Objective: To evaluate whether the efficacy and safety of finerenone varied by baseline hemoglobin A1c (HbA1c) levels, a proxy of glycemic control, and diabetes duration in people with type 1 diabetes and chronic kidney disease (CKD). Research Design and Methods: Adults with type 1 diabetes, urinary albumin-to-creatinine ratio (UACR) 200−<5000 mg/g and estimated glomerular filtration rate (eGFR) 25−<90 mL/min/1.73 m2 were randomized (1:1) to finerenone or placebo. UACR change from baseline over 6 months by baseline HbA1c and diabetes duration was analyzed. Results: Baseline HbA1c was available for 240/242 participants; mean (SD) HbA1c, diabetes duration, and eGFR were 7.6% (1.1; 60 [12] mmol/mol), 32.0 (14.2) years, and 58.9 (19.2) mL/min/1.73 m2, respectively. At 6 months, HbA1c (95% CI) remained unchanged (finerenone: +0.03% [–0.14, 0.20]; placebo: 0.00% [–0.12, 0.11]; between-group difference +0.04% [–0.17, 0.24]; P=0.74). Over 6 months, median UACR decreased from 574.6 to 373.5 mg/g with finerenone and from 506.4 to 475.6 mg/g with placebo, corresponding to a –25% placebo-corrected change (95% CI –35, –13; P=0.0001). Treatment effects were consistent across HbA1c tertiles (<7.1%, ≥7.1%−≤8.1%, and >8.1%), with placebo-corrected UACR changes (95% CI) of –17% (–40, 13), –18% (–39, 10), and –37% (–55, –13), respectively (P interaction=0.41). Effects were similarly consistent across diabetes duration tertiles (P interaction=0.70). Overall safety and incidence of hyperkalemia were similar across HbA1c tertiles. Conclusions: In adults with type 1 diabetes and CKD, finerenone reduced UACR and was well-tolerated irrespective of HbA1c levels or diabetes duration.

The FAIR principles guide data stewardship towards maximizing the value of scientific data while offering a high level of flexibility to accommodate differences in standards and scientific practices. Research communities have developed and implemented domain-specific workflows to make their data FAIR. This work compares the implementation of two externally developed structured FAIRification workflows-a generic workflow and a domain-specific workflow- using the example of metadata captured in diabetes research in Germany and applying the FAIR data maturity model developed by the Research Data Alliance. Interestingly, the implementation of both workflows required similar resources and led us to achieve the same FAIRness rating. We therefore conclude that the adaptations made in the FAIRification workflow for health research data improve efficiency but do not necessarily lead to higher FAIRness scores when applied to core data sets. Based on the results of our workflow comparison, we identified a list of requirements that should be met for the FAIRification of a core data set regardless of the workflow employed. In the future, FAIR data strategies and infrastructure should be planned and implemented as early as possible in the FAIRification journey. It is anticipated that this comparative analysis will help establish standard operating procedures for the FAIRification of core data sets for health studies.

ZUSAMMENFASSUNGSchwangerschaften mit präkonzeptionell bekanntem Typ-1- und Typ-2-Diabetes sind Hochrisiko-Schwangerschaften und bedürfen einer interdisziplinären Betreuung. Kinder diabetischer Mütter haben ein im Mittel 1,5- bis 3-fach erhöhtes Risiko für angeborene Fehlbildungen, Frühgeburtlichkeit, Hypertrophie, Atemstörungen, Plexusparese und Asphyxie. Das Risiko für Totgeburt und Tod in den ersten 7 Lebenstagen ist bei prägravidem Diabetes erhöht. Die mit Abstand häufigste Komplikation bei Neugeborenen diabetischer Mütter ist die postnatale Hypoglykämie. Diabetesassoziierte Begleiterkrankungen und maternale Adipositas sind unabhängige Risikofaktoren für Schwangerschaftskomplikationen und ein ungünstiges fetales Outcome. Für die Blutglukoseeinstellung während der Schwangerschaft wurde ein klarer Zusammenhang höherer Werte mit ungünstigen fetalen und maternalen Ereignissen gezeigt. Analoginsuline sind mittlerweile die Insuline der Wahl. Darüber hinaus konnte eine Überlegenheit einer CGM-Versorgung während der Schwangerschaft gegenüber der konventionellen Blutglukosemessung gezeigt werden. Die Rate an Sektiones ist bei Frauen mit Diabetes nach wie vor gegenüber der Grundgesamtheit in der Perinatalstatistik deutlich erhöht. Evidenzbasierte Erkenntnisse zum intrapartalen Vorgehen liegen nicht vor. Die Einstellungsziele orientieren sich daher an den während der Schwangerschaft geltenden Zielen.

