Diabetologia最新文献

{"title":"Autoimmune diseases and the risk and prognosis of latent autoimmune diabetes in adults.","authors":"Cornelia Santoso, Yuxia Wei, Emma Ahlqvist, Tiinamaija Tuomi, Sofia Carlsson","doi":"10.1007/s00125-024-06303-4","DOIUrl":"10.1007/s00125-024-06303-4","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The aim of this study was to clarify the impact of autoimmune disease (AD) comorbidity on the risk and prognosis of latent autoimmune diabetes in adults (LADA).</p><p><strong>Methods: </strong>We used data from a Swedish study comprising newly diagnosed cases of LADA (n=586, stratified into LADA^low and LADA^high by autoantibody levels), type 2 diabetes (n=2003) and matched control participants (n=2355). Information on 33 ADs and diabetic retinopathy was obtained by linkage to regional and national registers. We estimated the ORs for LADA and type 2 diabetes in relation to ADs before diabetes diagnosis, and the HRs for diabetic retinopathy after diabetes diagnosis. We performed functional pathway analyses to explore biological mechanisms driving the associations.</p><p><strong>Results: </strong>Individuals with ADs exhibit an increased susceptibility to LADA (OR 1.70; 95% CI 1.36, 2.13), particularly those with thyroid dysfunction (OR 1.88; 95% CI 1.38, 2.56), inflammatory bowel disease (OR 1.78; 95% CI 1.00, 3.16) or vitiligo (OR 3.91; 95% CI 1.93, 7.94), with stronger associations being observed for the LADA^high phenotype. Only psoriasis was linked to type 2 diabetes (OR 1.47; 95% CI 1.08, 1.99). The biological pathways shared by LADA and ADs revolved around immune responses, including innate and adaptive immune pathways. The HRs for diabetic retinopathy in LADA patients with and without AD vs those with type 2 diabetes were 2.11 (95% CI 1.34, 3.32) and 1.68 (95% CI 1.15, 2.45), respectively.</p><p><strong>Conclusions/interpretation: </strong>We confirm that several common ADs confer an excess risk of LADA, especially LADA with higher GADA levels, but having such a comorbidity does not appear to affect the risk of diabetic retinopathy.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"331-341"},"PeriodicalIF":8.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postprandial hypoglycaemia after gastric bypass in type 2 diabetes: pathophysiological mechanisms and clinical implications.","authors":"Domenico Tricò, Luca Sacchetta, Eleni Rebelos, Noemi Cimbalo, Martina Chiriacò, Diego Moriconi, Lorenzo Nesti, Giulia Nesti, Silvia Frascerra, Maria T Scozzaro, Giuseppe Daniele, Simona Baldi, Andrea Mari, Monica Nannipieri, Andrea Natali","doi":"10.1007/s00125-024-06312-3","DOIUrl":"10.1007/s00125-024-06312-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Postprandial hypoglycaemia (PPHG) is a frequent late complication of Roux-en-Y gastric bypass (RYGB) in people without diabetes. We aimed to examine the pathogenetic mechanisms of PPHG and its clinical consequences in people with a history of type 2 diabetes.</p><p><strong>Methods: </strong>In this case-control study, 24 participants with type 2 diabetes treated with RYGB (14 women; median [IQR] age 53.5 [13.8] years, BMI 29.3 [6.3] kg/m², HbA_1c 36.0 [6.2] mmol/mol [5.4% (0.6%)]) underwent a dual-tracer, frequently sampled, 300 min, 75 g OGTT for the diagnosis of PPHG (glucose nadir <3.0 mmol/l, or <3.3 mmol/l with symptoms). Plasma glucose, glucose tracers, insulin, C-peptide, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, adrenaline (epinephrine), noradrenaline (norepinephrine), cortisol and NEFAs were measured. Mathematical models were implemented to estimate glucose metabolic fluxes and beta cell function. ECG recordings, cognitive testing and hypoglycaemia awareness assessments were repeated during the OGTT. Glycaemic levels and dietary habits were assessed under free-living conditions.</p><p><strong>Results: </strong>PPHG occurred in 12 (50%) participants, mostly without symptoms, due to excessive tracer-derived glucose clearance (mean group difference ± SE in AUC_{0-180 min} +261±72 ml min^-1 kg^-1 × min) driven by higher whole-body insulin sensitivity and early glucose-stimulated hyperinsulinaemia, the latter depending on lower insulin clearance and enhanced beta cell function, regardless of incretin hormones. PPHG participants also had defective counterregulatory hormone responses to hypoglycaemia, preventing a physiological increase in endogenous glucose production and the appearance of symptoms and signs of sympathetic cardiovascular activation and neuroglycopenia. PPHG was associated with more frequent and prolonged hypoglycaemia on 14 day continuous glucose monitoring and alterations in free-living dietary habits.