Pub Date : 2026-02-03DOI: 10.1007/s00125-026-06669-7
Gechang Yu, Claudia H T Tam, Mai Shi, Alice E Hughes, Chuiguo Huang, Yuzhi Deng, Michael N Weedon, Cadmon K P Lim, Chi Chiu Wang, Juliana C N Chan, Wing Hung Tam, William Lowe, Rachel M Freathy, Richard A Oram, Ronald C W Ma
Aims/hypothesis: We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations.
Methods: In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants.
Results: Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1.
Conclusions/interpretation: Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA.
{"title":"Maternal and fetal genetic predispositions to insulin deficiency and resistance affect fetal growth through distinct pathways.","authors":"Gechang Yu, Claudia H T Tam, Mai Shi, Alice E Hughes, Chuiguo Huang, Yuzhi Deng, Michael N Weedon, Cadmon K P Lim, Chi Chiu Wang, Juliana C N Chan, Wing Hung Tam, William Lowe, Rachel M Freathy, Richard A Oram, Ronald C W Ma","doi":"10.1007/s00125-026-06669-7","DOIUrl":"https://doi.org/10.1007/s00125-026-06669-7","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations.</p><p><strong>Methods: </strong>In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants.</p><p><strong>Results: </strong>Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1.</p><p><strong>Conclusions/interpretation: </strong>Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112503","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}
Pub Date : 2026-02-03DOI: 10.1007/s00125-026-06674-w
Fernando Sebastian-Valles, Carolina Sager-La Ganga, Alicia Justel Enriquez, Sara Jimenez Blanco, Víctor Navas-Moreno, Jose Alfonso Arranz Martin, Mónica Marazuela
<p><strong>Aims/hypothesis: </strong>Connected insulin pens and smart caps automatically capture dosing data and can prompt patients about missed prandial boluses, but independent randomised evidence in type 1 diabetes is scarce. We aimed to assess whether a connected insulin pen cap improves glycaemic management and treatment satisfaction compared with an otherwise identical non-connected cap.</p><p><strong>Methods: </strong>We conducted an investigator-initiated, randomised, open-label, parallel-group trial in a European public hospital over 8 weeks. Adults with type 1 diabetes treated with multiple daily injections and who had suboptimal glycaemic management (baseline time above range [>10.0 mmol/l, >180 mg/dl] >25%) were randomly assigned (1:1) to a connected pen cap (Insulclock 2.0; Insulcloud, Madrid, Spain) or an identical cap for which the Bluetooth connectivity had been disabled (disconnected). Allocation was performed using opaque sealed envelopes, and no masking was applied. The primary outcome was time above range, with two thresholds (>10.0 mmol/l, >180 mg/dl and >13.9 mmol/l, >250 mg/dl) based on intermittently scanned CGM downloads. Analyses followed the intention-to-treat principle, using longitudinal mixed models and multiple imputation. Secondary outcomes included time in range, glycaemic variability (standard deviation and coefficient of variation), HbA<sub>1c</sub> and patient-reported outcomes (treatment satisfaction and fear of hypoglycaemia).</p><p><strong>Results: </strong>Forty-two participants were randomised for inclusion in the study (21 per group: 25 women, 17 men). One withdrew before baseline, leaving 41 in the intention-to-treat analysis. Compared with the control group, the connected-cap group had lower time above range >13.9 mmol/l (mean difference -4.8 percentage points; 95% CI -9.5, -0.1; p=0.045) and reduced glucose standard deviation (-0.35 mmol/l; 95% CI -0.64, -0.06; p=0.018). HbA<sub>1c</sub> showed a borderline reduction of -3.5 mmol/mol (-0.32%) (95% CI -7.1, 0.0 mmol/mol; -0.65, 0.00%; p=0.050). Per-protocol analyses suggested an 8% absolute increase in time in range among adherent users. No adverse events or device-related serious adverse events occurred. No between-group differences were observed in treatment satisfaction scores, and avoidance behaviours based on the hypoglycaemia fear survey significantly decreased in the treatment group (β=-2.44; 95% CI -4.45, -0.43; p=0.019).