Prediabetes and type 2 diabetes (T2D) are metabolic disorders characterized by insulin resistance and β-cell dysfunction. To understand the molecular mechanisms driving the transition from prediabetes to T2D, we performed a longitudinal proteogenomic analysis on 458 participants from the Prediabetes Lifestyle Intervention Study (PLIS). We identified 185 plasma proteins to be differentially expressed between conditions, 36 of which predict future T2D-onset. Integrating genetic data from 321 individuals, we generated a genome-wide protein quantitative trait loci (pQTL) map, identifying 86 differential and 700 shared cis-pQTLs between prediabetes and T2D. Mediation analysis revealed 60 putative causal links connecting allele-driven plasma protein expression to clinical traits, identifying body fat distribution, insulin resistance, and β-cell function as central drivers of pathogenesis. Collectively, these findings highlight specific proteins underlying disease progression and substantiate the view that prediabetes and T2D are not distinct conditions, but rather stages on a unified metabolic spectrum. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT01947595 ### Funding Statement Archit Singh, Dr Mauro Tutino and Dr Ozvan Bocher have received funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No 101017802 (OPTOMICS). PLIS and this post hoc analysis were supported by the German Center for Diabetes Research, which is funded by the German Federal Ministry for Education and Research and the German states where its partner institutions are located (01GI0925). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the ethics committee of the University Clinic of Tübingen (Tübingen, 55/2012; ClinicalTrials.gov registration: [NCT01947595][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01947595&atom=%2Fmedrxiv%2Fearly%2F2026%2F02%2F16%2F2026.02.13.26346161.atom

Introduction and Objective: Clinical sub-phenotypes of type 2 diabetes (T2D) have been identified and highly differ in their risk for complications. Yet, the reasons for this pleiotropic clinical presentation remain largely unknown. One of the factors associated with obesity, insulin resistance and T2D is the human gut microbiota. However, most studies rely on stool samples to study the gut microbiota, whereas the main site for nutrient absorption and incretin production is the small intestine which is scarcely explored. Here, we close this knowledge gap and investigate the human small intestinal microbiota an its association with T2D sub-phenotypes. Methods: We collected jejunal content fluids from 627 individuals undergoing bariatric surgery with metabolic phenotyping. Microbial DNA was extracted using an optimized protocol for low-abundance biomasses to recover three dominant microbial kingdoms: bacteria, fungi, and archaea. Microbe quantification was performed by digital PCR, with an accuracy of one gene copy. Results: Absolute quantification of microbial DNA revealed a bacterial range of < 2 to 56 x 106 Genome Copies (GC)/mL (median= 1023, [IQR= 3641]), 0 to 6343 GC/mL (median= 1, [4]) for fungi and 0 to 2387 GC/mL for archaea (median= 0, [0]). We found that Individuals with T2D had a significant higher bacterial load compared to those without T2D (median= 1410, [IQR= 9228] vs 902, [2416], p=0.0014). In association with the clinical sub-phenotypes, high-risk diabetes cluster (severe insulin resistant diabetes) had significantly higher bacterial DNA abundance vs the mild obesity-related cluster (median = 9908, [IQR=121163] vs 13623 [5578], p= 0.039). We did not observe associations of the clinical T2D clusters with archaea and fungi abundance. Conclusion: These are the first large-scale human jejunal microbiome data, showing increased bacterial colonization of the small intestine in individuals with T2D and specifically from a high-risk sub-phenotype. Disclosure A. Makour: None. S. Gschwendtner: None. M. Schloter: None. A.L. Birkenfeld: None. B. Diel: None. F. Pattou: Advisory Panel; Current; Lilly. Consultant; Current; Novo Nordisk. Advisory Panel; Current; Boehringer Ingelheim International GmbH. Consultant; Ended; Medtronic. Consultant; Current; Ethicon, Inc., ADOCIA. R.J. von Schwartzenberg: None.

