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Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested whether individuals with prediabetes with low risk (LR) benefit from conventional LI and individuals with high risk (HR) benefit from an intensification of LI in a multicenter randomized controlled intervention over 12 months with 2 years’ follow-up. A total of 1,105 individuals with prediabetes based on American Diabetes Association glucose criteria were stratified into an HR or LR phenotype based on previously described thresholds of insulin secretion, insulin sensitivity, and liver fat content. LR individuals were randomly assigned to conventional LI according to the Diabetes Prevention Program (DPP) protocol or control (1:1) and HR individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In HR individuals, the difference between conventional and intensified LI in postchallenge glucose change was −0.29 mmol/L [95% CI −0.54; −0.04], P = 0.025. Liver fat (−1.34 percentage points [95% CI −2.17; −0.50], P = 0.002) and cardiovascular risk (−1.82 percentage points [95% CI −3.13; −0.50], P = 0.007) underwent larger reductions with intensified than with conventional LI. During a follow-up of 3 years, intensified compared with conventional LI had a higher probability of normalizing glucose tolerance (P = 0.008). In conclusion, it is possible in HR individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk phenotype–based LI may be beneficial for the prevention of diabetes.

The design of active and selective co-catalysts constitutes one of the major challenges in developing heterogeneous photocatalysts for energy conversion applications. This work provides a comprehensive insight into thermally induced bottom-up generation and transformation of a series of promising Cu-based co-catalysts. We demonstrate that the volcano-type HER profile as a function of calcination temperature is independent of the type of the Cu precursor but is affected by changes in oxidation state and location of the copper species. Supported by DFT modeling, our data suggest that low temperature (200 °C) do not affect the Cu oxidation state, but induce a gradual, temperature-dependent surface-to-bulk diffusion of Cu, which results in interstitial, tetra-coordinated Cu+ species. The disappearance of Cu from the surface and the introduction of new defect states is associated with a drop in HER performance. This work examines electronic and structural effects that are in control of the photocatalytic activity and can be transferred to other systems for further advancing photocatalysis., Calcination of Cu/TiO2 is detrimental to its photocatalytic HER performance. We relate this to heat-activated Cu diffusion into the TiO2 lattice, which decreases accessibility of the Cu sites on the surface and generates charge recombination centers.

Aims/hypothesis Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver–alpha cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the alpha cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon–alanine index, an indicator of the functional integrity of the liver–alpha cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. Methods We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon–alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon–alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% (n = 39) or >0.5% (n = 40). Results The glucagon–alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort (ρ = 0.484, p ρ = 0.417, p 0.5% (liver fat, ρ = 0.550, p ρ = 0.429, p = 0.006). In linear regression analyses, the association of the glucagon–alanine index with liver fat remained significant after adjustment for age and HOMA-IR in all participants and in those with liver fat >0.5% (β = 0.246, p = 0.0.23 and β = 0.430, p = 0.007, respectively) but not in participants with liver fat ≤0.5% (β = −0.184, p = 0.286). Conclusions/interpretation We reproduced the previously reported association of liver fat content and HOMA-IR with the glucagon–alanine index in an independent study cohort of young women with low to high risk for type 2 diabetes. Furthermore, our data indicates an insulin-resistance-independent association of liver fat content with the glucagon–alanine index. In summary, our study supports the concept that even lower levels of liver fat (from 0.5%) are connected to relative hyperglucagonaemia, reflecting an imminent impairment of the liver–alpha cell axis.

Background: Diabetes mellitus is a major health problem in Southeast Asia and diabetic retinopathy is one of its most debilitating complications. Nevertheless, fundoscopy and systematic evaluation of non-adherence to drug therapy are not regularly done in individuals with diabetes in Bangladesh due to limited resources. Therefore, the prevalence of diabetic retinopathy and its determinants with non-adherence to drug therapy are not known. We, therefore, screened for diabetic retinopathy, non-adherence to drug therapy and other associated factors at a tertiary care hospital in Bangladesh.Methods: Between May 2017 to September 2017, we conducted a cross-sectional study of 489 systematically recruited asymptomatic, at least one-year type-2 diabetic individuals on medication and attending the outpatient department of the BIHS tertiary care centre in Dhaka, Bangladesh. We obtained a medical history, physical examination, routine laboratory tests, questionnaires, and fundus photography.Results: The prevalence of diabetic retinopathy among T2DM patients was 18.8%. Clinical factors associated with the presence of diabetic retinopathy were uncontrolled fasting blood glucose, known duration of diabetes of ≥10 years and self-reported non-adherence to drug therapy. With a known duration of diabetes of 15 years or more, the prevalence of diabetic retinopathy rose to 40%.Conclusions: Undiagnosed diabetic retinopathy is still common among patients in Bangladesh, even at tertiary care centres. It is associated with longer disease duration, poor metabolic control and self-reported non-adherence to therapy. Regular screening for diabetic retinopathy should therefore be implemented also in resource-limited settings and further efforts should be made to improve the patients’ drug adherence and metabolic control.

Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested if prediabetic individuals with low risk benefit from conventional LI and individuals with high risk benefit from an intensification of LI in a multi-center randomized controlled intervention over 12 months with 2 years follow up. 1105 prediabetic individuals based on ADA glucose criteria were stratified into a high- and low-risk phenotype, based on previously described thresholds of insulin secretion, insulin sensitivity and liver fat content. Low-risk individuals were randomly assigned to conventional LI according to the DPP protocol or control (1:1), high-risk individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In high-risk individuals, the difference between conventional and intensified LI in post-challenge glucose change was -0.29 mmol/l [CI:-0.54;-0.04], p=0.025. Liver fat (-1.34 percentage points [CI:-2.17;-0.50], p=0.002) and cardiovascular risk (-1.82[CI:-3.13-0.50],p=0.007) underwent larger reductions with intensified than with conventional LI. During a follow up of 3 years, intensified compared to conventional LI had a higher probability to normalize glucose tolerance (p=0.008). In conclusion, it is possible in high-risk individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk-phenotype-based LI may be beneficial for the prevention of diabetes.

Aims Women after gestational diabetes mellitus (GDM) are a risk group for cardiometabolic diseases but are hard to reach by conventional lifestyle programs. Therefore, we tested whether a novel, smartphone-delivered intervention, TRIANGLE, is accepted by women after GDM and alters cardiometabolic risk behaviors and outcomes. TRIANGLE targets gradual habit change of mind and emotion, physical activity, nutrition, and sleep. Methods We conducted a 6-month multicenter, randomized-controlled trial of TRIANGLE versus standard care with 66 women 3–18 months after GDM in Germany. The primary outcome was the proportion of women achieving ≥3 out of 5 Diabetes Prevention Program goals, i.e. physical activity ≥150 min/week (moderate to high intensity), fiber intake ≥15 g/1,000 kcal, fat intake 2 or weight maintenance if BMI 2. Intervention participants also rated the TRIANGLE app in the Mobile Application Rating Scale (uMARS). Results In the predefined, modified intention-to-treat analysis including 64 women, 6 out of 27 women in the intervention group [22%(10–40)] and 3 out of 27 women in the control group [11%(3–27)] reached the primary outcome (p = 0.47). In the predefined per-protocol intervention subgroup, the proportion was 4 out of 14 women [29%(11–55); p = 0.20 vs. control]. TRIANGLE app users were active on 42% of days and rated the app’s quality and perceived impact with 4.3±0.8 out of 5 uMARS points. Conclusions This first trial did not show the efficacy of the TRIANGLE intervention. However, the app was well accepted and considered helpful by most users. Therefore, this trial supports further development and testing of TRIANGLE and other app interventions for women after GDM. Additionally, it identifies necessary adaptations in trial design to better accommodate non-intensive lifestyle interventions for this target group. Trial registration Trial registration at drks.de (DRKS00012996).

Objective Metabolic syndrome and obesity are risk factors for chronic kidney disease. However, early kidney alterations may escape diagnosis in these conditions due to glomerular hyperfiltration. Uromodulin, a glycoprotein exclusively synthesized in tubular cells of the thick ascending limb of Henle's loop, is a novel tissue-specific biomarker for kidney function. In contrast to the commonly used markers creatinine and cystatin C, serum uromodulin does not primarily depend on glomerular filtration. We hypothesized that serum uromodulin is a marker for metabolic syndrome and related components. Design The analyses included 1088 participants of the population-based KORA F4 study aged 62–81 years. Metabolic syndrome was present in 554 participants. After a mean follow-up time of 6.5 years, 621 participants were reevaluated, of which 92 had developed incident metabolic syndrome. Methods The association of serum uromodulin with metabolic syndrome and its components were assessed using multivariable logistic regression models. Results Serum uromodulin was inversely associated with metabolic syndrome after adjustment for sex, age, estimated glomerular filtration rate, physical activity, smoking, alcohol consumption and high-sensitivity C-reactive protein (OR 0.65; 95% CI 0.56–0.76 per standard deviation uromodulin; P Conclusions Serum uromodulin is independently associated with prevalent, but not with incident metabolic syndrome. Low serum uromodulin may indicate a decreased renal reserve in the metabolic syndrome.

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs), which are anchored at the surface of mammalian cultured and tissue cells through a carboxy-terminal GPI glycolipid, are susceptible to release into incubation medium and (rat and human) blood, respectively, in response to metabolic stress and ageing. Those GPI-APs with the complete GPI still attached form micelle-like complexes together with (lyso)phospholipids and cholesterol and are prone to degradation by serum GPI-specific phospholipase D (GPLD1), as well as translocation to the surface of acceptor cells in vitro. In this study, the interaction of GPI-APs with GPLD1 or other serum proteins derived from metabolically deranged rat and humans and their translocation were measured by microfluidic chip- and surface acoustic wave-based sensing of micelle-like complexes reconstituted with model GPI-APs. The effect of GPI-AP translocation on the integrity of the acceptor cell surface was studied as lactate dehydrogenase release. For both rats and humans, the dependence of serum GPLD1 activity on the hyperglycemic/hyperinsulinemic state was found to be primarily based on upregulation of the interaction of GPLD1 with micelle-like GPI-AP complexes, rather than on its amount. In addition to GPLD1, other serum proteins were found to interact with the GPI phosphoinositolglycan of full-length GPI-APs. Upon incubation of rat adipocytes with full-length GPI-APs, their translocation from the micelle-like complexes (and also with lower efficacy from reconstituted high-density lipoproteins and liposomes) to acceptor cells was observed, accompanied by upregulation of their lysis. Both GPI-AP translocation and adipocyte lysis became reduced in the presence of serum proteins, including (inhibited) GPLD1. The reduction was higher with serum from hyperglycemic/hyperinsulinemic rats and diabetic humans compared to healthy ones. These findings suggest that the deleterious effects of full-length GPI-APs following spontaneous release into the circulation of metabolically deranged rats and humans are counterbalanced by upregulated interaction of their GPI anchor with GPLD1 and other serum proteins. Thereby, translocation of GPI-APs to blood and tissue cells and their lysis are prevented. The identification of GPI-APs and serum proteins interacting within micelle-like complexes may facilitate the prediction and stratification of diseases that are associated with impaired cell-surface anchorage of GPI-APs, such as obesity and diabetes.

