutic strategies. Graphical Abstract

Introduction In this systematic review, we investigated the diagnostic accuracy of surrogate measures of insulin secretion based on fasting samples and the oral glucose tolerance test (OGTT). The first phase of insulin secretion was calculated using two gold standard methods; the hyperglycemic clamp (HGC) test and intravenous glucose tolerance test (IVGTT).Research design and methods We conducted searches in the PubMed, Cochrane Central, and Web of Science databases, the last of which was conducted at the end of June 2021. Studies were included that measured first-phase insulin secretion in adults using both a gold-standard reference method (either HGC or IVGTT) and one or more surrogate measures from either fasting samples, OGTT or a meal-tolerance test. QUADAS-2, a revised tool for the quality assessment of diagnostic accuracy studies, was used for quality assessment. Random-effects meta-analyses were performed to examine the correlation between first-phase measured with gold standard and surrogate methods.Results A total of 33 articles, encompassing 5362 individuals with normal glucose tolerance, pre-diabetes or type 2 diabetes, were included in our systematic review. Homeostatic model assessment (HOMA)-beta and Insulinogenic Index 30 (IGI(30)) were the surrogate measures validated in the largest number of studies (17 and 13, respectively). HOMA-beta’s pooled correlation to the reference methods was 0.48 (95% CI 0.40 to 0.56) The pooled correlation of IGI to the reference methods was 0.61 (95% CI 0.54 to 0.68). The surrogate measures with the highest correlation to the reference methods were Kadowaki (0.67 (95% CI 0.61 to 0.73)) and Stumvoll’s first-phase secretion (0.65 (95% CI 0.58 to 0.71)), both calculated from an OGTT.Conclusions Surrogate measures from the first 30 min of an OGTT capture the first phase of insulin secretion and are a good choice for epidemiological studies. HOMA-beta has a moderate correlation to the reference methods but is not a measure of the first phase specifically.PROSPERO registration number The meta-analysis was registered at PROSPERO (Id: CRD42020169064) before inclusion started.

Abstract Background Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients. Methods We searched PubMed and Embase for publications that used ‘simple subclassification’ approaches using simple categorisation of clinical characteristics, or ‘complex subclassification’ approaches which used machine learning or ‘omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches. Results Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes. Conclusion Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.

Abstract Background Heterogeneous metabolic clusters have been identified in diabetic and prediabetic states. It is not known whether such pathophysiologic clusters impact survival in at-risk persons being evaluated for coronary heart disease. Methods The LURIC Study recruited patients referred for coronary angiography at a median age of 63 (IQR 56–70) with a follow-up of 16.1 (IQR 9.6, 17.7) years. Clustering of 1269 subjects without diabetes was performed with oGTT-derived glucose and insulin; fasting triglyceride, high-density lipoprotein, BMI, waist and hip circumference. Patients with T2D (n = 794) were clustered using age, BMI, glycemia, homeostasis model assessment, and islet autoantibodies. Associations of clusters with mortality were analysed using Cox regression. Results Individuals without diabetes were classified into six subphenotypes, with 884 assigned to subjects at low-risk (cluster 1,2,4) and 385 at high-risk (cluster 3,5,6) for diabetes. We found significantly increased mortality in clusters 3 (hazard ratio (HR)1.42), 5 (HR 1.43), and 6 (HR 1.46) after adjusting for age, BMI, HbA1c and sex. In the T2D group, 508 were assigned to mild age-related diabetes (MARD), 183 to severe insulin-resistant diabetes (SIRD), 84 to mild obesity-related diabetes (MOD), 19 to severe insulin-deficient diabetes (SIDD). Compared to the low-risk non-diabetes group, crude mortality was not different in MOD. Increased mortality was found for MARD (HR 2.2), SIRD (HR 2.2), and SIDD (HR 2.5). Conclusions Metabolic clustering successfully stratifies survival even among persons undergoing invasive coronary diagnostics. Novel clustering approaches based on glucose metabolism can identify persons who require special attention as they are at risk of increased mortality.

Abstract The interaction between nitrogen monoxide (NO) and organic peroxy radicals (RO2) greatly impacts the formation of highly oxygenated organic molecules (HOM), the key precursors of secondary organic aerosols. It has been thought that HOM production can be significantly suppressed by NO even at low concentrations. Here, we perform dedicated experiments focusing on HOM formation from monoterpenes at low NO concentrations (0 – 82 pptv). We demonstrate that such low NO can enhance HOM production by modulating the RO2 loss and favoring the formation of alkoxy radicals that can continue to autoxidize through isomerization. These insights suggest that HOM yields from typical boreal forest emissions can vary between 2.5%-6.5%, and HOM formation will not be completely inhibited even at high NO concentrations. Our findings challenge the notion that NO monotonically reduces HOM yields by extending the knowledge of RO2-NO interactions to the low-NO regime. This represents a major advance towards an accurate assessment of HOM budgets, especially in low-NO environments, which prevails in the pre-industrial atmosphere, pristine areas, and the upper boundary layer.

BCG vaccination affects other diseases beyond tuberculosis by unknown—potentially immunomodulatory—mechanisms. Recent studies have shown that BCG vaccination administered during overt type 1 diabetes (T1D) improved glycemic control and affected immune and metabolic parameters. Here, we comprehensively characterized Ghanaian T1D patients with or without routine neonatal BCG vaccination to identify vaccine-associated alterations. Ghanaian long-term T1D patients (n = 108) and matched healthy controls (n = 214) were evaluated for disease-related clinical, metabolic, and immunophenotypic parameters and compared based on their neonatal BCG vaccination status. The majority of study participants were BCG-vaccinated at birth and no differences in vaccination rates were detected between the study groups. Notably, glycemic control metrics, i.e., HbA1c and IDAA1c, showed significantly lower levels in BCG-vaccinated as compared to unvaccinated patients. Immunophenotype comparisons identified higher expression of the T cell activation marker CD25 on CD8+ T cells from BCG-vaccinated T1D patients. Correlation analysis identified a negative correlation between HbA1c levels and CD25 expression on CD8+ T cells. In addition, we observed fractional increases in glycolysis metabolites (phosphoenolpyruvate and 2/3-phosphoglycerate) in BCG-vaccinated T1D patients. These results suggest that neonatal BCG vaccination is associated with better glycemic control and increased activation of CD8+ T cells in T1D patients.