</p><p><strong>Conclusions/interpretation: </strong>In routine clinical care, use of a connected pen cap reduced severe hyperglycaemia, glycaemic variability and hypoglycaemia avoidance behaviours in adults with type 1 diabetes and suboptimal glycaemic management, without affecting treatment satisfaction. These findings support the integration of low-burden, data-driven tools into public diabetes care. Larger and longer trials should evaluate the durability and cost-effectiveness of these interventions.</p><p><strong>Trial regi
目的/假设：连接胰岛素笔和智能帽自动捕获剂量数据，并提示患者错过的餐丸，但1型糖尿病的独立随机证据很少。我们的目的是评估连接胰岛素笔帽与其他相同的非连接帽相比，是否能改善血糖管理和治疗满意度。方法：我们在欧洲一家公立医院进行了一项为期8周的研究者发起的、随机的、开放标签的平行组试验。每日多次注射治疗且血糖管理不佳的1型糖尿病成人（基线时间高于[>10.0 mmol/l, >180 mg/dl] >25%）被随机（1:1）分配到连接的笔帽（Insulclock 2.0; Insulcloud，马德里，西班牙）或相同的帽，蓝牙连接被禁用（断开）。分配是使用不透明的密封信封进行的，没有遮盖。主要结局是时间超过范围，有两个阈值（>10.0 mmol/l, >180 mg/dl和>13.9 mmol/l, >250 mg/dl）基于间歇扫描的CGM下载。分析遵循意向治疗原则，使用纵向混合模型和多重输入。次要结局包括治疗时间、血糖变异性（标准差和变异系数）、HbA1c和患者报告的结局（治疗满意度和对低血糖的恐惧）。结果：42名参与者被随机纳入研究（每组21人：25名女性，17名男性）。1人在基线前退出，剩下41人在意向治疗分析中。与对照组相比，连接帽组血糖高于正常值13.9 mmol/l的时间缩短（平均差值-4.8个百分点；95% CI -9.5, -0.1; p=0.045），血糖标准差降低（-0.35 mmol/l; 95% CI -0.64, -0.06; p=0.018）。HbA1c呈-3.5 mmol/mol（-0.32%）的临界降低（95% CI -7.1, 0.0 mmol/mol; -0.65, 0.00%; p=0.050）。每个协议分析表明，在固定用户中，范围的时间绝对增加了8%。未发生不良事件或与器械相关的严重不良事件。治疗组治疗满意度评分无组间差异，治疗组基于低血糖恐惧调查的回避行为显著降低（β=-2.44; 95% CI -4.45, -0.43; p=0.019）。结论/解释：在常规临床护理中，使用连接笔帽可减少成人1型糖尿病患者血糖管理欠佳的严重高血糖、血糖变异性和低血糖避免行为，且不影响治疗满意度。这些发现支持将低负担、数据驱动的工具整合到公共糖尿病护理中。规模更大、时间更长的试验应评估这些干预措施的持久性和成本效益。临床试验注册：ClinicalTrials.gov NCT06845891资助：研究者发起的研究，无行业资助；设备是医院采购的。资助者在研究设计、实施、分析或报告中没有任何作用。
{"title":"Analysis of glycaemic control and treatment satisfaction with a connected smart pen cap in adults with type 1 diabetes: a randomised, open-label, parallel-group trial.","authors":"Fernando Sebastian-Valles, Carolina Sager-La Ganga, Alicia Justel Enriquez, Sara Jimenez Blanco, Víctor Navas-Moreno, Jose Alfonso Arranz Martin, Mónica Marazuela","doi":"10.1007/s00125-026-06674-w","DOIUrl":"https://doi.org/10.1007/s00125-026-06674-w","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Connected insulin pens and smart caps automatically capture dosing data and can prompt patients about missed prandial boluses, but independent randomised evidence in type 1 diabetes is scarce. We aimed to assess whether a connected insulin pen cap improves glycaemic management and treatment satisfaction compared with an otherwise identical non-connected cap.</p><p><strong>Methods: </strong>We conducted an investigator-initiated, randomised, open-label, parallel-group trial in a European public hospital over 8 weeks. Adults with type 1 diabetes treated with multiple daily injections and who had suboptimal glycaemic management (baseline time above range [>10.0 mmol/l, >180 mg/dl] >25%) were randomly assigned (1:1) to a connected pen cap (Insulclock 2.0; Insulcloud, Madrid, Spain) or an identical cap for which the Bluetooth connectivity had been disabled (disconnected). Allocation was performed using opaque sealed envelopes, and no masking was applied. The primary outcome was time above range, with two thresholds (>10.0 mmol/l, >180 mg/dl and >13.9 mmol/l, >250 mg/dl) based on intermittently scanned CGM downloads. Analyses followed the intention-to-treat principle, using longitudinal mixed models and multiple imputation. Secondary outcomes included time in range, glycaemic variability (standard deviation and coefficient of variation), HbA<sub>1c</sub> and patient-reported outcomes (treatment satisfaction and fear of hypoglycaemia).