Introduction and Objective: Brain insulin sensitivity plays a central role in coordinating whole-body metabolism. In humans, reduced brain insulin responsiveness is linked to weight gain, visceral adiposity, and impaired metabolic control. Experimental work shows that intranasal insulin (INI) delivers insulin to the brain with minimal systemic effects. Building on this concept, we aimed to enhance central insulin signaling in humans through long-term INI treatment. We hypothesized that INI treatment enhances brain insulin sensitivity while leading to a more favorable body fat distribution. Methods: In this randomized, controlled, blinded study, 39 healthy individuals (age 60.6 ± 7.4 years; 67% women) were randomized to daily INI (160 IU, n=19) or placebo (PLA, n=20) spray treatment for 8 weeks. Before (t=0) and after (t=8wk) the treatment period, individuals were deeply phenotyped, including whole-body MRI for body fat quantification and functional MRI combined with acute INI to assess brain insulin sensitivity. Data are displayed as median ± 95% CI. Results: Body mass index (BMI) was similar between groups at baseline (t=0, INI: 28.2 ± 2.3 vs PLA 29.7 ± 3.1 kg/m2; p=0.51) and decreased only in the INI group (t=8wk, BMI: INI 27.3 ± 2.3, vs t=0; p=0.046, PLA: 30.2 ± 3.0 kg/m2, vs t=0; p=0.14). This was paralleled by a reduction in subcutaneous adipose tissue in the INI but not in the PLA group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI 13.3 ± 2.2 L vs 12.5 ± 2.3 L; p=0.03; PLA 14.0 ± 2.7 L vs 15.4 ± 3.0 L; p=0.93). Hypothalamic insulin sensitivity increased in the INI but not in the placebo group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI p=0.007; PLA p>0.99). Conclusion: Chronic INI treatment improves hypothalamic insulin sensitivity in adults with overweight or obesity, and this effect is accompanied by a reduction in BMI and subcutaneous fat. These findings highlight brain insulin responsiveness as a therapeutic target to counteract elevated body weight and body fat content. Disclosure L. Sandforth: None. R. Veit: None. C. Dannecker: None. R.J. von Schwartzenberg: None. A. Vosseler: None. M. Hallschmid: None. R. Wagner: Advisory Panel; Current; Sanofi. Speaker's Bureau; Ended; Daiichi Sankyo, Novo Nordisk. A.L. Birkenfeld: None. P. Hubert: None. A. Fritsche: None. M. Heni: Advisory Panel; Ended; Chiesi USA, Inc. Speaker's Bureau; Ended; Chiesi USA, Inc. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH, AstraZeneca, Lilly, Novartis AG, Novo Nordisk, Bayer AG. S. Kullmann: None.

AIMS:The epithelial sodium channel ENaC consists of the subunits α, β, and γ and is activated at an individual channel level by proteolytic processing. Murine γENaC contains a distal polybasic tract 186RKRK mediating proteolytic ENaC activation by serine proteases in vitro. The relevance of ENaC activation at this cleavage site for sodium homeostasis in vivo is unknown. METHODS:Mice were generated carrying a mutation of the distal polybasic tract (RKRK186QQQQ or γENaCki/ki) using CRISP/Cas9. Sodium homeostasis and proteolytic processing of γENaC were investigated under a low sodium diet, pharmacological ENaC blockade, and induction of nephrotic syndrome. RESULTS:Under control conditions, the response to bolus amiloride was reduced in γENaCki/ki mice compared to γENaCwt/wt mice. Under a low sodium diet for 4 days, urinary sodium excretion was similarly lowered in both genotypes; however, γENaCki/ki mice required significantly higher plasma aldosterone concentrations. Both genotypes were similarly tolerant to amiloride exposure for 4 days and developed similar sodium retention and body weight gain after induction of nephrotic syndrome. Proteolytic processing of γENaC leading to increased expression of distally cleaved γENaC at ~54 kDa was stimulated in both γENaCwt/wt and γENaCki/ki mice under all interventions without an appreciable difference in the migration pattern. CONCLUSION:Mice harboring the RKRK186QQQQ mutation of the distal polybasic tract develop hyperaldosteronism under a low sodium diet, pointing to the relevance of this tract for sodium preservation. However, proteolytical processing of γENaC in these mice appears to be compensated for by the involvement of other adjacent cleavage sites.