Abstract Inflammatory cytokines and non-esterified fatty acids (NEFAs) are obesity-linked factors that disturb insulin secretion. The aim of this study was to investigate whether pancreatic adipose tissue (pWAT) is able to generate a NEFA/cytokine overload within the pancreatic environment and as consequence to impact on insulin secretion. Pancreatic fat is a minor fat depot, therefore we used high-fat diet (HFD) feeding to induce pancreatic steatosis in mice. Relative Adipoq and Lep mRNA levels were higher in pWAT of HFD compared to chow diet mice. Regardless of HFD, Adipoq and Lep mRNA levels of pWAT were at least 10-times lower than those of epididymal fat (eWAT). Lipolysis stimulating receptors Adrb3 and Npr1 were expressed in pWAT and eWAT, and HFD reduced their expression in eWAT only. In accordance, HFD impaired lipolysis in eWAT but not in pWAT. Despite expression of Npr mRNA, lipolysis was stimulated solely by the adrenergic agonists, isoproterenol and adrenaline. Short term co-incubation of islets with CD/HFD pWAT did not alter insulin secretion. In the presence of CD/HFD eWAT, glucose stimulated insulin secretion only upon isoproterenol-induced lipolysis, i.e. in the presence of elevated NEFA. Isoproterenol augmented Il1b and Il6 mRNA levels both in pWAT and eWAT. These results suggest that an increased sympathetic activity enhances NEFA and cytokine load of the adipose microenvironment, including that of pancreatic fat, and by doing so it may alter beta-cell function.

Investigations that can be conducted at the Artemis III candidate landing regions will benefit from the knowledge of the thermal environment within permanently shadowed regions (PSRs). Within PSRs, secondary illumination controls the surface temperature, varying diurnally and seasonally, affecting the stability and concentration of volatiles cold-trapped within the PSRs. In this case study, we characterize the dynamic nature of secondary illumination at four PSRs that overlap five of the Artemis III candidate landing regions. Our analysis is based on secondary illumination model-generated images paired with PSR images acquired by ShadowCam on board the Korean Pathfinder Lunar Orbiter. We find that illumination and thermal conditions can change rapidly within the PSRs, and knowledge of time-variable secondary illumination can be decisive for the efficient design of investigations and sample collection operations at the PSRs.

Foods consumed raw, such as lettuce, can host food-borne human-pathogenic bacteria. In the worst-case, these diseases cause to death. To limit illness and industrial losses, one innovative sanitation method is non-thermal plasma, which offers an extremely efficient reduction of living microbial biomass. Unfortunately, the total viable count (TVC), one of the most common methods for quantifying antimicrobial effects, provides no detailed insights into the composition of the surviving microbial community after treatment. To address this information gap, different special agars were used to investigate the reduction efficiency of plasma-treated water (PTW) on different native cultivable microorganisms. All tested cultivable microbial groups were reduced using PTW. Gram-negative bacteria showed a reduction of 3.81 log10, and Gram-positive bacteria showed a reduction of 3.49 log10. Fungi were reduced by 3.89 log10. These results were further validated using a live/dead assay. MALDI-ToF (matrix-assisted laser-desorption-ionization time-of-flight)-based determination was used for a diversified overview. The results demonstrated that Gram-negative bacteria were strongly reduced. Interestingly, Gram-positive bacteria and fungi were reduced by nearly equal amounts, but could still recover from PTW treatment. MALDI-ToF mainly identified Pseudomonas spp. and groups of Bacillus on the tested lettuce. These results indicate that the PTW treatment could efficiently achieve a ubiquitous, spectrum-wide reduction of microbial life.

Coccidioidomycosis is a typically respiratory fungal disease that, in the United States, occurs primarily in Arizona and California. In California, most coccidioidomycosis cases occur in the San Joaquin Valley, a primarily agricultural region where the disease poses a risk for outdoor workers. We collected 710 soil samples and 265 settled dust samples from nine sites in the San Joaquin Valley and examined how Coccidioides detection varied by month, site, and the presence and abundance of other fungal species. We detected Coccidioides in 89 of 238 (37.4%) rodent burrow soil samples at five undeveloped sites and were unable to detect Coccidioides in any of 472 surface and subsurface soil samples at four agricultural sites. In what is the largest sampling effort undertaken on agricultural land, our results provide no evidence that agricultural soils in the San Joaquin Valley harbor Coccidioides. We found no clear association between Coccidioides and the greater soil fungal community, but we identified 19 fungal indicator species that were significantly associated with Coccidioides detection in burrows. We also did not find a seasonal pattern in Coccidioides detection in the rodent burrow soils we sampled. These findings suggest both the presence of a spore bank and that coccidioidomycosis incidence may be more strongly associated with Coccidioides dispersal than Coccidioides growth. Finally, we were able to detect Coccidioides in only five of our 265 near-surface settled dust samples, one from agricultural land, where Coccidioides was undetected in soils, and four from undeveloped land, where Coccidioides was common in the rodent burrow soils we sampled. Our ability to detect Coccidioides in few settled dust samples indicates that improved methods are likely needed moving forward, though raises questions regarding aerial dispersal in Coccidioides, whose key transmission event likely occurs over short distances in rodent burrows from soil to naïve rodent lungs.

The consumer demand for organic food including apples is increasing worldwide. Despite favorable environmental and health benefits, organic farming bears also disadvantages like high amounts of fruit losses due to storage rot. A novel treatment with plasma-processed air (PPA) to sanitize organic apples is investigated. The plasma source for the generation of PPA was operated at a frequency of 2.45 GHz, a power output of 1.1 kW and a gas flow of 18 standard liters per minute. The antimicrobial efficiency of the PPA was tested on the natural load of organic apples (cultivar Natyra) with a load ranging from 104 to 106 CFU/mL in an experimental laboratory setup. A larger application was applied on artificially inoculated (Pseudomonas fluorescens~108 CFU/mL and Pezicula malicorticis~106 CFU/mL) organic apples to test the up-scalability of the PPA treatment. The apples were photographically documented and their texture was analyzed during the 26-day storage phase to investigate the influence of the PPA treatment on the appearance of the apples. The laboratory experiments resulted in a log10-reduction of one to two log10 levels compared to untreated and compressed-air-treated apples. For apples inoculated with P. fluorescens, the up-scaled procedure resulted in up to four levels of log10 reduction. In apples inoculated with P. malicorticis, the up-scaled procedure resulted in no reduction. This indicates that the application of PPA to organic apples can be effective for bacteria but needs to be optimized for fungi. Therefore, further testing is needed to validate the results.

Plant-based foods like lettuce are an important part of the human diet and worldwide industry. On a global scale, the number of food-associated illnesses increased in the last decades. Conventional lettuce sanitation methods include cleaning either with tap or chloritized water. Beside these water-consuming strategies, physical plasma is an innovative and effective possibility for food sanitation. Recent studies with plasma-treated water showed an effective reduction of the microbial load. Plasma-processed air (PPA) is another great opportunity to reduce the microbial load and save water. To test the efficiency of PPA, the surface microbiome of treated lettuce was analyzed via proliferation assays with special agars, live/dead assays and tests for respiratory activity of the microorganisms. PPA showed a reduction of the colony forming units (CFU/mL) on all tested microbial groups (Gram-negative and Gram-positive bacteria, yeasts and molds). These results were supported by the live/dead assay. For further insights, the PPA-ingredients were detected with Fourier Transformation Infrared Spectroscopy (FTIR), which revealed NO2, NO and N2O5 as the main reactive species in the PPA. In the future, PPA could be an outstanding, on-demand sanitation step for higher food safety standards, especially in situations where humidity and high temperature should be avoided.

Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.

Ureterosciatic hernias are extremely rare, with fewer than 40 cases reported in the literature. We present a case of a patient with concurrent right ureterosciatic hernia (Lindbom hernia), ipsilateral bladder hernia, and appendix-containing inguinal hernia (Amyand hernia). These findings were discovered incidentally on imaging and the patient had no associated symptoms.

Abstract Parasympathetic nervous system innervates peripheral organs including pancreas, hepatic portal system, and gastrointestinal tract. It thereby contributes to the regulation of whole-body glucose metabolism especially in the postprandial state when it promotes secretion of insulin and enhances its action in major target organs. We now aimed to evaluate the effect of parasympathetic modulation on human glucose metabolism. We used slow deep breathing maneuvers to activate the parasympathetic nervous system and tested for effects on metabolism during an oral glucose tolerance test in a randomized, controlled, cross-over trial in 15 healthy young men. We used projections towards the heart as a readout for parasympathetic activity. When analyzing heart rate variability, there was a significant increase of RMSSD (root mean square of successive differences) when participants performed slow deep breathing compared to the control condition, indicating a modulation of parasympathetic activity. However, no statistically significant effects on peripheral glucose metabolism or energy expenditure after the glucose tolerance test were detected. Of note, we detected a significant association between mean heart rate and serum insulin and C-peptide concentrations. While we did not find major effects of slow deep breathing on glucose metabolism, our correlational results suggest a link between the autonomic nervous system and insulin secretion after oral glucose intake. Future studies need to unravel involved mechanisms and develop potential novel treatment approaches for impaired insulin secretion in diabetes.

Introduction With pre-diabetes and diabetes increasingly recognized as heterogeneous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of surrogate indices based on oral glucose tolerance test (OGTT) and fasting measurements in comparison with gold standard methods.Research design and methods The hyperglycemic clamp extended with glucagon-like peptide 1 (GLP-1) infusion and intravenous glucose tolerance test (IVGTT), as well as OGTT, was performed in two well-phenotyped cohorts. The gold standard–derived indices were compared with surrogate insulin secretion markers, derived from fasting state and OGTT, using both Pearson’s and Spearman’s correlation coefficients. The insulin-based and C-peptide-based indices were analyzed separately in different groups of glucose tolerance and the entire cohorts.Results The highest correlation coefficients were found for area under curve (AUC) (I0-30)/AUC (G0-30), I30/G30, first-phase Stumvoll and Kadowaki model. These indices have high correlation coefficients with measures obtained from both insulin and C-peptide levels from IVGTT and hyperglycemic clamp. AUC (I0-120)/AUC (G0-120), BIGTT-AIR0-60-120, I30/G30, first-phase Stumvoll and AUC (I0-30)/AUC (G0-30) demonstrated the strongest association with incretin-stimulated insulin response.Conclusions We have identified glucose-stimulated and GLP-1-stimulated insulin secretion indices, derived from OGTT and fasting state, that have the strongest correlation with gold standard measures and could be potentially used in future researches and clinical practice.

Recently, various methods to predict the future price of financial assets have emerged. One promising approach is to combine the historic price with sentiment scores derived via sentiment analysis techniques. In this article, we focus on predicting the future price of Bitcoin, which is currently the most popular cryptocurrency. More precisely, we propose a hybrid approach, combining time series forecasting and sentiment prediction from microblogs, to predict the intraday price of Bitcoin. Moreover, in addition to standard sentiment analysis methods, we are the first to employ a fine-tuned BERT model for this task. We also introduce a novel weighting scheme in which the weight of the sentiment of each tweet depends on the number of its creator’s followers. For evaluation, we consider periods with strongly varying ranges of Bitcoin prices. This enables us to assess the models w.r.t. robustness and generalization to varied market conditions. Our experiments demonstrate that BERT-based sentiment analysis and the proposed weighting scheme improve upon previous methods. Specifically, our hybrid models that use linear regression as the underlying forecasting algorithm perform best in terms of the mean absolute error (MAE of 2.67) and root mean squared error (RMSE of 3.28). However, more complicated models, particularly long short-term memory networks and temporal convolutional networks, tend to have generalization and overfitting issues, resulting in considerably higher MAE and RMSE scores.

Previously, we found that human pancreatic preadipocytes (PPAs) and islets influence each other and that the crosstalk with the fatty liver via the hepatokine fetuin-A/palmitate induces inflammatory responses. Here, we examined whether the mRNA-expression of pancreatic extracellular matrix (ECM)-forming and -degrading components differ in PPAs from individuals with normal glucose regulation (PPAs-NGR), prediabetes (PPAs-PD), and type 2 diabetes (PPAs-T2D), and whether fetuin-A/palmitate impacts ECM-formation/degradation and associated monocyte invasion. Human pancreatic resections were analyzed (immuno)histologically. PPAs were studied for mRNA expression by real-time PCR and protein secretion by Luminex analysis. Furthermore, co-cultures with human islets and monocyte migration assays in Transwell plates were conducted. We found that in comparison with NGR-PPAs, TIMP-2 mRNA levels were lower in PPAs-PD, and TGF-β1 mRNA levels were higher in PPAs-T2D. Fetuin-A/palmitate reduced fibronectin, decorin, TIMP-1/-2 and TGF-ß1 mRNA levels. Only fibronectin was strongly downregulated by fetuin-A/palmitate independently of the glycemic status. Co-culturing of PPAs with islets increased TIMP-1 mRNA expression in islets. Fetuin-A/palmitate increased MMP-1, usherin and dermatopontin mRNA-levels in co-cultured islets. A transmigration assay showed increased monocyte migration towards PPAs, which was enhanced by fetuin-A/palmitate. This was more pronounced in PPAs-T2D. The expression of distinct ECM components differs in PPAs-PD and PPAs-T2D compared to PPAs-NGR, suggesting that ECM alterations can occur even in mild hyperglycemia. Fetuin-A/palmitate impacts on ECM formation/degradation in PPAs and co-cultured islets. Fetuin-A/palmitate also enhances monocyte migration, a process which might impact on matrix turnover.