</p><p><strong>Results: </strong>Forty-two participants were randomised for inclusion in the study (21 per group: 25 women, 17 men). One withdrew before baseline, leaving 41 in the intention-to-treat analysis. Compared with the control group, the connected-cap group had lower time above range >13.9 mmol/l (mean difference -4.8 percentage points; 95% CI -9.5, -0.1; p=0.045) and reduced glucose standard deviation (-0.35 mmol/l; 95% CI -0.64, -0.06; p=0.018). HbA<sub>1c</sub> showed a borderline reduction of -3.5 mmol/mol (-0.32%) (95% CI -7.1, 0.0 mmol/mol; -0.65, 0.00%; p=0.050). Per-protocol analyses suggested an 8% absolute increase in time in range among adherent users. No adverse events or device-related serious adverse events occurred. No between-group differences were observed in treatment satisfaction scores, and avoidance behaviours based on the hypoglycaemia fear survey significantly decreased in the treatment group (β=-2.44; 95% CI -4.45, -0.43; p=0.019).</p><p><strong>Conclusions/interpretation: </strong>In routine clinical care, use of a connected pen cap reduced severe hyperglycaemia, glycaemic variability and hypoglycaemia avoidance behaviours in adults with type 1 diabetes and suboptimal glycaemic management, without affecting treatment satisfaction. These findings support the integration of low-burden, data-driven tools into public diabetes care. Larger and longer trials should evaluate the durability and cost-effectiveness of these interventions.</p><p><strong>Trial regi","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112416","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}
Pub Date : 2026-02-03DOI: 10.1007/s00125-026-06668-8
Sarah K P Black, Alexandra Tully, Elizabeth A Davis, Alison Roberts, Sabrina Binkowski, Leanne Cromb, Craig Taplin, Brydie-Rose Mellor, Keely Bebbington, Aveni Haynes
Aims/hypothesis: Children with early-stage (pre-symptomatic) type 1 diabetes are currently identified primarily via research-based screening programmes in Australia. Once identified, families live with the knowledge that their child has an increased chance of developing symptomatic, lifelong, insulin-requiring type 1 diabetes but have no specific clinical pathway available to them in Western Australia (WA) for accessing tailored support or education. This project aimed to co-design a new clinical pathway to address this unmet need.
Methods: Experience-based co-design (EBCD) methodology was applied, comprising three phases undertaken consecutively over 12 months. Recruitment for each phase was via open invitation with voluntary participation. Phases 1 and 2 involved facilitated community conversations and focus groups conducted separately for type 1 diabetes community members and healthcare professionals (HCPs). Data from these phases were analysed using deductive and inductive content analysis to identify key categories of information and a prototype clinical pathway was developed incorporating these. For phase 3, a combined workshop was held with all stakeholders to obtain feedback on the prototype, and refine it accordingly.
Results: In phase 1, 16 community members (people living with type 1 diabetes, families whose child or children had been screened for type 1 diabetes) and 36 HCPs (doctors, nurse educators, social workers, dietitians, a mental health nurse and administrative staff from Perth Children's Hospital) participated in separate community conversations. The following three key categories were identified: (1) the need for education; (2) the need for support and strategies for managing uncertainty; and (3) the need for information on disease-modifying therapies and access to clinical trials. In phase 2, seven community members and 11 HCPs participated in separate focus groups. The following key priorities were identified: (1) the need for access to HCPs skilled in supporting patients to manage uncertainty; (2) the need for flexibility in delivery modes (telehealth/in-person); (3) the need for early referral to relevant clinical trials; and (4) the need for reliable and up-to-date resources. In phase 3, three community members and three HCPs attended a combined workshop to provide feedback on a prototype clinical pathway and their feedback was incorporated into a final version.