</p><p><strong>Conclusions: </strong>Our results demonstrate that post-bypass PPHG occurs frequently in individuals with a history of type 2 diabetes, often without warning symptoms, and expose its complex pathogenetic mechanisms, revealing potential therapeutic targets.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"444-459"},"PeriodicalIF":8.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes knowledge and behaviour: a cross-sectional study of Jordanian adults.","authors":"Rula A Amr, Ahmed M Al-Smadi, Rand T Akasheh","doi":"10.1007/s00125-024-06304-3","DOIUrl":"10.1007/s00125-024-06304-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Diabetes mellitus is a significant global health concern that is projected to affect 7.7% of the global population by 2030. Understanding factors that influence diabetes knowledge and management adherence is crucial for effective diabetes mellitus management and prevention. This study investigates the relationships between demographic and clinical factors and their impact on diabetes knowledge and behaviour, as well as the potential influence of diabetes knowledge on management behaviours.</p><p><strong>Methods: </strong>The study comprised a cross-sectional survey of 1050 adults, collecting data on age, sex, marital status, education, employment, hypertension, dyslipidaemia (any lipid imbalance, such as high cholesterol, high LDL-cholesterol or low HDL-cholesterol), smoking and diabetes status. Two multiple linear regression models were used to identify factors associated with diabetes knowledge and behaviour, and a simple linear regression model was used to assess the relationship between knowledge and behaviour.</p><p><strong>Results: </strong>Significant associations were found between diabetes knowledge and the following factors: age (44.32 ± 9.53 for ≥50 years vs 39.73 ± 9.95 for 18 to <25 years; p<0.0001), sex (49.00 ± 12.35 for women vs 45.09 ± 13.27 for men; p<0.0001), marital status (50.92 ± 11.69 for married vs 45.39 ± 13.10 for single; p<0.0001), smoking status (45.78 ± 13.22 for smokers vs 48.22 ± 12.15 for non-smokers; p=0.003), hypertension (46.46 ± 13.11 for present vs 47.31 ± 12.87 for absent; p=0.007) and diabetes status (69.49 ± 17.35 for present vs 62.76 ± 16.88 for absent; p<0.001). Behaviour scores correlated similarly with these factors except for diabetes and smoking status. The adjusted simple linear regression model revealed that diabetes knowledge was significantly associated with better management behaviours (coefficient=0.0794, p<0.001) after adjusting for demographic and clinical factors.</p><p><strong>Conclusions/interpretation: </strong>This study highlights the importance of demographic and clinical factors in the context of diabetes knowledge and behaviours, underscoring the need for targeted educational and preventive programmes to improve diabetes management, especially in vulnerable populations. Additionally, the strong association between diabetes knowledge and management behaviours supports a knowledge-attitude-behaviour (KAB) model of diabetes management.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"320-330"},"PeriodicalIF":8.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simplified meal announcement study (SMASH) using hybrid closed-loop insulin delivery in youth and young adults with type 1 diabetes: a randomised controlled two-centre crossover trial.","authors":"Céline I Laesser, Camillo Piazza, Nina Schorno, Fabian Nick, Lum Kastrati, Thomas Zueger, Katharine Barnard-Kelly, Malgorzata E Wilinska, Christos T Nakas, Roman Hovorka, David Herzig, Daniel Konrad, Lia Bally","doi":"10.1007/s00125-024-06319-w","DOIUrl":"10.1007/s00125-024-06319-w","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The majority of hybrid closed-loop systems still require carbohydrate counting (CC) but the evidence for its justification remains limited. Here, we evaluated glucose control with simplified meal announcement (SMA) vs CC in youth and young adults with type 1 diabetes using the mylife CamAPS FX system.