Abstract The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calorimetry as a read-out for substrate oxidation following an overnight fast. This cross-sectional analysis consisted of 192 (92 women, 100 men) either lean or obese participants. Following an overnight fast, the respiratory quotient (RQ) was assessed, after which a 5-point 75-g oral glucose tolerance test was performed. Unlike glucose and insulin, fasting free fatty acids (FFA) correlated negatively with fasting RQ (p

IntroductionWhile oral glucose ingestion typically leads to a decrease in circulating glucagon levels, a substantial number of persons display stable or rising glucagon concentrations when assessed by radioimmunoassay (RIA). However, these assays show cross-reactivity to other proglucagon cleavage products. Recently, more specific assays became available, therefore we systematically assessed glucagon and other proglucagon cleavage products and their relation to metabolic health.Research Design and MethodsWe used samples from 52 oral glucose tolerance tests (OGTT) that were randomly selected from persons with different categories of glucose tolerance in an extensively phenotyped study cohort.ResultsGlucagon concentrations quantified with RIA were non-suppressed at 2 hours of the OGTT in 36% of the samples. Non-suppressors showed lower fasting glucagon levels compared to suppressors (p=0.011). Similar to RIA measurements, ELISA-derived fasting glucagon was lower in non-suppressors (p

Plasma-treated water (PTW) possess anti-microbial potential against Pseudomonas fluorescence, which is observable for both suspended cells and cells organized in biofilms. Against that background, the chemical composition of PTW tends to focus. Various analytical techniques have been applied for analyses, which reveal various traceable reactive oxygen and nitrogen compounds (RONS). Based on these findings, it is our aim to generate a PTW analog (anPTW), which has been compared in its anti-microbial efficiency with freshly generated PTW. Additionally, a solution of every traceable compound of PTW has been mixed according to their PTW concentration. As references, we treated suspended cells and mature biofilms of P. fluorescence with PTW that originates from a microwave-driven plasma source. The anti-microbial efficiency of all solutions has been tested based on a combination of a proliferation, an XTT, and a live–dead assay. The outcomes of the test proved an anti-microbial power of PTW that suggests more active ingredients than the traceable compounds HNO3, HNO2, and H2O2 or the combined mixture of the analog.

Abstract Hyperglycemia and insulin resistance contribute to vascular damage and are regulated by different pathophysiological processes. The aim of the study was to systematically investigate the relative contributions of multiple fasting state- and oral glucose tolerance test (oGTT)-derived glycemic traits to carotid intima-media thickness (cIMT), a surrogate parameter of subclinical atherosclerosis, in individuals with increased risk for type 2 diabetes mellitus (T2D). 667 volunteers (417 women and 250 men, mean age 44.1 years), who were free of cardiovascular disease (CVD), were included in this cross-sectional study. Glucose tolerance, insulin sensitivity, insulin secretion and insulin clearance were assessed by frequently sampled 75 g oGTT. CIMT was measured by high-resolution ultrasound. Insulin clearance was associated with cIMT in univariate analysis (ßst = − 0.17, p

Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosis in the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort were studied. LEOSS is a European non-interventional multi-center cohort study established in March 2020 to investigate the epidemiology and clinical course of SARS-CoV-2 infection. Data from hospitalized patients and those who received ambulatory care, with a positive SARS-CoV-2 test, were included in the study. An additive effect of obesity, diabetes and hypertension on the risk of mortality was observed, which was particularly strong in young and middle-aged patients. Compared to young and middle-aged (18–55 years) patients without obesity, diabetes and hypertension (non-obese and metabolically healthy; n = 593), young and middle-aged adult patients with all three risk parameters (obese and metabolically unhealthy; n = 31) had a similar adjusted increased risk of mortality [OR 7.42 (95% CI 1.55–27.3)] as older (56–75 years) non-obese and metabolically healthy patients [n = 339; OR 8.21 (95% CI 4.10–18.3)]. Furthermore, increased CRP levels explained part of the elevated risk of COVID-19-related mortality with age, specifically in the absence of obesity and impaired metabolic health. In conclusion, the modifiable risk factors obesity, diabetes and hypertension increase the risk of COVID-19-related mortality in young and middle-aged patients to the level of risk observed in advanced age.

Abstract Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.

Brain insulin action regulates eating behavior and whole-body energy fluxes, however the impact of brain insulin resistance on long-term weight and body fat composition is unknown. Here, the authors show that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution.

Introdução: Nas últimas décadas, os resultados das artroplastias totais de joelho (ATJ) melhoraram significativamente, contudo, ainda estão sujeitas a complicações, sendo a infecção a mais complexa de ser solucionada. Por isso, o caso relatado a seguir objetiva salientar as manifestações clínicas e o manejo de uma infecção fúngica após artroplastia total do joelho (IATJ). Descrição do caso: Paciente feminina, 83 anos, foi submetida a uma ATJ esquerda em outubro de 2013, com melhora gradual da dor e recuperação funcional. Um ano depois, apresentou dor súbita associada a derrame no joelho esquerdo, sendo realizada punção dessa articulação para cultura, a qual evidenciou a presença de Candida albicans. Diante desse quadro, o infectologista iniciou tratamento com micafungina. Sete dias após o início da terapia, ela estava sem dor, com secreção serosanguinolenta em pouca quantidade na ferida operatória (FO) e 2 dias depois encontrava-se limpa. Assim, a paciente seguiu com a terapia antifúngica via endovenosa em casa. Em dezembro de 2015, ela apresentou dor e derrame articular na prótese do joelho novamente, sendo realizado procedimento de revisão da prótese. Prescreveu-se antibiótico e a paciente permaneceu estável. No dia seguinte, iniciou-se Teicoplanina devido a um episódio de febre. Contudo, com o resultado da cultura - Staphylococcus aureus sensível a Oxacilina - ajustou-se a antibioticoterapia. Comentários: A partir desse caso e da literatura, sabe-se que condições ligadas ao paciente, ao procedimento cirúrgico e ao pós-operatório são fatores de risco para IATJ. Vários são os métodos complementares à investigação clínica para o diagnóstico infeccioso e melhor caracterização do quadro. A terapia para IATJ deve ser individualizada, mas geralmente envolve a combinação da antibioticoterapia sistêmica com a cirurgia. A troca do implante é o procedimento de escolha, sendo o desbridamento com retenção da prótese uma opção em casos agudos. No caso apresentado, o manejo inicial foi com o uso de antifúngico, tendo em vista a cultura positiva para Candida albicans. Posteriormente, com a recidiva dos sintomas, optou-se pela troca da prótese e administração de antimicrobianos. A IATJ está associada ao aumento da morbimortalidade e dos custos de internação, por isso, mesmo com a melhora da técnica da ATJ, é importante o conhecimento da IATJ para que a prevenção, o diagnóstico e o tratamento precoce sejam possíveis.

Primary cilia have been proposed to regulate glucose metabolism and insulin secretion in beta cells, but it is not known how. Here the authors show that primary cilia play a role in adult β-cell function via a mechanism involving endosomal EphA-processing.