ObjectiveMany anecdotal reports indicate the presence of ‘long COVID’ – COVID-19-related symptoms weeks to months after the acute illness. However, frequency and symptom-pattern of ‘long COVID’ in relation to acute disease severity are uncertain. As part of an ongoing, prospective cohort study we therefore conducted an online survey among adults 6 months after acute COVID-19.MethodsThe prospective online study Life&Covid is ongoing in Germany since May 2020. Participants were recruited 0 to 4 months after their SARS-CoV-2 infection und followed up by subsequent surveys. The survey 6 months after the infection was completed by 127 out of 148 individuals invited by email (86%). All grades of acute disease severity were included and 91% of the participants had been treated as outpatients during their acute illness.ResultsSix months after the infection, 67% of the study participants reported at least one symptom as a consequence of COVID-19. Exertional dyspnea (30% of participants), fatigue (25%) and diminished sense of taste/smell (19%) were the most common individual symptoms. At least one symptom, exertional dyspnea, and fatigue were reported more often after a severe acute illness, but diminished sense of taste/smell was unrelated to acute severity. Age group and sex did not associate with the frequency of symptoms at 6 months.ConclusionsBased on this study, the prevalence of COVID-19-related symptoms 6 months after the infection is high. Some bias for overestimation may have affected this result. Nevertheless, ‘long COVID’ requires attention in medical care and a better scientific understanding.

BackgroundLifestyle intervention (LI) can successfully prevent type 2 diabetes, but response to LI strongly varies depending on risk subphenotypes. We tested if individuals with prediabetes and a high-risk phenotype benefit from an intensification of LI.Methods and findingsWe conducted a risk stratified multicenter randomized controlled intervention study over 12 months with additional 2 year follow up. In eight University Hospitals in Germany, 1105 individuals (female 59%, age 58±11 years, BMI 31.1±6.0 kg/m2 (mean±SD)) with impaired fasting glucose and/or impaired glucose tolerance were included between May 2012 and May 2016 in the study. Participants were stratified into 2 groups; a high- and low-risk phenotype, based on insulin secretion, insulin sensitivity and liver fat content. Low-risk individuals were randomly assigned to conventional LI or control (1:1), high-risk individuals to conventional or intensified LI (1:1), each over one year. Intensified LI included doubling of physical exercise and time of counselling. The primary endpoint was change in post-challenge glucose levels, assessed by frequently sampled oral glucose tolerance tests. Secondary endpoints included changes in liver fat content, assessed by magnetic resonance spectroscopy. A total of 908 (82%) participants completed the study after 12 months of LI. In high-risk individuals, the mean difference estimate between conventional and intensified LI in change in post-challenge glucose levels from baseline was −0.290 mmol/l [CI: −0.544;−0.036], p=0.025. Liver fat content was more reduced by intensified LI than by conventional LI (mean difference estimate: −1.34 percentage points [CI: −2.17;−0.50], p=0.002), and cardiovascular risk decreased stronger with intensified LI than with conventional LI (mean difference estimate −1.82 [CI: −3.13−0.50], p=0.007). In low-risk individuals, conventional LI was not superior to control in reducing postprandial glucose, liver fat or cardiovascular risk. During the total observation period of 3 years, high-risk participants with intensified LI had a higher probability to normalize glucose tolerance compared to conventional LI (p=0.003). The limitations of this study include a relative short duration of LI, a non-completer rate of 18% and an underrepresentation of low risk individuals.ConclusionsIn high-risk individuals with prediabetes it is possible to improve glycemic and cardiometabolic outcomes by intensification of the commonly recommended conventional LI. Our results show that individualized, risk-phenotype-based LI can be implemented for the prevention of diabetes.RegistrationNCT01947595Author summaryWhy Was This Study Done?Clinical trials in individuals with prediabetes have shown that the onset of type 2 diabetes can be delayed or prevented with lifestyle intervention.Among individuals with prediabetes, there is a large variability in the response to lifestyle intervention.It is unknown whether an intensification of intervention is able to improve the beneficial response.What Did the Researchers Do and Find?The present multicenter, risk stratified randomized and controlled intervention trial in 1105 German individuals with prediabetes prospectively confirms the existence of a high-risk prediabetes phenotypeThe intensification of lifestyle intervention in high-risk individuals improves the glycemic outcome after 1 year of lifestyle intervention, and additionally results in a higher frequency of regression to normal glucose tolerance after 3 years of follow up..Intensification of lifestyle intervention results in a larger reduction of liver fat content and stronger improves cardiometabolic outcomes in high-risk individuals.What Do These Findings Mean?Strategies for the prevention of type 2 diabetes should include risk stratification and individualised interventions.Our results highlight a dose-effect relationship for lifestyle intervention and suggest that “one size fits NOT all” in the field of diabetes prevention.It remains to be clarified whether low risk individuals benefit from lifestyle intervention, as there was a low number of individuals in this risk group in the current study.