Importance:Heart failure (HF) is a common complication of type 2 diabetes (T2D). Oral semaglutide reduced the risk of major adverse cardiovascular (CV) events (MACE; comprising CV death, nonfatal myocardial infarction, or nonfatal stroke) in people with T2D in the SOUL trial, but the impact on HF outcomes in these participants is unknown. Objective:To evaluate the effect of oral semaglutide on HF events, MACE, and safety among participants with or without HF at baseline. Design, Setting, and Participants:This is a secondary analysis of the double-blind, placebo-controlled, event-driven, phase 3b SOUL randomized clinical trial, which was conducted at 444 centers in 33 countries. Participants were enrolled from June 17, 2019, to March 24, 2021, and had T2D and atherosclerotic CV disease and/or chronic kidney disease, stratified according to the presence or absence of HF history at baseline. Data were analyzed from December 2024 to August 2025. Intervention:Once-daily oral semaglutide or placebo in addition to standard of care. Main Outcomes and Measures:Prespecified composite HF outcome (time to first occurrence of HF hospitalization, urgent HF visit, or CV death). Results:Overall, 9650 participants (median [IQR] age, 66.0 [61.0-72.0] years; 2790 [28.9%] female) were randomized, with a mean (SD) follow-up of 47.5 (10.9) months. Of these participants, 2229 (23.1%) had HF history (991 [10.3%] with preserved ejection fraction, 592 [6.1%] with reduced ejection fraction, and 646 [6.7%] with unknown subtype). For participants with HF at baseline, the hazard ratio (HR) for risk of the composite HF outcome with oral semaglutide vs placebo was 0.78 (95% CI, 0.63-0.96) and was 1.01 (95% CI, 0.84-1.20) in those without HF at baseline (P for interaction = .06). Among participants with HF, the HR was 0.59 (95% CI, 0.39-0.86) in those with preserved ejection fraction and 0.98 (95% CI, 0.70-1.38) in those with reduced ejection fraction. There was no heterogeneity in the risk reduction of MACE with oral semaglutide in participants with HF history (HR, 0.83; 95% CI, 0.68-1.01) or without HF history (HR, 0.86; 95% CI, 0.75-0.98) (P for interaction = .77). Serious adverse event occurrence among participants with HF was similar with oral semaglutide (594 [53.8%]) and placebo (642 [57.1%]). Conclusions and Relevance:In this secondary analysis of the SOUL randomized clinical trial, among individuals with T2D, atherosclerotic CV disease, and/or chronic kidney disease, a reduction of HF events was observed with use of oral semaglutide compared with placebo in those with a history of HF, without increasing the risk of serious adverse events. These data support the potential benefit of oral semaglutide in reducing HF events in people with T2D and HF. Trial Registration:ClinicalTrials.gov Identifier: NCT03914326.

Affiliations 1 German Diabetes Foundation, Munich, Germany 2 Division of Endocrinology and Diabetology, University Obesity Centre Hamburg, University Hospital HamburgEppendorf, Germany 3 German Centre for Diabetes Research (DZD e. V.), Neuherberg, Germany 4 Department of Internal Medicine IV, Diabetology, Endocrinology, Nephrology, University Hospital Tübingen, Germany 5 Department of Internal Medicine I, Marienhospital, Stuttgart, Germany 6 Department of Internal Medicine I, University Hospital Bergmannsheil, Bochum, Germany 7 Department of Internal Medicine I, University Hospital RWTH, Aachen, Germany 8 Diabetes Centre Bochum-Hattingen, St.-Josef-Hospital, Ruhr-University, Bochum, Germany 9 MVZ Metabolic Medicine Leipzig, Leipzig, Germany 10 Department of Internal Medicine – Gastroenterology, Diabetology/Endocrinology and Nutritional Medicine, St. Josefkrankenhaus Heidelberg GmbH, Heidelberg, Germany Bibliography Exp Clin Endocrinol Diabetes DOI 10.1055/a-1624-3449 ISSN 0947-7349 © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

A joint statement by the Committee on Lipid Metabolism and the Heart and Diabetes Working Group of the German Diabetes Society (DDG), the Diabetes, Obesity, and Metabolism Section of the German Society of Endocrinology (DGE), the Heart and Diabetes Working Group of the German Cardiac Society (DGK), and the Heart-Hormones-Diabetes Joint Working Group of the DGK, DGE and DDG

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.

Updated global estimates confirm that a substantial fraction of cancers remains attributable to modifiable or preventable exposures. Yet many risk factors converge on shared physiological states (namely, dysglycaemia, hyperinsulinaemia, chronic inflammation and altered substrate flux) that might shape tumour initiation and progression.