Conclusions/interpretation: Application of EBCD methodology enabled the development of a new clinical pathway tailored to the needs of WA families with a child living with early-stage type 1 diabetes.
{"title":"Co-designing a new clinical pathway to support families with children identified as having early-stage type 1 diabetes in Western Australia.","authors":"Sarah K P Black, Alexandra Tully, Elizabeth A Davis, Alison Roberts, Sabrina Binkowski, Leanne Cromb, Craig Taplin, Brydie-Rose Mellor, Keely Bebbington, Aveni Haynes","doi":"10.1007/s00125-026-06668-8","DOIUrl":"https://doi.org/10.1007/s00125-026-06668-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Children with early-stage (pre-symptomatic) type 1 diabetes are currently identified primarily via research-based screening programmes in Australia. Once identified, families live with the knowledge that their child has an increased chance of developing symptomatic, lifelong, insulin-requiring type 1 diabetes but have no specific clinical pathway available to them in Western Australia (WA) for accessing tailored support or education. This project aimed to co-design a new clinical pathway to address this unmet need.</p><p><strong>Methods: </strong>Experience-based co-design (EBCD) methodology was applied, comprising three phases undertaken consecutively over 12 months. Recruitment for each phase was via open invitation with voluntary participation. Phases 1 and 2 involved facilitated community conversations and focus groups conducted separately for type 1 diabetes community members and healthcare professionals (HCPs). Data from these phases were analysed using deductive and inductive content analysis to identify key categories of information and a prototype clinical pathway was developed incorporating these. For phase 3, a combined workshop was held with all stakeholders to obtain feedback on the prototype, and refine it accordingly.</p><p><strong>Results: </strong>In phase 1, 16 community members (people living with type 1 diabetes, families whose child or children had been screened for type 1 diabetes) and 36 HCPs (doctors, nurse educators, social workers, dietitians, a mental health nurse and administrative staff from Perth Children's Hospital) participated in separate community conversations. The following three key categories were identified: (1) the need for education; (2) the need for support and strategies for managing uncertainty; and (3) the need for information on disease-modifying therapies and access to clinical trials. In phase 2, seven community members and 11 HCPs participated in separate focus groups. The following key priorities were identified: (1) the need for access to HCPs skilled in supporting patients to manage uncertainty; (2) the need for flexibility in delivery modes (telehealth/in-person); (3) the need for early referral to relevant clinical trials; and (4) the need for reliable and up-to-date resources. In phase 3, three community members and three HCPs attended a combined workshop to provide feedback on a prototype clinical pathway and their feedback was incorporated into a final version.</p><p><strong>Conclusions/interpretation: </strong>Application of EBCD methodology enabled the development of a new clinical pathway tailored to the needs of WA families with a child living with early-stage type 1 diabetes.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112399","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}
Pub Date : 2026-02-01Epub Date: 2025-11-09DOI: 10.1007/s00125-025-06577-2
Thijs T Jansz, Katherine G Young, Rhian Hopkins, Andrew P McGovern, Beverley M Shields, Andrew T Hattersley, Angus G Jones, Ewan R Pearson, Coralie Bingham, Richard A Oram, John M Dennis