Abstract Spatial heterogeneities in soil hydrology have been confirmed as a key control on CO2 and CH4 fluxes in the Arctic tundra ecosystem. In this study, we applied a mechanistic ecosystem model, CLM‐Microbe, to examine the microtopographic impacts on CO2 and CH4 fluxes across seven landscape types in Utqiaġvik, Alaska: trough, low‐centered polygon (LCP) center, LCP transition, LCP rim, high‐centered polygon (HCP) center, HCP transition, and HCP rim. We first validated the CLM‐Microbe model against static‐chamber measured CO2 and CH4 fluxes in 2013 for three landscape types: trough, LCP center, and LCP rim. Model application showed that low‐elevation and thus wetter landscape types (i.e., trough, transitions, and LCP center) had larger CH4 emissions rates with greater seasonal variations than high‐elevation and drier landscape types (rims and HCP center). Sensitivity analysis indicated that substrate availability for methanogenesis (acetate, CO2 + H2) is the most important factor determining CH4 emission, and vegetation physiological properties largely affect the net ecosystem carbon exchange and ecosystem respiration in Arctic tundra ecosystems. Modeled CH4 emissions for different microtopographic features were upscaled to the eddy covariance (EC) domain with an area‐weighted approach before validation against EC‐measured CH4 fluxes. The model underestimated the EC‐measured CH4 flux by 20% and 25% at daily and hourly time steps, suggesting the importance of the time step in reporting CH4 flux. The strong microtopographic impacts on CO2 and CH4 fluxes call for a model‐data integration framework for better understanding and predicting carbon flux in the highly heterogeneous Arctic landscape.

Objective: The intrauterine environment is known to affect the offspring’s long-term risk for obesity and diabetes. Previous data show that maternal metabolism and gestational weight gain (GWG) are associated with fetal autonomic nervous system (ANS) function, which can be assessed with heart rate variability (HRV). We investigated whether this association is also present in 2-year-old children and addressed the impact of gestational diabetes (GDM). Research design and methods: We examined the 2-year-old offspring of mothers who had undergone a 5-point, 75 g oral glucose tolerance test during pregnancy. To assess HRV, a 10-minute ECG was recorded, and time domain and frequency domain parameters were analyzed. Body composition was assessed using bioelectrical impedance testing. Results: We examined 67 children (33 girls, 34 boys), 30 of whom were born to mothers with treated GDM and normoglycemic pregnancies (NGT), respectively. No differences were found between the groups with regard to birth weight, weight at the age of 2 years, and body fat content. We observed that GWG was associated with heart rate and HRV, indicating that children of mothers with low GWG had a lower parasympathetic tone. This association was detected in NGT-exposed—but not in GDM-exposed—children. HR and HRV correlated with body fat and fat-free mass in children from normoglycemic pregnancies only. Conclusion: We found that the impact of maternal GWG on offspring ANS function was missing in the presence of treated GDM. The balance of the ANS was related to offspring body composition in children from NGT pregnancies only. Our results suggest that maternal weight gain during pregnancy has a critical impact on the developing ANS, which might be disturbed in the presence of GDM.

Obesity is one of the main drivers of type 2 diabetes, but it is not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution, such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown, features of body fat distribution that could additionally contribute to the disease. We used machine learning with dense convolutional neural networks to detect diabetes-related variables from 2371 T1-weighted whole-body MRI data sets. MRI was performed in participants undergoing metabolic screening with oral glucose tolerance tests. Models were trained for sex, age, BMI, insulin sensitivity, HbA1c, and prediabetes or incident diabetes. The results were compared with those of conventional models. The area under the receiver operating characteristic curve was 87% for the type 2 diabetes discrimination and 68% for prediabetes, both superior to conventional models. Mean absolute regression errors were comparable to those of conventional models. Heatmaps showed that lower visceral abdominal regions were critical in diabetes classification. Subphenotyping revealed a group with high future diabetes and microalbuminuria risk.Our results show that diabetes is detectable from whole-body MRI without additional data. Our technique of heatmap visualization identifies plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in diabetes pathogenesis.

Objective: Obesity, in particular visceral obesity, and insulin resistance emerged as major risk factors for severe coronavirus disease 2019 (COVID-19), which is strongly associated with hemostatic alterations. Because obesity and insulin resistance predispose to thrombotic diseases, we investigated the relationship between hemostatic alterations and body fat distribution in participants at risk for type 2 diabetes. Subjects: Body fat distribution (visceral and subcutaneous abdominal adipose tissue) and liver fat content of 150 participants – with impaired glucose tolerance and/or impaired fasting glucose – were determined using magnetic resonance imaging and spectroscopy. Participants underwent precise metabolic characterization and major hemostasis parameters were analyzed. Results: Procoagulant factors (FII, FVII, FVIII, and FIX) and anticoagulant proteins (antithrombin, protein C, and protein S) were significantly associated with body fat distribution. In patients with fatty liver, fibrinogen (298 mg/dl vs. 264 mg/dl, p = 0.0182), FVII (99% vs. 90%, p = 0.0049), FVIII (114% vs. 90%, p = 0.0098), protein C (124% vs. 111%, p = 0.0006), and protein S (109% vs. 89%, p

The control of the pathogenic load on foodstuffs is a key element in food safety. Particularly, seafood such as cold-smoked salmon is threatened by pathogens such as Salmonella sp. or Listeria monocytogenes. Despite strict existing hygiene procedures, the production industry constantly demands novel, reliable methods for microbial decontamination. Against that background, a microwave plasma-based decontamination technique via plasma-processed air (PPA) is presented. Thereby, the samples undergo two treatment steps, a pre-treatment step where PPA is produced when compressed air flows over a plasma torch, and a post-treatment step where the PPA acts on the samples. This publication embraces experiments that compare the total viable count (tvc) of bacteria found on PPA-treated raw (rs) and cold-smoked salmon (css) samples and their references. The tvc over the storage time is evaluated using a logistic growth model that reveals a PPA sensitivity for raw salmon (rs). A shelf-life prolongation of two days is determined. When cold-smoked salmon (css) is PPA-treated, the treatment reveals no further impact. When PPA-treated raw salmon (rs) is compared with PPA-untreated cold-smoked salmon (css), the PPA treatment appears as reliable as the cold-smoking process and retards the growth of cultivable bacteria in the same manner. The experiments are flanked by quality measurements such as color and texture measurements before and after the PPA treatment. Salmon samples, which undergo an overtreatment, solely show light changes such as a whitish surface flocculation. A relatively mild treatment as applied in the storage experiments has no further detected impact on the fish matrix.