Objective Clinically, type 2 diabetes mellitus (T2DM) is heterogeneous, but the prevailing pathophysiologic hypothesis nevertheless contends that components of metabolic syndrome are central to all cases of T2DM. Here, we re-evaluated this hypothesis. Research Design and Methods We conducted a cross-sectional analysis of 138 women from the monocenter, post gestational diabetes study PPSDiab, 73 of which had incident prediabetes or T2DM. Additionally, we examined all the 412 incident cases of T2DM in phases 3 to 9 of the Whitehall II study in comparison to healthy controls. Our analysis included a medical history, anthropometrics, oral glucose tolerance testing, and laboratory chemistry in both studies. Additional analyses from the PPSDiab Study consisted of cardiopulmonary exercise testing, magnetic resonance imaging, auto-antibody testing, and the exclusion of glucokinase maturity-onset diabetes of the young. Results We found that 33 (45%) of the women with prediabetes or T2DM in the PPSDiab study displayed no components of metabolic syndrome. They reached no point for metabolic syndrome in the National Cholesterol Education Program Adult Treatment Panel III score other than hyperglycemia and, moreover, had levels of liver fat content, plasma triglycerides, high-density lipoprotein cholesterol, c-reactive protein, and blood pressure that were comparable to healthy controls. In the Whitehall II study, 62 (15%) of the incident T2DM cases fulfilled the same criteria. In both studies, these cases without metabolic syndrome revealed insulin resistance and inadequately low insulin secretion. Conclusions Our results contradict the hypothesis that components of metabolic syndrome are central to all cases of T2DM. Instead, they suggest the common occurrence of a second, unrelated pathophysiology.

BACKGROUND Gestational diabetes mellitus (GDM) is the most common complication during pregnancy and is associated with an increased risk for the development of cardiometabolic diseases. Behavioral interventions can reduce this risk, but current solutions insufficiently address the requirements for such a program. The systematic development of a scalable mobile health (mHealth) promotion program for mothers during the first years post-GDM may contribute to solving this problem. OBJECTIVE The aim of this project was to systematically plan and develop a theory- and evidence-based mHealth intervention to change cardiometabolic risk behaviors in women during the first 5 years post-GDM that meets women’s expected standards of commercial health apps. METHODS The intervention mapping steps 1 to 4 structured the systematic planning and development of the mHealth program described in this paper. Steps 1 and 2 led to a theory- and evidence-based logic model of change for cardiometabolic health. Based on this model, the prevention program was designed (step 3) and produced (step 4) in cooperation with industrial partners to ensure a high technological standard of the resulting smartphone app for the iPhone (Apple Inc). Step 4 included a user study with women during the first 5 years post-GDM once a beta version of the app (“TRIANGLE”) was available. The user study comprised 2 test rounds of 1 week (n=5) and 4 weeks (n=6), respectively. The tests included validated questionnaires on user acceptance, user logs, and think-alouds with semistructured interviews. RESULTS The novel TRIANGLE app is among the first self-paced smartphone apps for individual habit change in the 3 lifestyle areas of physical activity, nutrition, and psychosocial well-being. The 3 core features—a challenge system, human coaching, and a library—address 11 behavioral determinants with 39 behavior change methods to support lifestyle changes. Participants in the user study showed a high acceptance, high perceived quality, and high perceived impact of the TRIANGLE app on their health behaviors. Participants tested the app regularly, used it intuitively, and suggested improvements. We then adapted the TRIANGLE app according to the insights from the user study before the full TRIANGLE program production. CONCLUSIONS The intervention mapping approach was feasible to plan and develop an innovative and scalable smartphone solution for women during the first 5 years post-GDM. The resulting TRIANGLE intervention has the potential to support behavior change for cardiometabolic disease prevention. However, the app needs further refinement and testing in clinical trials. Intervention mapping steps 5 (implementation plan) and 6 (evaluation plan) may support the integration of the TRIANGLE intervention into routine care. CLINICALTRIAL German Clinical Trials Register DRKS00012736; https://www.drks.de/DRKS00012736

IntroductionTen years ago, Germany started offering screening for gestational diabetes mellitus (GDM) to all pregnant women. This approach revealed more but also, on average, less severe cases of GDM than the risk-based screening practiced previously. We now examined the incidence of pre-diabetes and diabetes following a GDM diagnosis in the era of universal screening in Germany and compared our results with studies in the previous period. Additionally, we examined the year-to-year fluctuations of glucose tolerance after a pregnancy complicated by GDM.Research design and methodsWe report 5-year follow-up data from 202 women in the prospective, monocenter, postpartum study PPSDiab. Consecutive recruitment took place in Munich, Germany between 2011 and 2016. In the study, we conducted yearly examinations that included anthropometrics, laboratory chemistry and oral glucose tolerance testing.ResultsDuring the first 5 years post partum, 111 (55%) and 12 (6%) of the women developed pre-diabetes and type 2 diabetes, respectively, while 2 (1%) developed type 1 diabetes. Impaired fasting glucose (IFG) was the most common first manifestation of disturbed glucose tolerance, followed by impaired glucose tolerance (IGT), the combination of IFG and IGT, and diabetes. Glucose tolerance did not deteriorate steadily in most women but fluctuated from year to year.ConclusionsIn our analysis, the incidence of diabetes, both type 1 and type 2, after GDM diagnosed in universal screening was substantially lower than in studies from the previous period of risk-based screening. Nevertheless, the high incidence of pre-diabetes we observed after GDM still confirms the importance of this diagnosis as a risk marker. Additionally, we documented frequent fluctuations of glucose tolerance from 1 year to the next. Therefore, a single postpartum glucose tolerance test, as currently practiced in routine care, may be insufficient for reliable risk stratification after GDM.