<p><strong>Aims/hypothesis: </strong>Current guidelines recommend use of sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) for kidney protection in people with type 2 diabetes and early-stage chronic kidney disease (CKD) based on a urinary albumin/creatinine ratio (uACR) of ≥3 mg/mmol. However, individuals with a normal uACR or low-level albuminuria were not represented in kidney outcome trials, leaving uncertainty about absolute treatment benefit in this group. To address this gap and support treatment decisions in clinical practice, we developed and validated a model to predict individual-level kidney protection benefit through the use of SGLT2 inhibitors.</p><p><strong>Methods: </strong>This observational cohort study used electronic health record data from UK primary care (Clinical Practice Research Datalink, 2013-2020) of adults with type 2 diabetes, eGFR ≥60 ml/min per 1.73 m<sup>2</sup> and uACR <30 mg/mmol, without heart failure or atherosclerotic vascular disease, who were starting treatment with either SGLT2 inhibitors or the comparator drugs dipeptidyl peptidase-4 (DPP4) inhibitors/sulfonylureas. First, we confirmed the real-world applicability of the relative treatment effect from a previous SGLT2 inhibitor trial meta-analysis, using overlap-weighted Cox proportional hazards models. Second, we assessed calibration of the CKD-PC risk score for kidney disease progression (≥50% eGFR decline, end-stage kidney disease or kidney-related death). Third, we integrated the relative treatment effect with the risk score to predict 3 year individual-level absolute risk reductions for SGLT2 inhibitors, and validated the accuracy of predictions vs overlap-weighted estimates based on observed data. Finally, we compared the clinical utility of a model-based treatment strategy with that of the ≥3 mg/mmol albuminuria threshold.</p><p><strong>Results: </strong>In 53,096 initiations of SGLT2 inhibitor treatment compared with 88,404 initiations of DPP4 inhibitor/sulfonylurea treatment, there was a 42% lower relative risk of kidney disease progression with SGLT2 inhibitors (HR 0.58; 95% CI 0.48, 0.69), consistent with a previous trial meta-analysis. The CKD-PC risk score did not require recalibration (calibration slope 1.05; 95% CI 0.94, 1.17). The median overall model-predicted absolute risk reduction with SGLT2 inhibitors was 0.37% at 3 years (IQR 0.26-0.55), and showed good calibration (calibration slope 1.10; 95% CI 1.09, 1.12). As an illustration of clinical utility, using the model predictions to target the same proportion of the population (n=25,303, 17.9%) as the albuminuria threshold would prevent over 10% more events over 3 years (253 vs 228) by identifying a subgroup of 6.7% of individuals with uACR <3 mg/mmol who showed significantly greater absolute risk reduction in response to SGLT2 inhibitor treatment than the remainder with uACR <3 mg/mmol (3.2% vs 1.2% in extended 5 year observational analyses, p=0.05).</p><p><strong>Conclusions
目的/假设：根据尿白蛋白/肌酐比值(uACR)≥3mg /mmol，目前的指南推荐使用钠-葡萄糖共转运蛋白-2抑制剂（SGLT2抑制剂）用于2型糖尿病和早期慢性肾病（CKD）患者的肾脏保护。然而，uACR正常或蛋白尿水平低的个体在肾脏结局试验中未被代表，这使得该组的绝对治疗效果不确定。为了解决这一差距并支持临床实践中的治疗决策，我们开发并验证了一个模型，通过使用SGLT2抑制剂来预测个体水平的肾脏保护益处。方法：这项观察性队列研究使用来自英国初级保健（临床实践研究数据链，2013-2020）的2型糖尿病成人电子健康记录数据，eGFR≥60 ml/min / 1.73 m2和uACR结果：在53,096例SGLT2抑制剂治疗中，与88,404例DPP4抑制剂/磺脲类药物治疗相比，SGLT2抑制剂治疗中肾脏疾病进展的相对风险降低42% (HR 0.58；95% CI 0.48, 0.69)，与之前的试验荟萃分析一致。CKD-PC风险评分不需要重新校准（校准斜率1.05;95% CI 0.94, 1.17）。总体模型预测SGLT2抑制剂在3年时的绝对风险降低中位数为0.37% (IQR 0.26-0.55)，并显示出良好的校准（校准斜率1.10;95% CI 1.09, 1.12）。作为临床应用的例证，使用该模型预测的目标人群比例相同（n=25,303, 17.9%），因为蛋白尿阈值将通过识别6.7%的uACR个体亚组，在3年内预防超过10%的事件（253 vs 228）。采用国际CKD- pc风险评分的模型可以准确预测2型糖尿病患者无或早期CKD患者使用SGLT2抑制剂治疗的个体水平肾保护益处。这可以指导全球临床实践中的治疗决策，并且可以比当前国际指南推荐的≥3mg /mmol蛋白尿阈值更有效地靶向治疗。
{"title":"Precision medicine in type 2 diabetes: targeting SGLT2 inhibitor treatment for kidney protection.","authors":"Thijs T Jansz, Katherine G Young, Rhian Hopkins, Andrew P McGovern, Beverley M Shields, Andrew T Hattersley, Angus G Jones, Ewan R Pearson, Coralie Bingham, Richard A Oram, John M Dennis","doi":"10.1007/s00125-025-06577-2","DOIUrl":"10.1007/s00125-025-06577-2","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Current guidelines recommend use of sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) for kidney protection in people with type 2 diabetes and early-stage chronic kidney disease (CKD) based on a urinary albumin/creatinine ratio (uACR) of ≥3 mg/mmol. However, individuals with a normal uACR or low-level albuminuria were not represented in kidney outcome trials, leaving uncertainty about absolute treatment benefit in this group. To address this gap and support treatment decisions in clinical practice, we developed and validated a model to predict individual-level kidney protection benefit through the use of SGLT2 inhibitors.