This secondary analysis of a randomized clinical trial evaluates the effect of oral semaglutide on heart failure events, major adverse cardiovascular events, and safety among participants with or without heart failure at baseline. QuestionWhat are the effects of oral semaglutide on heart failure (HF) and other cardiovascular outcomes according to baseline HF status in people with type 2 diabetes?FindingsIn this secondary analysis of 9650 participants in the SOUL randomized clinical trial, a lower risk of composite HF outcome events was observed with oral semaglutide compared with placebo in participants with HF at baseline, while there was no effect in participants without baseline HF, with similar proportions of serious adverse events.MeaningThese data support that oral semaglutide may benefit people with type 2 diabetes and HF to reduce HF events. ImportanceHeart failure (HF) is a common complication of type 2 diabetes (T2D). Oral semaglutide reduced the risk of major adverse cardiovascular (CV) events (MACE; comprising CV death, nonfatal myocardial infarction, or nonfatal stroke) in people with T2D in the SOUL trial, but the impact on HF outcomes in these participants is unknown.ObjectiveTo evaluate the effect of oral semaglutide on HF events, MACE, and safety among participants with or without HF at baseline.Design, Setting, and ParticipantsThis is a secondary analysis of the double-blind, placebo-controlled, event-driven, phase 3b SOUL randomized clinical trial, which was conducted at 444 centers in 33 countries. Participants were enrolled from June 17, 2019, to March 24, 2021, and had T2D and atherosclerotic CV disease and/or chronic kidney disease, stratified according to the presence or absence of HF history at baseline. Data were analyzed from December 2024 to August 2025.InterventionOnce-daily oral semaglutide or placebo in addition to standard of care.Main Outcomes and MeasuresPrespecified composite HF outcome (time to first occurrence of HF hospitalization, urgent HF visit, or CV death).ResultsOverall, 9650 participants (median [IQR] age, 66.0 [61.0-72.0] years; 2790 [28.9%] female) were randomized, with a mean (SD) follow-up of 47.5 (10.9) months. Of these participants, 2229 (23.1%) had HF history (991 [10.3%] with preserved ejection fraction, 592 [6.1%] with reduced ejection fraction, and 646 [6.7%] with unknown subtype). For participants with HF at baseline, the hazard ratio (HR) for risk of the composite HF outcome with oral semaglutide vs placebo was 0.78 (95% CI, 0.63-0.96) and was 1.01 (95% CI, 0.84-1.20) in those without HF at baseline (P for interaction = .06). Among participants with HF, the HR was 0.59 (95% CI, 0.39-0.86) in those with preserved ejection fraction and 0.98 (95% CI, 0.70-1.38) in those with reduced ejection fraction. There was no heterogeneity in the risk reduction of MACE with oral semaglutide in participants with HF history (HR, 0.83; 95% CI, 0.68-1.01) or without HF history (HR, 0.86; 95% CI, 0.75-0.98) (P for interaction = .77). Serious adverse event occurrence among participants with HF was similar with oral semaglutide (594 [53.8%]) and placebo (642 [57.1%]).Conclusions and RelevanceIn this secondary analysis of the SOUL randomized clinical trial, among individuals with T2D, atherosclerotic CV disease, and/or chronic kidney disease, a reduction of HF events was observed with use of oral semaglutide compared with placebo in those with a history of HF, without increasing the risk of serious adverse events. These data support the potential benefit of oral semaglutide in reducing HF events in people with T2D and HF.Trial RegistrationClinicalTrials.gov Identifier: NCT03914326