IntroductionRelationships between endogenous female sex hormones and glycemic traits remain understudied, especially in men. We examined whether endogenous 17α-hydroxyprogesterone (17-OHP), progesterone, estradiol (E2), and free estradiol (fE2) were associated with glycemic traits and glycemic deterioration.Research design and methods921 mainly middle-aged and elderly men and 390 perimenopausal/postmenopausal women from the German population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort study were followed up for a median of 6.4 years. Sex hormones were measured at baseline using mass spectrometry. We calculated regression coefficients (β) and ORs with 95% CIs using multivariable-adjusted linear and logistic regression models for Z-standardized hormones and glycemic traits or glycemic deterioration (ie, worsening of categorized glucose tolerance status), respectively.ResultsIn the cross-sectional analysis (n=1222 men and n=594 women), in men, 17-OHP was inversely associated with 2h-glucose (2hG) (β=−0.067, 95% CI −0.120 to −0.013) and fasting insulin (β=−0.074, 95% CI −0.118 to −0.030), and positively associated with Quantitative Insulin Sensitivity Check Index (QUICKI) (β=0.061, 95% CI 0.018 to 0.105). Progesterone was inversely associated with fasting insulin (β=−0.047, 95% CI −0.088 to −0.006) and positively associated with QUICKI (β=0.041, 95% CI 0.001 to 0.082). E2 was inversely associated with fasting insulin (β=−0.068, 95% CI −0.116 to −0.020) and positively associated with QUICKI (β=0.059, 95% CI 0.012 to 0.107). fE2 was positively associated with glycated hemoglobin (HbA1c) (β=0.079, 95% CI 0.027 to 0.132). In women, 17-OHP was positively associated with fasting glucose (FG) (β=0.068, 95% CI 0.014 to 0.123). fE2 was positively associated with FG (β=0.080, 95% CI 0.020 to 0.141) and HbA1c(β=0.121, 95% CI 0.062 to 0.180). In the sensitivity analyses restricted to postmenopausal women, we observed a positive association between 17-OHP and glycemic deterioration (OR=1.518, 95% CI 1.033 to 2.264).ConclusionsInter-relations exist between female sex hormones and glucose-related traits among perimenopausal/postmenopausal women and insulin-related traits among men. Endogenous progestogens and estrogens appear to be involved in glucose homeostasis not only in women but in men as well. Further well-powered studies assessing causal associations between endogenous female sex hormones and glycemic traits are warranted.

Animal data link high circulating fetuin-A to low insulin sensitivity and observational studies identify the hepatokine as a marker of future incident type 2 diabetes mellitus in humans. However, a recent, well-powered Mendelian randomization study finds no causal role. We therefore tested in a deeply-phenotyped human cohort if circulating fetuin-A correlates independently with insulin sensitivity and how it relates to the metabolic syndrome and ectopic fat deposition. We analyzed data from 290 young women with and without recent gestational diabetes mellitus. We found that circulating fetuin-A correlates inversely with insulin sensitivity in univariate analyses, but that this correlation is lost after adjustment for markers of the metabolic syndrome and of fatty liver. Additionally, we investigated which fat compartment associates most strongly with circulating fetuin-A. In whole body MRI data from a subcohort of 152 women, this was liver fat content. We conclude that high circulating fetuin-A occurs as part of the metabolic syndrome in young women and associates most strongly with liver fat content. Its close link to the metabolic syndrome may also cause the inverse correlation of circulating fetuin-A with insulin sensitivity as we found no independent association.

Objective: MRI is established for measurement of body fat mass (FM) and abdominal visceral adipose tissue (VAT). Anthropometric measurements and bioelectrical impedance analysis (BIA) have been proposed as surrogates to estimation by MRI. Aim of this work is to assess the predictive value of these methods for FM and VAT measured by MRI. Methods: Patients were selected from cohort study PPS-Diab (prediction, prevention and subclassification of Type 2 diabetes). Total FM and VAT were quantified by MRI and BIA together with clinical variables like age, waist and hip circumference and height. Least-angle regressions were utilized to select anthropometric and BIA parameters for their use in multivariable linear regression models to predict total FM and VAT. Bland–Altman plots, Pearson correlation coefficients, Wilcoxon signed-rank tests and univariate linear regression models were applied. Results: 116 females with 35 ± 3 years and a body mass index of 25.1 ± 5.3 kg/m2 were included into the analysis. A multivariable model revealed weight (β = 0.516, p < 0.001), height (β = −0.223, p < 0.001) and hip circumference (β = 0.156, p = 0.003) as significantly associated with total FM measured by MRI. A additional multivariable model also showed a significant predictive value of FMBIA (β = 0.583, p < 0.001) for FM. In addition, waist circumference (β = 0.054, p < 0.001), weight (β = 0.016, p = 0.031) in one model and FMBIA (β = 0.026, p = 0.018) in another model were significantly associated with VAT quantified by MRI. However, deviations reached more than 5 kg for total FM and more than 1 kg for VAT. Conclusion: Anthropometric measurements and BIA show significant association with total FM and VAT. Advances in knowledge: As these measurements show significant deviations from the absolute measured values determined by MRI, MRI should be considered the gold-standard for quantification.

Background Uromodulin, a tissue-specific tubular glycoprotein, has recently emerged as a promising biomarker for kidney function and tubular integrity. However, the association of serum uromodulin (sUmod) with renal function decline is still unknown in an older general population. Methods We analysed the association of sUmod with the estimated glomerular filtration rate (eGFR) and albuminuria in 1075 participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study, ages 62–81 years, at baseline and prospectively after a mean follow-up time of 6.5 years (n = 605) using logistic and linear regression models as well as receiver operating characteristics (ROC) analyses. Results Cross-sectionally, sUmod was positively associated with eGFR (β = 0.31 ± 0.02 per higher standard deviation sUmod; P Conclusions Higher sUmod was inversely associated with progression to advanced kidney disease but does not provide additional predictive value for the development of CKD in elderly participants of the population-based KORA study.