</p><p><strong>Methods: </strong>This observational cohort study used electronic health record data from UK primary care (Clinical Practice Research Datalink, 2013-2020) of adults with type 2 diabetes, eGFR ≥60 ml/min per 1.73 m<sup>2</sup> and uACR <30 mg/mmol, without heart failure or atherosclerotic vascular disease, who were starting treatment with either SGLT2 inhibitors or the comparator drugs dipeptidyl peptidase-4 (DPP4) inhibitors/sulfonylureas. First, we confirmed the real-world applicability of the relative treatment effect from a previous SGLT2 inhibitor trial meta-analysis, using overlap-weighted Cox proportional hazards models. Second, we assessed calibration of the CKD-PC risk score for kidney disease progression (≥50% eGFR decline, end-stage kidney disease or kidney-related death). Third, we integrated the relative treatment effect with the risk score to predict 3 year individual-level absolute risk reductions for SGLT2 inhibitors, and validated the accuracy of predictions vs overlap-weighted estimates based on observed data. Finally, we compared the clinical utility of a model-based treatment strategy with that of the ≥3 mg/mmol albuminuria threshold.</p><p><strong>Results: </strong>In 53,096 initiations of SGLT2 inhibitor treatment compared with 88,404 initiations of DPP4 inhibitor/sulfonylurea treatment, there was a 42% lower relative risk of kidney disease progression with SGLT2 inhibitors (HR 0.58; 95% CI 0.48, 0.69), consistent with a previous trial meta-analysis. The CKD-PC risk score did not require recalibration (calibration slope 1.05; 95% CI 0.94, 1.17). The median overall model-predicted absolute risk reduction with SGLT2 inhibitors was 0.37% at 3 years (IQR 0.26-0.55), and showed good calibration (calibration slope 1.10; 95% CI 1.09, 1.12). As an illustration of clinical utility, using the model predictions to target the same proportion of the population (n=25,303, 17.9%) as the albuminuria threshold would prevent over 10% more events over 3 years (253 vs 228) by identifying a subgroup of 6.7% of individuals with uACR <3 mg/mmol who showed significantly greater absolute risk reduction in response to SGLT2 inhibitor treatment than the remainder with uACR <3 mg/mmol (3.2% vs 1.2% in extended 5 year observational analyses, p=0.05).</p><p><strong>Conclusions","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"374-385"},"PeriodicalIF":10.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12779664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480593","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}
Pub Date : 2026-02-01Epub Date: 2025-11-06DOI: 10.1007/s00125-025-06584-3
Rebecca L Thomson, Guinevere Martin, Kelly J McGorm, Timothy Spelman, Maria E Craig, Megan A S Penno, John M Wentworth, Peter G Colman, Elizabeth A Davis, Aveni Haynes, Tony Huynh, Georgia Soldatos, Jason A Tye-Din, Helena Oakey, Jennifer J Couper
Aim/hypothesis: We aimed to assess perceived stress and influencing factors in mothers with children at risk of type 1 diabetes and coeliac disease who did, or did not, develop islet autoantibodies (IA) or coeliac autoantibodies (CA) by 4 years of age.
Methods: Maternal perceived stress was assessed postpartum and when their child was approximately 4 years of age using the Perceived Stress Scale (range 1-56) in mothers followed prospectively in the multicentre Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort. Data were analysed using linear mixed models.
Results: In total, 818 mothers were included (642 children had no detected IA or CA [Ab negative], 97 had IA detected [IA positive] and 79 had CA detected [CA positive]). The development of IA or CA in young children did not add significantly to the perceived stress of their mothers at a median of 1.8 [IQR 0.8-2.5] and 1.6 [IQR 0.9-2.3] years later, respectively (Ab negative, adjusted predicted mean score 23.8 [95% CI 22.7, 24.9]; IA positive, 22.8 [21.0, 24.6]; CA positive, 25.2 [23.3, 27.2]). Maternal type 1 diabetes did not alter this result. On exploratory predictor analysis a higher perceived stress score at 4 years was associated with a history of mental health illness (β=4.66 [95% CI 3.30, 6.02]) and mental health medication use (β=2.71 [0.64, 4.78]), independent of child autoantibody status or maternal type 1 diabetes status.