Introduction and Objective: The nonsteroidal mineralocorticoid receptor antagonist finerenone has been reported to improve UACR in people with T1D and CKD. This prespecified analysis evaluated whether safety and efficacy of finerenone varied by baseline HbA1c levels and diabetes duration. Methods: In total, 242 adults with T1D, CKD (eGFR ≥25 to <90 mL/min/1.73 m2; UACR ≥200 to <5000 mg/g), and on stable ACEi/ARB therapy were randomized 1:1 to receive finerenone (10 or 20 mg per day) or matching placebo. The primary outcome was the relative change in UACR from baseline over 6 months. Results: Baseline HbA1c (mean ± SD: 7.6 ± 1.1%) was available for 240 (99%) FINE-ONE participants. At 6 months, HbA1c was unchanged in both treatment arms (change from baseline [95% CI]: finerenone 0.03% [-0.14, 0.20]; placebo 0% [-0.12, 0.11]; between-group difference 0.04% [-0.17, 0.24]; p=0.74). Participants were stratified by HbA1c tertiles: 1 (HbA1c <7.1%), 2 (HbA1c ≥7.1 to ≤8.1%), and 3 (HbA1c >8.1%). Across the 6-month trial duration, median UACR decreased from 574.6 to 373.5 mg/g with finerenone and from 506.4 to 475.6 mg/g with placebo, corresponding to a 25% (95% CI 35, 13) UACR reduction (p=0.0001). There was no heterogeneity in the treatment effect of finerenone on UACR across HbA1c tertiles 1, 2, and 3 (geometric mean [95% CI]: -17% [-40, 13], -18% [-39, 10], and -37% [-55, -13], respectively; p interaction = 0.41). When analyzed by diabetes duration, the reduction in UACR with finerenone vs placebo was also consistent across tertiles (<25 years, ≥25 to ≤38 years, and >38 years; p interaction = 0.70). Hyperkalemia was the most common adverse event. Safety was comparable across tertiles of HbA1c and diabetes duration. Conclusion: In adults with T1D and CKD, finerenone reduced UACR compared with placebo irrespective of baseline HbA1c levels or diabetes duration, and it was well tolerated. Disclosure P. Rossing: Advisory Panel; Ended; Abbott Diagnostics. Advisory Panel; Current; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Eli Lilly and Company. Consultant; Current; Lexicon Pharmaceuticals, Inc., Roche Pharmaceuticals. Consultant; Ended; Amgen Inc. H. Heerspink: Consultant; Current; AstraZeneca, Alnylam Pharmaceuticals, Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Dimerix, Eli Lilly and Company, Novo Nordisk, Novartis AG, Roche Pharmaceuticals. A.J. Amor: Speaker's Bureau; Ended; Lilly. Research Support; Ended; Novo Nordisk. A.L. Birkenfeld: None. L. Caramori: Consultant; Current; Bayer AG. Research Support; Ended; Bayer AG, Eli Lilly and Company. Research Support; Current; Boehringer Ingelheim International GmbH. Consultant; Current; Novo Nordisk. Other - Content reviewer; Current; UpToDate. D. Cherney: Consultant; Current; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK,. Research Support; Current; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Lexicon, Novo-Nordisk, Bayer. H.M. Colhoun: Research Support; Current; Diabetes UK, IQVIA Inc., Sanofi, JDRF, Chief Scientist Office. Research Support; Ended; Medical Research Council (UKRI). Other - Personal payment for consultancy (ENDED);Research support (ongoing); Current; Sanofi. Other - Advisory board member (ongoing); Support for attendance at meetings /conferences and travel; Current; Novo Nordisk. Other - Advisory panel member (ongoing);Stockholder (up to January 2025- ENDED); Current; Bayer AG. Other - Stockholder (ongoing);Institutional payment for consultancy (ongoing); Current; Roche Pharmaceuticals. P. Henrick Groop: Other - Lecture Fees; Current; Astellas Pharma Inc., AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim, Eli Lilly and Company, Elo Water, Medscape, MSD, Mundipharma, Nestlé, Novartis AG, Novo Nordisk, Sanofi. P. Fiorina: Board Member; Ended; A. Menarini Diagnostics, Novo Nordisk, AstraZeneca, Bristol-Myers Squibb Company. L. Ji: None. N. Jongs: Other - Travel Support; Current; AstraZeneca. C. Mathieu: Advisory Panel; Current; Abbott Diagnostics, Dexcom, Inc. Board Member; Current; European Association for the Study of Diabetes. Advisory Panel; Current; Novo Nordisk, Eli Lilly and Company, Sanofi, Vertex Pharmaceuticals Incorporated, Medtronic. U. Pagotto: Advisory Panel; Ended; Eli Lilly and Company. Speaker's Bureau; Ended; Eli Lilly and Company. Advisory Panel; Ended; Novo Nordisk. Speaker's Bureau; Ended; Novo Nordisk. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Rhythm Pharmaceuticals, Inc. Research Support; Current; Novo Nordisk. S. Rosas: Advisory Panel; Current; Bayer AG. Research Support; Ended; Bayer AG. Advisory Panel; Current; Novo Nordisk. Advisory Panel; Ended; Travere. E. Setola: Speaker's Bureau; Ended; Sanofi, Eli Lilly and Company. Advisory Panel; Ended; Novo Nordisk, Boehringer Ingelheim International GmbH. J. Skyler: Advisory Panel; Ended; AbbVie Inc. Consultant; Current; ADOCIA. Board Member; Current; Applied Therapeutics. Advisory Panel; Current; Avotres Inc., Bayer AG. Consultant; Current; Eli Lilly and Company. Advisory Panel; Current; Kriya Therapeutics. Consultant; Current; Novo Nordisk. Board Member; Current; SAB Biotherapeutics, Inc. Consultant; Current; Sanofi, Vertex Pharmaceuticals Incorporated. K. Tuttle: Consultant; Ended; Alnylam Pharmaceuticals, Inc. Consultant; Current; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Novo Nordisk, Lilly, ProKidney. Consultant; Ended; Roche Diabetes Care. Research Support; Ended; Travere. R. Lawatscheck: Employee; Current; Bayer AG. M. Brinker: Employee; Current; Bayer AG. Other - pending patent for finerenone for treatment of patients with CKD and T1D; Current; Bayer AG. Stock/Shareholder; Current; Bayer AG. J. jRussell: Employee; Current; Bayer PLC. P. Schloemerk: Employee; Current; Bayer AG. J.B. McGill: Consultant; Current; Bayer AG. Advisory Panel; Current; MannKind Corporation. Advisory Panel; Ended; Novo Nordisk, Abbott Diagnostics. Consultant; Ended; Pfizer Inc. Research Support; Ended; Lexicon Pharmaceuticals, Inc. Research Support; Current; Novo Nordisk A/S, Lilly, Viking Therapeutics, Diamyd, Cour Pharmaceutical. Funding Funding Bayer. FINE-ONE Trial registration number: NCT05901831

