German Center for Diabetes Research

Mastering emotion regulation is crucial for social skills and mental health. Hormonal fluctuations, particularly in estradiol (E2) levels across the menstrual cycle, significantly impact emotion processing. E2 is known to influence emotion regulation, mental health, and the plasticity of limbic and striatal regions, which are involved in emotion processing and are rich in E2 receptors. Although research indicates that E2 levels may impact gray matter volume (GMV) of limbic and striatal areas, sufficient causal evidence is missing so far. Furthermore, because of the additional fluctuations of progesterone across the menstrual cycle, the sole impact of E2 on brain volume has been difficult to disentangle. To isolate the effects of E2 from other fluctuating sex hormones, we used a randomized, placebo-controlled, double-blind, crossover design and administered oral E2 to 27 naturally cycling females during their early follicular phase (low endogenous sex hormone levels). We analyzed emotion regulation strategies and E2 levels to assess their impact on regional GMV. Our data showed that a rapid increase of E2 was negatively associated with right striatal GMV. Moreover, greater use of reappraisal was associated with reduced GMV of the right striatum. Rapidly increased E2 did not influence GMV of other limbic regions. These results highlight that rapid increases in E2 and individual differences in emotion regulation dynamically modulate GMV. This offers important implications for female mental and brain health associated with hormonal fluctuations. Considering female endocrine profiles improves hormone-informed health care and therefore supports individualized medicine.

Abstract Heart weight (HW) is a critical parameter in cardiology and mouse research, commonly normalized to body weight (BW) or tibia length (TL) to account for size differences. Ratio-based normalization, however, assumes strict proportionality between variables, an assumption that is rarely tested and may bias group comparisons. We analysed HW, BW, and TL measurements from over 25,000 C57BL/6N wildtype mice generated by the International Mouse Phenotyping Consortium. Sex- and age-stratified analyses were combined with simulation-based modelling to evaluate empirical scaling relationships and the statistical behaviour of ratio-based normalization. Across all age and sex groups, correlations between HW, BW, and TL were negligible to weak, indicating substantial deviations from proportionality. Simulations demonstrated that ratio-based normalization can generate misleading results, including spurious or reversed group differences, when proportionality assumptions are violated. Ratios were consistent with linear and allometric models only under strictly proportional conditions, characterized by regression lines passing through the origin. Linear models with covariate adjustment and allometric scaling provide more robust and biologically meaningful frameworks for organ weight analysis. Ratio-based normalization should be avoided unless key mathematical assumptions are met.

Unimolecular triagonists drive substantial weight loss in patients with obesity by engaging the glucagon-like peptide 1 receptor (GLP-1R) and glucose dependent insulinotropic polypeptide receptor (GIPR) to reduce food intake (FI) and the hepatic glucagon receptor (GcgR) to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects, including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R mono-agonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. We used an adeno-associated virus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. Agonism of the ectopic GLP-1R with either semaglutide, a cAMP biased GLP-1R analogue (NNC5840), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to peptide agonist treatment alone. This represents a novel mechanism for achieving poly-pharmacology to treat obesity.

Negative affect is a key factor in Alcohol Use Disorder (AUD) associated with craving and relapse risk that is insufficiently treated by approved medications. Cannabidiol (CBD) has shown promising effects on negative affect, indicating its potential for addressing the neurocircuitry underlying negative affect in AUD. This study investigates CBD's effects on neural response to negative emotional stimuli and subjective alcohol craving in individuals with AUD. We conducted the first neuroimaging study investigating CBD's effects on neural responses to negative emotional stimuli and craving in AUD. The study was designed as two armed, 1:1 randomized, double blind, parallel group neuroimaging trial, enrolled N = 28 individuals with AUD. It compared the effects of 800mg oral CBD versus matched Placebo (PLC) on blood oxygenated level dependent (BOLD) response in the amygdala during a validated emotion processing task and explored associations with CBD plasma levels and subjective alcohol craving. CBD versus PLC attenuated bilateral amygdala reactivity to angry and fearful faces (pFWE <.05, small volume corrected), while CBD showed no effect on amygdala activation during the presentation of neutral shape stimuli. Amygdala response to negative emotional stimuli correlated positively with the extent of subjective alcohol craving (rLeft Amygdala =.52, pFDR =.01; rRight Amygdala =.52, pFDR =.01) and negatively with CBD plasma levels (rLeft Amygdala = -.68, pFDR = 0.002; rRight Amygdala = -.65, pFDR = 0.002). In summary, CBD's effects on amygdala reactivity to negative emotional stimuli in individuals with AUD support CBD's potential for modulating emotion-processing circuits in AUD and CBD's treatment potential for craving and relapse driven by negative affective states.