Background: It is now generally accepted that obesity is a major risk factor for type 2 diabetes mellitus (T2DM). Hepatic steatosis in particular, as well as visceral and ectopic fat accumulation within tissues, is associated with the development of the disease. We recently presented the first study on isolated human pancreatic adipocytes and their interaction with islets [Gerst, F., Wagner, R., Kaiser, G., Panse, M., Heni, M., Machann, J., et al., 2017. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia 60(11):2240–2251.]. The results indicate that the function of adipocytes depends on the overall metabolic status in humans which, in turn, differentially affects islet hormone release. Scope of Review: This review summarizes former and recent studies on factors derived from adipocytes and their effects on insulin-secreting β-cells, with particular emphasis on the human pancreas. The adipocyte secretome is discussed with a special focus on its influence on insulin secretion, β-cell survival and apoptotic β-cell death. Major Conclusions: Human pancreatic adipocytes store lipids and release adipokines, metabolites, and pro-inflammatory molecules in response to the overall metabolic, humoral, and neuronal status. The differentially regulated adipocyte secretome impacts on endocrine function, i.e., insulin secretion, β-cell survival and death which interferes with glycemic control. This review attempts to explain why the extent of pancreatic steatosis is associated with reduced insulin secretion in some studies but not in others. Keywords: Fatty pancreas, Adipocytes, Paracrine signalling, Insulin secretion, β-cell mass, Type 2 diabetes mellitus (T2DM)

Abstract Background Tuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on their safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in TSC patients under the age of 2 years. Results A total of 17 children (median age at study inclusion 2.4 years, range 0–6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0–19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1–2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3–4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction. Conclusion This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.

Aims Insulin sensitivity and insulin secretion can be estimated by multiple indices from fasting blood samples or blood samples obtained during oral glucose tolerance tests. The test-retest reliability of these indices in repeated measurements within the same individuals can strongly vary. Methods We analyzed data of persons without diabetes who underwent two repeated OGTTs. For each measurement pair, we calculated multiple commonly used indices for the assessment of insulin secretion and insulin sensitivity. We then evaluated the coefficient of variation (standard deviation/mean) and discriminant ratio for each index. Results 89 persons underwent two OGTTs with a median interval of 86 days (IQR 64–249). Among indices of insulin sensitivity derived from fasting blood samples, the revised quantitative insulin sensitivity check index had the smallest coefficient of variation (2.8 ± 2.1%) whereas the C-peptide based homeostasis model assessment 2 had the highest discriminant ratio (1.97 (1.65–2.39)). As for insulin sensitivity indices that are based on OGTT, the oral glucose insulin sensitivity index had the smallest coefficient of variation (6.5 ± 5.1%). The highest discriminant ratio was found for the non-esterified fatty acids-based insulin sensitivity index (NEFA-ISI, 2.70 (2.30–3.22)). For the assessment of insulin secretion from fasting variables, the lowest mean coefficient of variation was found for C-peptide based homeostasis model assessment 2 beta with 10.8 ± 8% and the highest discriminant ratio for the C-peptide / Glucose-Ratio (2.18 (1.84–2.63)). Among indices assessing insulin secretion from an OGTT, the lowest coefficient of variation was found for the ratio of the areas under the C-peptide and glucose curves from 0 to 120 minutes with 11.3 ± 9.7%. Conclusion The data reveal large differences in the reproducibility and the discrimination capability of different indices that assess insulin sensitivity or insulin secretion. Our findings can aid the selection of an appropriate index in clinical studies.

IntroductionAs base excess had shown superiority over lactate as a prognostic parameter in intensive care unit (ICU) surgical patients we aimed to evaluate course of lactate, base excess and pH for prediction of mortality of medical ICU patients.Materials and methodsFor lactate, pH and base excess, values at the admission to ICU, at 24 ± 4 hours, maximum or minimum in the first 24 hours and in 24-48 hours after admission were collected from all patients admitted to the Medical ICU of the University Hospital Tübingen between January 2016 until December 2018 (N = 4067 at admission, N = 1715 with ICU treatment > 48 h) and investigated for prediction of in-hospital-mortality.ResultsMortality was 22% and significantly correlated with all evaluated parameters. Strongest predictors of mortality determined by ROC were maximum lactate in 24 h (AUROC 0.74, cut off 2.7 mmol/L, hazard ratio of risk group with value > cut off 3.20) and minimum pH in 24 h (AUROC 0.71, cut off 7.31, hazard ratio for risk group 2.94). Kaplan Meier Curves stratified across these cut offs showed early and clear separation. Hazard ratios per standard deviation increase were highest for maximum lactate in 24 h (HR 1.65), minimum base excess in 24 h (HR 1.56) and minimum pH in 24 h (HR 0.75).ConclusionLactate, pH and base excess were all suitable predictors of mortality in internal ICU patients, with maximum / minimum values in 24 and 24-48 h after admission altogether stronger predictors than values at admission. Base excess and pH were not superior to lactate for prediction of mortality.

Introduction Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).Research design and methods We investigated longitudinal data from participants of the ‘Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration’ Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer’s Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1–3: 2.2–4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%–6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.Results Insulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.Conclusions Insulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.

Results from an experimental profile loss study are presented of an additive manufactured linear turbine cascade placed in the test section of a closed-loop organic vapor wind tunnel. This test facility at Muenster University of Applied Sciences allows the investigation of high subsonic and transonic organic vapor flows under ORC turbine flow conditions at elevated pressure and temperature levels. An airfoil from the open literature was chosen for the cascade, and the organic vapor was Novec 649TM. Pitot probes measured the flow field upstream and downstream of the cascade. The inflow turbulence level was 0.5%. The roughness parameters of the metal-printed blades were determined, and the first set of flow measurements was performed. Then, the blade surfaces were further finished, and the impact of roughness on profile losses was assessed in the second flow measurement set. Although the Reynolds number level was relatively high, further surface treatment reduces the profile loss noticeably in organic vapor flows through the printed cascade.

Objective: While prostate cancer does not occur more often in men with diabetes, survival is markedly reduced in this patient group. Androgen signaling is a known and major driver for prostate cancer progression. Therefore, we analyzed major components of the androgen signaling chain and cell proliferation in relation to type 2 diabetes. Methods: Tumor content of 70 prostate tissue samples of men with type 2 diabetes and 59 samples of patients without diabetes was quantified by an experienced pathologist, and a subset of 51 samples was immunohistochemically stained for androgen receptor (AR). mRNA expression of AR, insulin receptor isoform A (IR-A) and B (IR-B), IGF-1 receptor (IGF1R), Cyp27A1 and Cyp7B1, PSA gene KLK3, PSMA gene FOLH1, Ki-67 gene MKI67, and estrogen receptor beta (ESR2) were analyzed by RT-qPCR. Results: AR mRNA and protein expression were associated with the tumor content only in men with diabetes. AR expression also correlated with downstream targets PSA (KLK3) and PSMA (FOLH1) and increased cell proliferation. Only in diabetes, AR expression was correlated to higher IR-A/IR-B ratio and lower IR-B/IGF1R ratio, thus, in favor of the mitogenic isoforms. Reduced Cyp27A1 and increased Cyp7B1 expressions in tumor suggest lower levels of protective estrogen receptor ligands in diabetes. Conclusions: We report elevated androgen receptor signaling and activity presumably due to altered insulin/IGF-1 receptors and decreased levels of protective estrogen receptor ligands in prostate cancer in men with diabetes. Our results reveal new insights why these patients have a worse prognosis. These findings provide the basis for future clinical trials to investigate treatment response in patients with prostate cancer and diabetes. Keywords: Prostate cancer, Androgen receptor, Insulin receptor, IGF-1 receptor, Cyp27A1, Cyp7B1