Introduction and Objective: The German Prediabetes Lifestyle Intervention Study (PLIS) demonstrated that weight loss-induced prediabetes remission is driven by improved insulin sensitivity and reduced visceral adipose tissue (VAT) mass. This analysis aims to investigate potential sex differences in these mechanisms, which remains underexplored. Methods: Of 908 PLIS participants with prediabetes who completed a 12-months lifestyle intervention, 298 achieved a clinically significant weight loss of ≥5%. Linear mixed models were used to compare within- and between-sex changes in body fat distribution (whole body MRI), insulin sensitivity (Matsuda index) and secretion (AUCc_pept0-30 divided by AUCglu0-30), and glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) from baseline to 12 months. Kaplan-Meier analyses evaluated the 9-year type 2 diabetes survival risk by sex. Results: Among those who reached weight loss targets, 69 females and 59 males achieved prediabetes remission. Both sexes showed similar reduction in overall fat mass (p=0.35) and VAT (p=0.99). Sex-specific differences included muscle insulin sensitivity, which increased in males only (0.019±0.014 AU in females [p=0.19] vs. 0.067±0.016 in males [p<0.0001], p=0.015), accompanied by greater improvements in maximal aerobic capacity (0.019±0.015 ml min kg−1 [p=0.020] vs. 0.067±0.016 [p<0.0001], p=0.019). In contrast, females showed enhanced insulin secretion (14.85±6.14 pmol mmol-1 [p=0.016] vs. -5.17±6.87 [p=0.45], p=0.014). At 12 months, which may be explained by significantly stronger GLP-1 (p=0.012) and GIP (p=0.007) responses during OGTT compared to males. Both sexes showed comparable 9-year diabetes prevention (p=0.51). Conclusion: Weight loss-induced prediabetes remission exhibits sex-specific pathways, with males uniquely increasing muscle insulin sensitivity paralleled by aerobic fitness and females enhancing β-cell function associated with improved incretin responses. Disclosure Y. Wang: None. L. Sandforth: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Echosens. N. Stefan: Speaker's Bureau; Current; AstraZeneca. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Ended; Lilly. Speaker's Bureau; Current; Lilly. Advisory Panel; Ended; Pfizer Inc., Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Ended; Madrigal Pharmaceuticals, Inc. Research Support; Ended; Sanofi. Speaker's Bureau; Current; Sanofi. A. Fritsche: None. A.L. Birkenfeld: None. Funding German Federal Ministry for Education and Research via the German Center for Diabetes Research