</p><p><strong>Methods: </strong>We conducted a two-centre, randomised crossover, non-inferiority trial in two University Hospitals in Switzerland in 46 participants (aged 12-20 years) with type 1 diabetes using multiple daily injections (n=35), sensor-augmented pump (n=4) or hybrid closed-loop (n=7) therapy before enrolment. Participants underwent two 3 month periods with the mylife CamAPS FX system (YpsoPump, Dexcom G6) to compare SMA (individualised carbohydrate meal sizes) with CC, in a randomly assigned order using computer-generated sequences. The primary endpoint was the proportion of time glucose was in target range (3.9-10.0 mmol/l) with a non-inferiority margin of 5 percentage points. Secondary endpoints were other sensor glucose and insulin metrics, usability and safety endpoints.</p><p><strong>Results: </strong>Forty-three participants (18 women and girls) completed the trial. In the intention-to-treat analysis, time in range (mean±SD) was 69.9±12.4% with SMA and 70.7±13.0% with CC (estimated mean difference -0.6 percentage points [95% CI -2.4, 1.1], demonstrating non-inferiority). Time <3.9 mmol/l (median [IQR] 1.8 [1.2-2.2]% vs 1.9 [1.6-2.5]%) and >10.0 mmol/l (28.2±12.6% vs 27.2±13.4%) was similar between periods. Total daily insulin dose was higher with SMA (54.0±14.7 U vs 51.7±12.1 U, p=0.037). Three participants experienced serious adverse events, none of which were intervention-related.</p><p><strong>Conclusions/interpretation: </strong>Glucose control using the CamAPS FX algorithm with SMA was non-inferior to its use with CC in youth and young adults with type 1 diabetes.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov NCT05481034.</p><p><strong>Funding: </strong>The study was supported by the Swiss Diabetes Foundation and by a YTCR grant from the Bangerter-Rhyner Foundation and the Swiss Academy of Medical Sciences. Dexcom and Ypsomed provided product support.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"295-307"},"PeriodicalIF":8.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Birthweight and risk of chronic kidney disease after a type 2 diabetes diagnosis in the DD2 cohort","authors":"Aleksander L. Hansen, Christian F. Christiansen, Charlotte Brøns, Leonie M. Engelhard, Torben Hansen, Jens S. Nielsen, Peter Vestergaard, Kurt Højlund, Niels Jessen, Michael H. Olsen, Henrik T. Sørensen, Peter Rossing, Reimar W. Thomsen, Allan Vaag","doi":"10.1007/s00125-024-06357-4","DOIUrl":"https://doi.org/10.1007/s00125-024-06357-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Low birthweight (LBW) is associated with younger age, less obesity and more hypertension among people recently diagnosed with type 2 diabetes, as well as increased cardiovascular morbidity and mortality risk. It is not known whether LBW is associated with an increased risk of incident chronic kidney disease (CKD) among people with a type 2 diabetes diagnosis.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Original midwife records were retrieved for 5982 participants with recently diagnosed type 2 diabetes enrolled in the Danish Center for Strategic Research in Type 2 Diabetes (DD2) cohort between 2010 and 2024. They were followed until first incident CKD diagnosis, defined as either two eGFR measurements &lt;60 ml/min per 1.73m² or two urine albumin/creatinine ratio (UACR) measurements &gt;3 mg/mmol, each 90–365 days apart. Confounder-standardised 10 year risks of CKD were estimated, with death considered as a competing risk. Adjusted hazard ratios (aHRs) for CKD were computed using Cox and spline regression analyses. All analyses were controlled for differences in sex, age at enrolment, calendar year at birth, family history of diabetes and born-at-term status. Mixed-effects models were used to examine the trajectories of eGFR and UACR following enrolment.