ObjectivesUromodulin has been associated with arterial hypertension in genome-wide association studies, but data from clinical and preclinical studies are inconsistent. We here analyzed the association of serum uromodulin (sUmod) with arterial hypertension and vasoactive hormones in a population-based study.MethodsIn 1108 participants of the KORA F4 study aged 62-81 years, sUmod was measured and the association of sUmod with arterial hypertension was assessed using logistic regression models. The associations of sUmod with renin and aldosterone and with the vasoconstrictive prohormone C-terminal pro-endothelin-1 (CT-proET-1) were analyzed in 1079 participants and in 618 participants, respectively, using linear regression models.ResultsAfter multivariable adjustment including sex, age, eGFR, BMI, fasting glucose, current smoking, previous stroke and myocardial infarction, sUmod was inversely associated with arterial hypertension (OR 0.78; 95% CI 0.68-0.91; p = 0.001). SUmod was not significantly associated with renin and aldosterone after adjustment for sex, age and eGFR. However, sUmod was inversely associated with CT-proET-1 (β -0.19 ± 0.04; p < 0.001) after adjustment for sex, age, eGFR, BMI, arterial hypertension, fasting glucose, current smoking, previous stroke and myocardial infarction. The association with CT-proET-1 was stronger in participants with hypertension (β -0.22 ± 0.04) than in normotensive participants (β -0.13 ± 0.06; p for interaction hypertension = 0.003 in the model adjusted for hypertension).ConclusionsSUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of sUmod on blood pressure regulation.

Background and aims: Serum uromodulin, a novel biomarker of kidney function and tubular integrity, has been linked to cardiovascular events and total mortality in patients at high cardiovascular risk. Here, we analyze the association of serum uromodulin with cardiovascular morbidity and cardiovascular as well as total mortality in the population-based KORA F4 study stratified by sex.Methods: Baseline serum uromodulin was measured in 1079 participants of the KORA F4 study (age 62-81 years). Using multivariable adjusted Cox proportional hazards models, the associations of serum uromodulin with total mortality and cardiovascular mortality were analyzed after a median follow-up period of 8.6 years, and with non-fatal and fatal stroke and myocardial infarction/coronary death after a median follow-up time of 8.4 years.Results: Serum uromodulin was significantly inversely associated with total mortality (HR 0.65; 95% CI 0.53-0.79 per standard deviation of logarithmized serum uromodulin; p < 0.001) and cardiovascular mortality (HR 0.70; 95% CI 0.52-0.93) in men, but not in women (HR for all-cause mortality in women 0.98; 95% CI 0.77-1.25, HR for cardiovascular mortality 0.78; 95% CI 0.56-1.11) after adjustment for age, BMI, diabetes and eGFR. In addition, serum uromodulin was significantly inversely associated with incident stroke in men (HR 0.68; 95% CI 0.50-0.92), but not in women (HR 0.96; 95% CI 0.68-1.38) after multivariable adjustment. The association of serum uromodulin with incident myocardial infarction was attenuated and lost significance after multivariable adjustment in both sexes.Conclusions: Serum uromodulin is an independent biomarker for total and cardiovascular mortality in men from the general community aged 62 years or older.

Background Uromodulin is a kidney-specific glycoprotein synthesized in tubular cells of Henle’s loop exerting nephroprotective and immunomodulatory functions in the urinary tract. A small amount of uromodulin is also released into the systemic circulation, where its physiological role is unknown. Serum uromodulin (sUmod) has been associated with metabolic risk factors and with cardiovascular events and mortality, where these associations were partly stronger in men than in women. In this study, we investigated the associations of sUmod with biomarkers of subclinical inflammation in a population-based sample of women and men. Methods Associations of sUmod with 10 biomarkers of subclinical inflammation were assessed in 1065 participants of the Cooperative Health Research in the Region of Augsburg (KORA) F4 study aged 62–81 years using linear regression models adjusted for sex, age, body mass index, estimated glomerular filtration rate and diabetes. Analyses were performed in the total study sample and stratified by sex. Results sUmod was inversely associated with white blood cell count, high-sensitive C-reactive protein, interleukin (IL)-6, tumour necrosis factor-α, myeloperoxidase, superoxide dismutase-3, IL-1 receptor antagonist and IL-22 after multivariable adjustment and correction for multiple testing (P Conclusions sUmod was inversely associated with biomarkers of subclinical inflammation in older participants of the KORA F4 study. The association of sUmod with IL-6 differed between women and men. Future research should focus on whether the immunomodulatory properties of sUmod are one explanation for the association of sUmod with cardiovascular outcomes and mortality.