Background/Aims: Posttransplantation diabetes mellitus (PTDM) impacts patient and allograft survival after kidney transplantation. Prediabetes, which is an independent risk factor for PTDM, is modifiable also in a post-transplant setting. Understanding the risks and dynamics of impaired glucose metabolism after transplantation is a key component for targeted intervention. Methods: A retrospective chart analysis of all adult non-diabetic renal allograft recipients (n=251, 2007-2014) was performed. Longitudinal follow-up included fasting plasma glucose and HbA1c, as well as data on allograft function and immunosuppression at consecutive time points (months 3-6 to >5 years post transplantation). Results: Throughout follow-up, median prevalence of prediabetes and PTDM was 53.3 [52.4-55.7]% and 15.4 [15.0-16.5]%, respectively. Continuously high fluxes between states of glucose metabolism, with individual patients’ state deteriorating or improving over time, resulted in a high number of incident patients even long after transplantation. The greatest number of patients shifted between normal glucose tolerance and prediabetes, followed by those between prediabetes and PTDM. Conclusion: Prediabetes and PTDM are highly prevalent after kidney transplantation and incidences remain relevant throughout follow-up. Patient fluxes into and out of the prediabetic state show that glucose metabolism is highly dynamic after transplantation. This provides a continuous opportunity for intervention in an aim to reduce diabetes-associated complications.

Background: Adequate removal of sodium (Na) and phosphorus (P) is of paramount importance for patients with dialysis-dependent kidney disease can easily quantified in peritoneal dialysis (PD) patients. Some studies suggest that automated PD (APD) results in lower Na and P removal. Methods: In this study we retrospectively analysed our data on Na and P removal in PD patients after implementation of a routine monitoring in 2011. Patients were stratified in those treated with continuous ambulatory PD (CAPD, n=24), automated PD (APD, n=23) and APD with one bag change (CAPD+APD, n=10). Until 2015 we collected time-varying data on Na and P removal from each patient (median 5 [interquartile range 4-8] values). Results: Peritoneal Na and P removal (mmol per 24h ± standard deviation) was 102 ± 48 and 8 ± 2 in the CAPD, 90 ± 46 and 9 ± 3 in the APD and 126 ± 39 and 13 ± 2 in the CAPD+APD group (ANOVA P=0.141 and

Background: Testosterone levels are differentially linked with diabetes risk in men and women: lower testosterone levels in men and higher testosterone levels in women are associated with type 2 diabetes, though, the mechanisms are not fully clear. We addressed sex-specific links between testosterone and major pathogenetic mechanisms of diabetes.Methods: We analyzed data of 623 subjects (202 male, 345 female without, and 76 female with oral contraceptive therapy [OCT]) for whom insulin sensitivity and insulin secretion were assessed by oral glucose tolerance test. Body fat percentage was assessed by bioelectrical impedance. Testosterone was measured by enzyme-linked immunoassay; free testosterone and Framingham risk score were calculated.Results: There were significant interactions between testosterone and sex for all tested metabolic traits. Increasing testosterone was associated with less body fat, elevated insulin sensitivity, and reduced glycemia, independent of adiposity in men. In women without OCT, testosterone correlated with more body fat, insulin resistance, and higher glucose concentrations. Testosterone was not associated with insulin secretion in either sex, but with lower Framingham risk score in men and higher Framingham risk score in women.Conclusions: Similar to diabetes risk, insulin resistance has different association directions with testosterone levels in males and females. Insulin resistance could therefore constitute the best biological candidate linking testosterone levels and diabetes prevalence. The question of antiandrogen therapy being able to improve metabolism, glucose tolerance and cardiovascular risk in women was not clarified in our study but should be reviewed with higher numbers in a carefully matched study to reduce the influence of confounding variables.

Objectives: The systemic inflammatory response syndrome (SIRS) after cardiac surgery with cardiopulmonary bypass (CPB) exacerbates organ dysfunction and increases postoperative mortality. The aim of this study was to reduce SIRS after CPB in a pig model by profoundly decreasing all blood defence factors (complement, coagulation and fibrinolytic and contact systems, leukocytes and thrombocytes) using pre‑operative aphaeresis. Methods: Thirty-three pigs underwent 3 h of hypothermic CPB with 2 h of cardioplegic arrest, followed by 4 days of observation. One half of the sample underwent prebypass plasma-thrombo-leukocyte aphaeresis with the adjuvant leukofiltration. Results: In the control group, there were classical signs of SIRS (tachycardia, tachypnea and leukocytosis) postoperatively. There was also myocardial ischaemia and the need for inotropic support in 90% of the control animals. Neutrophils showed an increase in superoxide anion production (P < 0.001), and surface neutral protease activity (P < 0.001) and blood endotoxin levels increased (P < 0.01) compared with preoperative levels. In contrast, in the aphaeretic group, there were no classical signs of SIRS; no myocardial ischaemia; minimum neutrophil production of the superoxide anion and protease activity were recorded (P < 0.001); and endotoxin levels were also decreased (P < 0.05) compared with the controls. In the control group, the haemodynamic problems associated with disconnecting from CPB correlated with the histologic findings in the myocardium (leukocyte endothelial adhesion and leukodiapedesis). Conclusions: Pre‑operative plasma‑thrombo-leukocyte aphaeresis significantly reduces the major symptoms of SIRS and organ dysfunction after 3 h of CPB without adverse effects, such as bleeding and infection, during the postoperative course.