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 1501 incident CKD endpoints occurred, corresponding to an incidence rate of 42.4 per 1000 person-years over a median follow-up time of 8.3 years. Spline models with birthweight as a continuous measure showed progressively increasing aHRs for CKD with decreasing birthweight. The 10-year standardised risk of CKD was 36.0% in people with LBW (&lt;2500 g) and 30.6% in people with a normal birthweight (2500–4000 g), yielding a risk difference (RD) of 5.5% (95% CI −0.5%, 11.8%) and an aHR of 1.23 (95% CI 0.98, 1.55). People with type 2 diabetes and high birthweight (&gt;4000 g) had a similar 10-year standardised CKD risk compared with normal birthweight (33.1% and 30.6%, respectively). This yielded an RD of 2.5% (95% CI −1.6%, 6.7%) and an aHR of 1.10 (95% CI 0.93, 1.29). In mixed-effects models examining eGFR and UACR trajectories, each 1 kg decrease in birthweight was associated with a 6.6% (95% CI 1.9, 11.1) increase in UACR, whereas no association was found for eGFR.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>A history of LBW was associated with elevated risk of CKD among people with a recent type 2 diabetes diagnosis, although the precision of risk estimates was limited.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"20 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterising impaired awareness of hypoglycaemia and associated risks through HypoA-Q: findings from a T1D Exchange cohort.","authors":"Yu Kuei Lin, Wen Ye, Emily Hepworth, Annika Agni, Austin M Matus, Anneliese J Flatt, James A M Shaw, Michael R Rickels, Stephanie A Amiel, Jane Speight","doi":"10.1007/s00125-024-06310-5","DOIUrl":"10.1007/s00125-024-06310-5","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>We aimed to: (1) externally validate the five-item Hypoglycaemia Awareness Questionnaire (HypoA-Q) impaired awareness subscale (HypoA-Q IA); (2) examine how impaired awareness of hypoglycaemia (IAH) relates to the risk of severe hypoglycaemia and level 2 hypoglycaemia; and (3) identify factors associated with IAH.</p><p><strong>Methods: </strong>Nationwide survey of T1D Exchange registrants was conducted to collect data on demographics, 6 month severe-hypoglycaemia history, hypoglycaemia awareness status (via HypoA-Q IA, the Gold instrument and the Clarke instrument) and continuous glucose monitor (CGM) measures. The Clarke hypoglycaemia awareness factor (Clarke-HAF) was calculated to exclude severe-hypoglycaemia history items. Analyses included Cronbach's α, Spearman correlations and logistic regression.</p><p><strong>Results: </strong>Valid survey responses were collected from N=1580 adults with type 1 diabetes (median age, 44 years; 52% female participants; median HbA_1c, 48 mmol/mol [6.5%]). Of these, 94% of participants were using CGMs and 69% were using hybrid closed-loop (HCL) systems; 30% had at least one severe-hypoglycaemia episode in the past 6 months. The HypoA-Q IA had satisfactory internal reliability (α=0.79) and construct validity. Higher HypoA-Q IA scores were independently associated with greater risk of severe hypoglycaemia (p<0.001), performing comparably to the Gold instrument and the Clarke-HAF instrument. HypoA-Q IA-determined IAH was independently associated with 88% higher odds of developing severe hypoglycaemia (p<0.001) and twofold higher odds for spending ≥1% of time in level 2 hypoglycaemia (p=0.011). Higher age and longer diabetes duration were associated with higher IAH risk (p<0.001). CGM and HCL use was associated with lower IAH risk (p<0.001).</p><p><strong>Conclusions/interpretation: </strong>The HypoA-Q IA is a brief, valid and reliable tool for assessing IAH in today's technology-oriented era. IAH was independently associated with severe hypoglycaemia and level 2 hypoglycaemia in a cohort with high prevalence of advanced diabetes technology use and HbA_1c within the recommended range. CGM and HCL use was related to lower IAH risk.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"433-443"},"PeriodicalIF":8.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of continuous glucose monitoring with self-monitoring of blood glucose in type 1 diabetes in the changing atmospheric pressures in aviation: a hypobaric flight simulation.","authors":"Ka Siu Fan, Antonios Manoli, Petra M Baumann, Fariba Shojaee-Moradie, Fereshteh Jeivad, Gerd Koehler, Monika Cigler, A Margot Umpleby, David Russell-Jones, Julia K Mader","doi":"10.1007/s00125-025-06364-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06364-z","url":null,"abstract":"<p><strong>Aim/hypothesis: </strong>Pilots with type 1 diabetes are required to perform capillary glucose monitoring regularly during flights. Continuous glucose monitoring (CGM) may be an effective and more practical alternative. This study aimed to assess the accuracy of CGM systems against self-monitoring of blood glucose (SMBG) during a hypobaric flight simulation.