Pleural mesothelioma (PM) is a rare, asbestos-linked cancer with a long asymptomatic latency, delaying diagnosis and limiting treatment options. Identifying blood‐based biomarkers that signal disease before symptoms onset could improve surveillance of at‐risk individuals. In our work, we conducted a prospective proteomic study of pre-diagnostic serum from 21 PM cases (< 5 years before diagnosis) and 21 asbestos‐exposed controls in the EPIC cohort using SWATH‐MS, followed by ELISA validation. Findings were tested in an independent MoMar cohort of 32 pre‐diagnostic plasma samples (< 1 year before diagnosis) and 32 matched controls. SWATH-MS identified 12 differentially expressed proteins (nominal p < 0.05, fold change > 1.3 or < 0.75). Transferrin and complement C4A were elevated, while beta‐2‐microglobulin and dermcidin were reduced in pre‐diagnostic cases. ELISA confirmed a borderline significant rise in beta‐2‐microglobulin within two years of diagnosis in EPIC. Calretinin and mesothelin were also detected in both cohorts, with the five‐marker panel achieving an AUC of 0.91 (p = 0.001) in MoMar but not reaching significance in EPIC (AUC = 0.88, p = 0.17). Integrating novel proteomic biomarker candidates with established markers enhances early PM detection in high-risk populations. Larger, multi‐cohort validation is warranted to refine this biomarker panel for clinical surveillance.

Abstract Aims Gestational diabetes mellitus (GDM) is the most common pregnancy-related medical complication. GDM is linked to aberrant immune responses in both mothers and offsprings, specifically, the subsequent development of inflammatory diseases. Whereas prior research has focused on specific immune cell subsets, a comprehensive overview of the impacts of GDM on maternal and fetal immune landscape is lacking. Here, we aim to comprehensively decipher how GDM modulates various immune cell populations in mothers and offsprings. Methods A prospective, longitudinal case-control study was carried out. Maternal blood from GDM-affected (GDM, n=18) and non-GDM-affected (Ctrl, n=21) mothers were collected at ante-(36-38 weeks of gestation) and post-partum (6-8 weeks post-partum) timepoints. Cord blood from GDM (n=7) and Ctrl (n=11) pregnancies were collected upon C-section. They were analyzed with the state-of-the-art cytometry by time of flight (CyTOF) with a 40-marker panel. Additionally, a publicly available RNA-seq dataset for cord blood mononuclear cells was re-analyzed to confirm results from CyTOF experiments. Results Compared to Ctrl, GDM was associated with more activated maternal T cell subsets ante-partum, including increased CD45RO + and Ki67 + CD4 + T cell populations, which reverted post-partum. GDM-affected maternal innate lymphoid cell (ILC) also exhibited increased granzyme B production ante-partum. On the other hand, in GDM-impacted cord blood, fetal T and B cells were more activated, displaying less naïve and more effector phenotypes, further supported by RNA-seq analyses. Conclusions Our comprehensive analyses revealed that GDM is linked to profound changes in the immune landscapes of the mothers (ante-/post-partum) and foetuses (at birth), casting novel insights towards GDM pathophysiology. Longitudinal immune profiling might be warranted for early detection and stratification of risk, and development of targeted interventions to prevent inflammatory disorders in GDM mothers and their offspring. Research in context What is already known about this subject? The maternal and intrauterine environments are important contributors to long-term health outcomes of mothers and offsprings . Some maternal and fetal immunity changes have been observed in gestational diabetes mellitus (GDM)-affected pregnancies . GDM is associated with increased risk of later-life metabolic and inflammatory diseases in mothers as well as offsprings . What is the key question? What are the longitudinal alterations in maternal and fetal immune landscapes in GDM-affected pregnancies? What are the new findings? High-dimensional immune profiling provided the most comprehensive overview of alterations in maternal and fetal immune landscapes associated with GDM . GDM is associated with skewing of maternal CD4 + T cell and ILC towards activated phenotypes ante-partum . GDM is linked to more activated fetal T and B cell profiles . How might this impact on clinical practice in the foreseeable future? Understanding the complex alterations in the maternal and fetal immune landscape in GDM-affected pregnancy provides insights into the long-term impacts of GDM on the mother and offspring .