Visceral adipose tissue (VAT) plays an important role in the pathogenesis of insulin resistance (IR), prediabetes and type 2 diabetes. However, VAT volume alone might not be the best marker for insulin resistance and prediabetes or diabetes, as a given VAT volume may impact differently on these metabolic traits based on body height, gender, age and ethnicity. In a cohort of 1295 subjects from the Tübingen Diabetes Family Study (TDFS) and in 9978 subjects from the UK Biobank (UKBB) undergoing magnetic resonance imaging for quantification of VAT volume, total adipose tissue (TAT) in the TDFS, total abdominal adipose tissue (TAAT) in the UKBB, and total lean tissue (TLT), VAT volume and several VAT-indices were investigated for their relationships with insulin resistance and glycemic traits. VAT-related indices were calculated by correcting for body height (VAT/m:VAT/body height; VAT/m2:VAT/(body height)2, and VAT/m3:VAT/(body height)3), TAT (%VAT), TLT (VAT/TLT) and weight (VAT/WEI), with closest equivalents used within the UKBB dataset. Prognostic values of VAT and VAT-related indices for insulin sensitivity, HbA1c levels and prediabetes/diabetes were analyzed for males and females. Males had higher VAT volume and VAT-related indices than females in both cohorts (p < 0.0001) and VAT volume has shown to be a stronger determinant for insulin sensitivity than anthropometric variables. Among the parameters uncorrected VAT and derived indices, VAT/m3 most strongly correlated negatively with insulin sensitivity and positively with HbA1c levels and prediabetes/diabetes in the TDFS (R2 = 0.375/0.305 for females/males for insulin sensitivity, 0.178/0.148 for HbA1c levels vs., e.g., 0.355/0.293 and 0.144/0.133 for VAT, respectively) and positively with HbA1c (R2 = 0.046/0.042) in the UKBB for females and males. Furthermore, VAT/m3 was found to be a significantly better determinant of insulin resistance or prediabetes than uncorrected VAT volume (p < 0.001/0.019 for females/males regarding insulin sensitivity, p < 0.001/< 0.001 for females/males regarding HbA1c). Evaluation of several indices derived from VAT volume identified VAT/m3 to correlate most strongly with insulin sensitivity and glucose metabolism. Thus, VAT/m3 appears to provide better indications of metabolic characteristics (insulin sensitivity and pre-diabetes/diabetes) than VAT volume alone.

In the last decade atmospheric pressure plasma jets (APPJs) have been routinely employed for surface processing of polymers due to their capability of generating very reactive chemistry at near-ambient temperature conditions. Usually, the plasma jet modification effect spans over a limited area (typically a few cm²), therefore, for industrial applications, where treatment of large and irregular surfaces is needed, jet and/or sample manipulations are required. More specifically, for treating hollow objects, like pipes and containers, the plasma jet must be introduced inside of them. In this case, a normal jet incidence to treated surface is difficult if not impossible to maintain. In this paper, a plasma jet produced at the end of a long flexible plastic tube was used to treat polyethylene terephthalate (PET) samples with different incidence angles and using different process parameters. Decreasing the angle formed between the plasma plume and the substrate leads to increase in the modified area as detected by surface wettability analysis. The same trend was confirmed by the distribution of reactive oxygen species (ROS), expanding on starch-iodine-agar plates, where a greater area was covered when the APPJ was tilted. Additionally, UV-VUV irradiation profiles obtained from the plasma jet spreading on the surface confirms such behavior.

Aims: GPR40/FFAR1 mediates palmitate-induced stimulation of insulin secretion but its involvement in lipotoxicity is controversial. Our previous observations suggest that FFAR1/GPR40 agonists protect against lipotoxicity although the underlying mechanism remains elusive. The present study examines the role of ERK1/2 and GPR40/FFAR1 in palmitate-induced stimulation of insulin secretion and beta cell death. Methods: Insulin secretion of INS-1E cells was measured by radioimmunoassay. Protein phosphorylation was examined on Western blots. Apoptosis was assessed by TUNEL staining. Results: Palmitate and the GPR40/FFAR1 agonist TUG-469 increased phosphorylation of ERK1/2 at low (2.8 mmol/L) and high (12 mmol/L) glucose but stimulated insulin secretion only at high glucose. The MEK1 inhibitor PD98059 significantly reduced phosphorylation of ERK1/2 but did not reverse the stimulation of secretion induced by glucose, palmitate or TUG-469. PD98059 rather augmented glucose-induced secretion. Prolonged exposure to palmitate stimulated apoptosis, an effect counteracted by TUG-469. PD98059 accentuated palmitate-induced apoptosis and reversed TUG-469-mediated inhibition of cell death. Conclusions: Activation of ERK1/2 by palmitate and GPR40/FFAR1 agonist correlates neither with stimulation of insulin secretion nor with induction of apoptosis. The results suggest a significant anti-apoptotic role of ERK1/2 under conditions of lipotoxicity.

OBJECTIVE:Dipeptidyl-peptidase 4 (DPP-4) cleaves and inactivates the insulinotropic hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide, collectively termed incretins. DPP-4 inhibitors entered clinical practice as approved therapeutics for type-2 diabetes in 2006. However, inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). RESEARCH DESIGN AND METHODS:Fourteen common (minor allele frequencies ≥0.05) DPP4 tagging single nucleotide polymorphisms (SNPs) were genotyped in 1,976 non-diabetic TÜF participants characterized by oral glucose tolerance tests and bioimpedance measurements. In a subgroup of 168 subjects, plasma incretin levels were determined. RESULTS:We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. CONCLUSIONS:A common variant, i.e., SNP rs6741949, in the DPP4 gene interacts with body adiposity and negatively affects glucose-stimulated GLP-1 levels, insulin secretion, and glucose tolerance. Whether this SNP underlies the reported inter-individual variance in responsiveness to DPP-4 inhibitors, at least in subjects with high body fat content, remains to be shown.

Inhibition of sodium/glucose cotransporter 2 (SGLT2), the key transport protein in renal glucose reabsorption, promotes glucose excretion and represents a new concept in the therapy of type-2 diabetes. In addition, SGLT2 inhibition elevates circulating glucagon concentrations and enhances hepatic glucose production. Since SGLT2 is expressed in human pancreatic α-cells and regulates glucagon release, we tested whether common variants of the SGLT2 gene SLC5A2 associate with altered plasma glucagon concentrations in the fasting state and upon glucose challenge.A study population of 375 healthy subjects at increased risk for type-2 diabetes, phenotyped by a 5-point oral glucose tolerance test (OGTT) and genotyped for recently described SLC5A2 tagging single nucleotide polymorphisms (SNPs), was selected for plasma glucagon measurements.After adjustment for gender, age, body mass index, and insulin sensitivity, the four tagging SNPs (rs9924771, rs3116150, rs3813008, rs9934336), tested separately or as genetic score, were neither significantly nor nominally associated with plasma glucagon concentrations at any time during the OGTT, with the inverse AUC of glucagon or the glucagon fold-change during the OGTT (p ≥ 0.2, all). Testing for genotype-related differences in the time course of the glucagon response using MANOVA did also not reveal any significant or nominal associations (p ≥ 0.5, all).We could not obtain statistically significant evidence for a role of common SLC5A2 variants in the regulation of glucagon release in the fasting state or upon glucose challenge. Moreover, the reported nominal effects of individual SLC5A2 variants on fasting and post-challenge glucose levels may probably not be mediated by altered glucagon release.