</p><p><strong>Methods: </strong>Twelve insulin pump users with type 1 diabetes were studied using two simulation protocols. Protocol A consisted of a ground phase, ascent, a 190 min cruise with ingestion of a liquid meal, descent and then ground. Protocol B consisted of a ground phase, ascent, a 60 min cruise while fasting, descent, a 20 min ground phase, ascent, a second flight of 120 min with ingestion of a meal, followed by descent and ground. Insulin was administered with or before the meal according to the participants' carbohydrate-counting regimen during both protocols. In Protocol A, capillary, interstitial and plasma glucose were measured during flight and at ground, while in Protocol B, glucose and oxygen were measured. Measurements from three CGM brands and two SMBG devices were recorded during the flight simulations. Findings at cabin pressures during flight (550 mmHg) and ground (750 mmHg) were compared. Fasted and postprandial glucose measurements were analysed using Spearman's correlations and mean absolute relative differences (MARDs).</p><p><strong>Results: </strong>Eleven men and one woman (n=6 men in Protocol A; n=5 men and n=1 woman in Protocol B) were studied. A total of 1533 data points were recorded. During flight vs ground level, Spearman's correlations for CGM system- and SMBG-derived glucose values were very strong in both Protocol A (r=0.96 during flight vs r=0.94 at ground) and Protocol B (r=0.85 during flight vs r=0.69 at ground). The differences in aggregated CGM MARDs during flight vs ground level were minimal across Protocol A (11.85%; 95% CI [9.78, 13.92] vs 9.08%; 95% CI [7.02, 11.14]) and Protocol B (12.01%; 95% CI [3.34, 20.69] vs 12.97%; 95% CI [4.30, 21.65]).</p><p><strong>Conclusions/interpretation: </strong>The performance of CGM systems and SMBG are comparable during flight-associated atmospheric pressure changes. All tested measurement devices for CGM and SMBG were suitable for diabetes-care-based decisions during flight simulation.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High glucose/ChREBP-induced Hif-1α transcriptional activation in CD4⁺ T cells reduces the risk of diabetic kidney disease by inhibiting the Th1 response.","authors":"Shaoyong Zhuang, Nan Sun, Junwen Qu, Qian Chen, Conghui Han, Hao Yin, Xiaodong Yuan, Ming Zhang","doi":"10.1007/s00125-024-06354-7","DOIUrl":"https://doi.org/10.1007/s00125-024-06354-7","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Diabetic kidney disease (DKD) features intrarenal inflammation, in which T cells play a part. Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor regulating cellular responses to hypoxia, is reportedly involved in the course of inflammation. The role of HIF-1α in DKD has been investigated, but the conclusions are controversial so far. We report a previously unrecognised high glucose/carbohydrate response element binding protein (ChREBP)/Hif-1α transcription axis in CD4⁺ T cells.</p><p><strong>Methods: </strong>Lck-Cre⁺Hif1a^loxp/loxp (Hif-1α^-/-) mice were generated to explore the role of T cell HIF-1α in the pathogenesis of DKD. CD4⁺ T cells sorted from T cell-specific Hif-1α-ablated mice and wild-type mice were used for functional studies and transcriptional profiling.</p><p><strong>Results: </strong>In this study, we used Lck-Cre transgenic mice to specifically disrupt Hif-1α in T cells and found that ablation of Hif-1α greatly accelerated the progression of DKD in a streptozocin-induced model of diabetes. Adoptive transfer of splenic CD4⁺ T cells from Hif-1α^-/- mice rather than wild-type controls to diabetic mice elicited severe renal damage. Compared with wild-type controls, Hif-1α knockout markedly promoted IFN-γ secretion by CD4⁺ T cells in response to high glucose. Additional Ifn-γ ablation negated the effect of Hif-1α knockout on DKD progression. Mechanistically, the background Hif-1α mRNA synthesis rate in resting T cells was very low, but culture of T cells under high glucose led to significantly promoted Hif-1α expression, which was dependent on the transcription factor ChREBP. Consistent with results from Hif-1α^-/- CD4⁺ T cells, adoptive transfer of Chrebp^-/- CD4⁺ T cells to wild-type diabetic mice also elicited severe diabetic renal damage. By contrast, Chrebp^-/-Ifn-γ^-/- CD4⁺ T cells failed to show nephrotoxic effects. Examination of the Hif-1α promoter identified a ChREBP-binding sequence that mediated transcriptional upregulation of Hif-1α by high glucose.