Type 2 diabetes (T2D) is a chronic disease currently affecting around 500 million people worldwide with often severe health consequences. Yet, histopathological analyses are still inadequate to infer the glycaemic state of a person based on morphological alterations linked to impaired insulin secretion and β-cell failure in T2D. Giga-pixel microscopy can capture subtle morphological changes, but data complexity exceeds human analysis capabilities. In response, we generate a dataset of pancreas whole-slide images from living donors with multiple chromogenic and multiplex immunofluorescence stainings and train deep learning models to predict the T2D status. Using explainable AI, we make the learned relationships interpretable, quantify them as biomarkers, and assess their association with T2D. Remarkably, the highest prediction performance is achieved by simultaneously focusing on islet α- and δ-cells and neuronal axons, alongside subtle pancreatic alterations in T2D donors such as larger adipocyte clusters, altered islet-adipocyte proximity and smaller islets. This data-driven approach provides a foundation for future research into relevant diagnostic and therapeutic targets, refining several hypotheses regarding tissue alterations associated with T2D.

The relationship between childhood maltreatment (CM) and obesity is nuanced, and recent evidence suggests stronger associations between CM and obesity-related traits in females compared to males. This study aims to validate and extend these findings in a large sample from the German National Cohort (NAKO). The NAKO is a population-based cohort study including 204,744 adults. For the present analyses, 151,143 individuals (74,596 female) were included. CM was assessed using the Childhood Trauma Screener (CTS). From the CTS, an overall severity score (CTS sum score), a cumulative CM score (number of CM subtypes with at least moderate severity), and five CTS subtypes were considered as exposures. Obesity-related traits included anthropometric (height, weight, body mass index [BMI], waist circumference [WC]) and body fat markers (relative fat mass [rFM], subcutaneous [SAT], visceral adipose tissue [VAT]). Sex-stratified linear and logistic regression models were adjusted for age, education, and examination center to associate CTS-based scores with obesity-related traits. Associations of the CTS sum score with weight, BMI, WC, rFM, and SAT were stronger in females compared to males, while similar associations were observed for VAT. In both sexes, most obesity-related traits exhibited dose-response relationships with increasing numbers of CM subtypes. Compared to unexposed females, females with exposure to ≥3 CM subtypes had a higher risk for obesity (i.e., BMI ≥ 30 kg/m2; OR = 1.56; 95% CI: 1.43, 1.71) and high WC (i.e., WC ≥ 88 cm; OR = 1.39; 95% CI: 1.29, 1.50). In males, exposure to ≥3 CM subtypes was also associated with increased obesity risk (OR = 1.51; 95% CI: 1.32, 1.72) and high WC (i.e., WC ≥ 102 cm; OR = 1.31; 95% CI: 1.18, 1.44). Physical and emotional abuse exhibited the strongest average associations and were associated with the most outcomes. Associations of CM exposure with adult anthropometric and body fat markers are stronger in females compared to males.