Objective The occurrence of pneumonia separates severe cases of COVID-19 from the majority of cases with mild disease. However, the factors determining whether or not pneumonia develops remain to be fully uncovered. We therefore explored the associations of several lifestyle factors with signs of pneumonia in COVID-19. Methods Between May and July 2020, we conducted an online survey of 201 adults in Germany who had recently gone through COVID-19, predominantly as outpatients. Of these, 165 had a PCR-based diagnosis and 36 had a retrospective diagnosis by antibody testing. The survey covered demographic information, eight lifestyle factors, comorbidities and medication use. We defined the main outcome as the presence vs. the absence of signs of pneumonia, represented by dyspnea, the requirement for oxygen therapy or intubation. Results Signs of pneumonia occurred in 39 of the 165 individuals with a PCR-based diagnosis of COVID-19 (23.6%). Among the lifestyle factors examined, only overweight/obesity was associated with signs of pneumonia (odds ratio 2.68 (1.29–5.59) p = 0.008). The observed association remained significant after multivariate adjustment, with BMI as a metric variable, and also after including the antibody-positive individuals into the analysis. Conclusions This exploratory study finds an association of overweight/obesity with signs of pneumonia in COVID-19. This finding suggests that a signal proportional to body fat mass, such as the hormone leptin, impairs the body’s ability to clear SARS-CoV-2 before pneumonia develops. This hypothesis concurs with previous work and should be investigated further to possibly reduce the proportion of severe cases of COVID-19.

Introduction Skeletal muscle contributes significantly to insulin sensitivity in humans. However, which non-invasive measurement best reflects this contribution remains unknown. Consequently, this paper compares morphologic and functional measurements. Research methods and design We conducted a cross-sectional analysis of 144 premenopausal women enrolled in the “Prediction, Prevention, and Sub-classification of Type 2 Diabetes” (PPSDiab) cohort study. For the analysis, we quantified insulin sensitivity by oral glucose tolerance testing and, in a subgroup of 30 women, euglycemic clamp. To assess skeletal muscle, we measured volume by magnetic resonance imaging, intramyocellular lipid content by magnetic resonance spectroscopy, and physical fitness by cardiopulmonary exercise testing. Results The mean age of the cohort was 35.7 ± 4.1 years and 94 participants (65%) had a history of gestational diabetes mellitus. Of the morphologic and functional muscle parameters, the maximum workload achieved during cardiopulmonary exercise testing associated most closely with insulin sensitivity (standardized beta = 0.39; p < .001). Peak oxygen uptake also demonstrated significant associations, whereas muscle volume and intramyocellular lipid content displayed none. Conclusion Functional measurements provided a better assessment of the muscular contribution to insulin sensitivity than morphologic measurements in premenopausal women. In particular, exercise testing rendered an easy and cost-effective method applicable in clinical settings and other human studies.

Background High-fat diets (HFDs) have been linked to low-grade inflammation and insulin resistance. Objective The main purpose of the present study was to assess whether acute overfeeding with an HFD affects insulin sensitivity, gut barrier function, and fecal microbiota in humans. Methods In a prospective intervention study, 24 healthy men [mean ± SD: age 23.0 ± 2.8 y, body mass index (in kg/m2) 23.0 ± 2.1] received an HFD (48% of energy from fat) with an additional 1000 kcal/d (as whipping cream) above their calculated energy expenditure for 7 d. Insulin sensitivity (hyperinsulinemic euglycemic clamp), gut permeability (sugar and polyethylene glycol absorption tests, plasma zonulin), and gut microbiota profiles (high-throughput 16S rRNA gene sequencing) were assessed before and after overfeeding, and 14 d after intervention. Additionally, inflammation markers such as high-sensitivity C-reactive protein, lipopolysaccharide-binding protein, leptin, high-molecular-weight adiponectin, calprotectin, regulated on activation normal, T cell expressed and secreted (RANTES), and monocyte chemoattractant protein-1 were measured in plasma by ELISA. Finally, lipid parameters were analyzed in serum by a laboratory service. Results Although participants gained 0.9 ± 0.6 kg (P < 0.001) body weight, overnutrition was not associated with a significant change in insulin sensitivity (M value and glucose disposal). Overfeeding for 7 d resulted in elevated serum total (10.2%), LDL (14.6%) and HDL (14.8%) cholesterol concentrations (P < 0.01). In contrast, fasting plasma triglyceride significantly declined (29.3%) during overfeeding (P < 0.001). In addition, there were no significant changes in inflammatory markers. Urine excretion of 4 sugars and polyethylene glycol, used as a proxy for gut permeability, and plasma concentration of zonulin, a marker of paracellular gut permeability, were unchanged. Moreover, overfeeding was not associated with consistent changes in gut microbiota profiles, but marked alterations were observed in a subgroup of 6 individuals. Conclusions Our findings suggest that short-term overfeeding with an HFD does not significantly impair insulin sensitivity and gut permeability in normal-weight healthy men, and that changes in dominant communities of fecal bacteria occur only in certain individuals. The study was registered in the German Clinical Trial Register as DRKS00006211.

Objective Growth hormone (GH) nadir (GHnadir) during oral glucose tolerance test (OGTT) is an important tool in diagnosing acromegaly, but data evaluating the need to adjust cut-offs to biological variables utilizing today's assay methods are scarce. We therefore investigated large cohorts of healthy subjects of both sexes to define normal GHnadir concentrations for a modern, sensitive, 22 kD-GH-specific assay. Design Multicenter study with prospective and retrospective cohorts (525 healthy adults: 405 females and 120 males). Methods GH concentrations were measured by the IDS-iSYS immunoassay after oral application of 75 g glucose. Results GHnadir concentrations (µg/L) were significantly higher in lean and normal weight subjects (group A) compared to overweight and obese subjects (group B); (males (M): A vs B, mean: 0.124 vs 0.065, P = 0.0317; premenopausal females without estradiol-containing OC (OC-EE) (FPRE): A vs B, mean: 0.179 vs 0.092, P POST): A vs B, mean: 0.173 vs 0.078, P nadir. However, premenopausal females on OC-EE (FPREOC) exhibited significantly higher GHnadir compared to all other groups (all P nadir in FPREOC (A vs B, mean: 0.624 vs 0.274, P = 0.1228). Conclusions BMI, sex and OC-EE intake are the major determinants for the GHnadir during OGTT in healthy adults. Using a modern sensitive GH assay, GHnadir concentrations in healthy subjects are distinctly lower than cut-offs used in previous guidelines for diagnosis and monitoring of acromegaly.