</p><p><strong>Conclusions/interpretation: </strong>Our study reveals a previously unrecognised high glucose/ChREBP/Hif-1α transcription axis in CD4⁺ T cells, which serves as a self-protection mechanism against DKD progression via limiting T helper 1 response.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes","authors":"Jason L. Floyd, Ram Prasad, Mariana D. Dupont, Yvonne Adu-Rutledge, Shambhavi Anshumali, Sarbodeep Paul, Sergio Li Calzi, Xiaoping Qi, Akanksha Malepati, Emory Johnson, Patricia Jumbo-Lucioni, Jason N. Crosson, John O. Mason, Michael E. Boulton, Robert S. Welner, Maria B. Grant","doi":"10.1007/s00125-024-06349-4","DOIUrl":"https://doi.org/10.1007/s00125-024-06349-4","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Within the small intestine, neutrophils play an integral role in preventing bacterial infection. Upon interaction with bacteria or bacteria-derived antigens, neutrophils initiate a multi-staged response of which the terminal stage is NETosis, formation of protease-decorated nuclear DNA into extracellular traps. NETosis has a great propensity to elicit ocular damage and has been associated with diabetic retinopathy and diabetic macular oedema (DME) progression. Here, we interrogate the relationship between gut barrier dysfunction, endotoxaemia and systemic and intestinal neutrophilia in diabetic retinopathy.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;In a cohort of individuals with type 2 diabetes (&lt;i&gt;n&lt;/i&gt;=58) with varying severity of diabetic retinopathy and DME, we characterised the abundance of circulating neutrophils by flow cytometry and markers of gut permeability and endotoxaemia by plasma ELISA. In a mouse model of type 2 diabetes, we examined the effects of diabetes on abundance and function of intestinal, blood and bone marrow neutrophils, gut barrier integrity, endotoxaemia and diabetic retinopathy severity. Pharmacological inhibition of NETosis was achieved by i.p. injection of the peptidyl arginine deiminase 4 inhibitor (PAD4i) GSK484 daily for 4 weeks between 6 and 7 months of type 2 diabetes.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;In human participants, neutrophilia was unique to individuals with type 2 diabetes with diabetic retinopathy and DME and was accompanied by heightened circulating markers of gut permeability. At late-stage diabetes, neutrophilia and gut barrier dysfunction were seen in &lt;i&gt;db/db&lt;/i&gt; mice. The &lt;i&gt;db/db&lt;/i&gt; mice exhibited an increase in stem-like pre-neutrophils in the intestine and bone marrow and a decrease in haematopoietic vascular reparative cells. In the &lt;i&gt;db/db&lt;/i&gt; mouse intestine, enhanced loss of gut barrier integrity was associated with elevated intestinal NETosis. Inhibition of NETosis by the PAD4i GSK484 resulted in decreased abundance of premature neutrophils in the intestine and blood and resulted in neutrophil retention in the bone marrow compared with vehicle-treated &lt;i&gt;db/db&lt;/i&gt; mice. Additionally, the PAD4i decreased senescence within the gut epithelium and yielded a slowing of diabetic retinopathy progression.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Severity of diabetic retinopathy and DME were associated with peripheral neutrophilia, gut barrier dysfunction and endotoxaemia in the human participants. &lt;i&gt;db/db&lt;/i&gt; mice exhibited intestinal neutrophilia, specifically stem-like pre-neutrophils, which was associated with elevated NETosis and decreased levels of vascular reparative cells. Chronic inhibition of NETosis in &lt;i&gt;db/db&lt;/i&gt; mice reduced intestinal senescence and NETs in the retina. These changes were associated with reduced endotoxaemia and an anti-inflammatory b","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"59 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Up Front","authors":"","doi":"10.1007/s00125-025-06361-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06361-2","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"27 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}