Background:In cohort studies, intake of insoluble cereal fiber is associated with multiple health benefits, including preserved cognitive functions. However, evidence from intervention studies is sparse. In the Optimal Fiber Trial (OptiFiT), lifestyle changes and supplementation with oat fiber in prediabetes patients improved glycemic metabolism and body composition, which could be linked to cognitive changes. Methods:In OptiFiT, 180 patients with impaired glucose tolerance received either an insoluble fiber supplement or a placebo for 2 years in a double-blind, randomized approach, and underwent a parallel 1-year complex lifestyle intervention program. Annual visits included metabolic, anthropometric, and cognitive assessments: Mini-Mental State Examination (MMSE), Verbal Learning Memory Test (VLMT), Regensburg Word Fluency Test (RWFT), Number Connection Test (NCT), Number Recall Test (NRT), and Rey-Osterrieth Complex Figure Test (RCFT). Group-wise comparisons were conducted both globally as well as stratified by age. Results:Cognitive functions only slightly improved-particularly in VLMT and RWFT-without major differences by group or age. At baseline, cognitive function measured by RCFT recall, VLMT, RWFT, and backwards NRT was inversely correlated with age, but not with HbA1c, fasting, or postprandial glucose levels. Conclusion:Beneficial effects of insoluble fiber and lifestyle intervention on glycemia might not translate into preserved cognitive capabilities in middle-to-higher aged patients with prediabetes in a 2-year intervention period. Long-term intervention studies in patients with both cognitive vulnerability and metabolic susceptibility are warranted. Such large RCTs should also corroborate putatively involved mechanisms in the epidemiologically assumed protection from cognitive decline. Clinical trial registration:Clinicaltrials.gov, identifier NCT01681173.

Impairments in peripheral glucose metabolism and reduced brain insulin sensitivity are linked to an increased risk of both metabolic and neurodegenerative diseases. Brain insulin resistance represents a shared pathological mechanism underlying these disorders. Notably, hippocampal insulin responsiveness declines with age and differs between men and women. This study aimed to identify clinically relevant metabolic predictors of hippocampal insulin sensitivity in the context of age and sex. In 260 non-diabetic participants (165 women, mean BMI 29.7 ± 6.2 kg/m2, mean age 44.2 ± 16.6 years), functional MRI was performed before and after intranasal insulin administration to assess hippocampal insulin response. Metabolic phenotyping comprised laboratory assessments including oral glucose tolerance tests, whole-body MRI and 1H-MRS. In addition, participants were assigned to high- and low-risk prediabetes clusters using the Tübingen risk cluster tool. Prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance and/or elevated HbA1c. We used linear regression models to select the most relevant predictors, including interactions with sex and age. Fasting plasma glucose levels predicted lower hippocampal insulin response with age independently of sex (estimate 0.533, p=0.016). Significant interactions were present between age, sex and body fat distribution (waist-to-hip ratio [WHR]: estimate 0.233, p=0.010; visceral adipose tissue [VAT]: estimate 0.007, p=0.013; intrahepatic lipid content [IHL]: estimate 0.003, p=0.010). In women, higher WHR, VAT and IHL were predictors of lower hippocampal insulin responsiveness with increasing age. These effects remained significant after adjusting for BMI. Postmenopausal women showed lower hippocampal insulin responsiveness with higher WHR and IHL (p<0.05), and women in high-risk Tübingen prediabetes clusters also showed lower hippocampal insulin responsiveness than men (sex × cluster type: estimate 0.39, p=0.02). The hippocampal insulin response did not correlate with hippocampal volume (p>0.05). Unhealthy body fat distribution was a sex-dependent predictor for decreased hippocampal insulin sensitivity with increasing age. Older women with high abdominal fat and/or those assigned to high-risk clusters were most vulnerable to impaired insulin responsiveness in the hippocampus. These findings may contribute to explaining sex differences in the development of type 2 diabetes and neurodegenerative diseases.

Human skeletal muscle is the principal site of insulin-stimulated glucose disposal and a major mediator of exercise-induced metabolic benefits, yet human models that preserve metabolic and exercise responsiveness remain limited. We generated primary human skeletal muscle organoids from donor-derived CD56+ myoblasts using a collagen-based extracellular matrix and serum-free IGF1-guided differentiation. The organoids formed aligned contractile tissues containing oxidative and glycolytic fiber type-like myotubes, displayed enhanced mitochondrial respiration, insulin-stimulated glucose uptake, and reproducible force generation. Electrical pulse stimulation induced AMPK activation, increased glucose utilization and lactate production, and upregulated canonical exercise-responsive genes including NR4A3 and PPARGC1A. Notably, transcriptional responses to in vitro exercise overlapped with acute exercise responses observed in skeletal muscle biopsies from the same donors. The organoids further detected functional impairments of skeletal muscle performance induced by TGF-β1 and metformin and increased speed generation by testosterone treatment. These findings establish a donor-specific human skeletal muscle platform that recapitulates key features of insulin action and exercise adaptation and may enable mechanistic studies of skeletal muscle metabolism, exercise responsiveness, and therapeutic interventions relevant to diabetes.