To study the possibility that certain components of eukaryotic plasma membranes are released under certain (patho)physiological conditions, a chip-based sensor was developed for the detection of cell surface proteins, which are anchored at the outer leaflet of eukaryotic plasma membranes by a covalently attached glycolipid, exclusively, and might be prone to spontaneous or regulated release on the basis of their amphiphilic character. For this, unprocessed, full-length glycosylphosphatidylinositol-anchored proteins (GPI-AP), together with associated phospholipids, were specifically captured and detected by a chip- and microfluidic channel-based sensor, leading to changes in phase and amplitude of surface acoustic waves (SAW) propagating over the chip surface. Unprocessed GPI-AP in complex with lipids were found to be released from rat adipocyte plasma membranes immobilized on the chip, which was dependent on the flow rate and composition of the buffer stream. The complexes were identified in the incubation medium of primary rat adipocytes, in correlation to the cell size, and in rat as well as human serum. With rats, the measured changes in SAW phase shift, reflecting specific mass/size or amount of the unprocessed GPI-AP in complex with lipids, and SAW amplitude, reflecting their viscoelasticity, enabled the differentiation between the lean and obese (high-fat diet) state, and the normal (Wistar) and hyperinsulinemic (Zucker fatty) as well as hyperinsulinemic hyperglycemic (Zucker diabetic fatty) state. Thus chip-based sensing for complexes of unprocessed GPI-AP and lipids reveals the inherently labile anchorage of GPI-AP at plasma membranes and their susceptibility for release in response to (intrinsic/extrinsic) cues of metabolic relevance and may, therefore, be useful for monitoring of (pre-)diabetic disease states.

Background Gestational diabetes mellitus (GDM) is the most common complication during pregnancy and is associated with an increased risk for the development of cardiometabolic diseases. Behavioral interventions can reduce this risk, but current solutions insufficiently address the requirements for such a program. The systematic development of a scalable mobile health (mHealth) promotion program for mothers during the first years post-GDM may contribute to solving this problem. Objective The aim of this project was to systematically plan and develop a theory- and evidence-based mHealth intervention to change cardiometabolic risk behaviors in women during the first 5 years post-GDM that meets women’s expected standards of commercial health apps. Methods The intervention mapping steps 1 to 4 structured the systematic planning and development of the mHealth program described in this paper. Steps 1 and 2 led to a theory- and evidence-based logic model of change for cardiometabolic health. Based on this model, the prevention program was designed (step 3) and produced (step 4) in cooperation with industrial partners to ensure a high technological standard of the resulting smartphone app for the iPhone (Apple Inc). Step 4 included a user study with women during the first 5 years post-GDM once a beta version of the app (“TRIANGLE”) was available. The user study comprised 2 test rounds of 1 week (n=5) and 4 weeks (n=6), respectively. The tests included validated questionnaires on user acceptance, user logs, and think-alouds with semistructured interviews. Results The novel TRIANGLE app is among the first self-paced smartphone apps for individual habit change in the 3 lifestyle areas of physical activity, nutrition, and psychosocial well-being. The 3 core features—a challenge system, human coaching, and a library—address 11 behavioral determinants with 39 behavior change methods to support lifestyle changes. Participants in the user study showed a high acceptance, high perceived quality, and high perceived impact of the TRIANGLE app on their health behaviors. Participants tested the app regularly, used it intuitively, and suggested improvements. We then adapted the TRIANGLE app according to the insights from the user study before the full TRIANGLE program production. Conclusions The intervention mapping approach was feasible to plan and develop an innovative and scalable smartphone solution for women during the first 5 years post-GDM. The resulting TRIANGLE intervention has the potential to support behavior change for cardiometabolic disease prevention. However, the app needs further refinement and testing in clinical trials. Intervention mapping steps 5 (implementation plan) and 6 (evaluation plan) may support the integration of the TRIANGLE intervention into routine care. Trial Registration German Clinical Trials Register DRKS00012736; https://www.drks.de/DRKS00012736

Correction for ‘Elucidating the formation and active state of Cu co-catalysts for photocatalytic hydrogen evolution’ by Jasmin S. Schubert et al., J. Mater. Chem. A, 2021, DOI: 10.1039/d1ta05561e.

To study the possibility that components of eukaryotic plasma membranes are released in spontaneous or controlled fashion, a chip-based sensor was developed for complete glycosylphosphatidylinositol-anchored proteins (GPI-AP), which may form together with (phospho)lipids so far unknown (non-vesicular) extracellular complexes (GLEC). The sensor relies on changes in phase shift and amplitude of surface acoustic waves propagating over the chip surface upon specific capturing of the GPI-AP and detection of associated phospholipids and renders isolation of the labile GLEC unnecessary. GLEC were found to be released from isolated rat adipocyte plasma membranes immobilized on the chip, dependent on the flow rate and composition of the buffer stream. Moreover, incubation medium of isolated adipocytes and serum of rats are sources for GLEC which enables their differentiation according to cell size and genotype or body weight, respectively, as well as human serum.