Conclusions/interpretation: Detection of IA or CA in their child did not increase ongoing maternal perceived stress after 1-2 years in a cohort that received consistent support and education. History of mental health illness and mental health medication use were associated with increased perceived stress in mothers regardless of their child's autoantibody status.
目的/假设：我们旨在评估具有1型糖尿病和乳糜泻风险的孩子的母亲的感知压力及其影响因素，这些母亲在4岁时患有或未患胰岛自身抗体（IA）或乳糜泻自身抗体（CA）。方法：在多中心胰岛自身免疫环境决定因素（ENDIA）妊娠分娩队列中，使用感知压力量表（范围1-56）对母亲产后和孩子大约4岁时的感知压力进行评估。数据采用线性混合模型进行分析。结果：共纳入818例母亲，其中未检出IA或CA [Ab阴性]的642例，检出IA [IA阳性]的97例，检出CA [CA阳性]的79例。幼儿IA或CA的发展并未显著增加其母亲的感知压力，其中位数分别为1.8 [IQR 0.8-2.5]和1.6 [IQR 0.9-2.3]年（Ab阴性，调整后预测平均评分23.8 [95% CI 22.7, 24.9]； IA阳性，22.8 [21.0,24.6]；CA阳性，25.2[23.3,27.2]）。母亲患1型糖尿病没有改变这一结果。在探索性预测分析中，4岁时较高的感知压力评分与精神病史（β=4.66 [95% CI 3.30, 6.02]）和精神健康药物使用（β=2.71[0.64, 4.78]）相关，与儿童自身抗体状况或母亲1型糖尿病状况无关。结论/解释：在接受持续支持和教育的队列中，在孩子中检测到IA或CA并没有增加持续的母亲感知压力1-2年。无论孩子的自身抗体状况如何，母亲的精神健康病史和精神健康药物使用与感知压力增加有关。
{"title":"Perceived stress in mothers of children with and without islet and coeliac autoimmunity in the ENDIA study.","authors":"Rebecca L Thomson, Guinevere Martin, Kelly J McGorm, Timothy Spelman, Maria E Craig, Megan A S Penno, John M Wentworth, Peter G Colman, Elizabeth A Davis, Aveni Haynes, Tony Huynh, Georgia Soldatos, Jason A Tye-Din, Helena Oakey, Jennifer J Couper","doi":"10.1007/s00125-025-06584-3","DOIUrl":"10.1007/s00125-025-06584-3","url":null,"abstract":"<p><strong>Aim/hypothesis: </strong>We aimed to assess perceived stress and influencing factors in mothers with children at risk of type 1 diabetes and coeliac disease who did, or did not, develop islet autoantibodies (IA) or coeliac autoantibodies (CA) by 4 years of age.</p><p><strong>Methods: </strong>Maternal perceived stress was assessed postpartum and when their child was approximately 4 years of age using the Perceived Stress Scale (range 1-56) in mothers followed prospectively in the multicentre Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort. Data were analysed using linear mixed models.</p><p><strong>Results: </strong>In total, 818 mothers were included (642 children had no detected IA or CA [Ab negative], 97 had IA detected [IA positive] and 79 had CA detected [CA positive]). The development of IA or CA in young children did not add significantly to the perceived stress of their mothers at a median of 1.8 [IQR 0.8-2.5] and 1.6 [IQR 0.9-2.3] years later, respectively (Ab negative, adjusted predicted mean score 23.8 [95% CI 22.7, 24.9]; IA positive, 22.8 [21.0, 24.6]; CA positive, 25.2 [23.3, 27.2]). Maternal type 1 diabetes did not alter this result. On exploratory predictor analysis a higher perceived stress score at 4 years was associated with a history of mental health illness (β=4.66 [95% CI 3.30, 6.02]) and mental health medication use (β=2.71 [0.64, 4.78]), independent of child autoantibody status or maternal type 1 diabetes status.</p><p><strong>Conclusions/interpretation: </strong>Detection of IA or CA in their child did not increase ongoing maternal perceived stress after 1-2 years in a cohort that received consistent support and education. History of mental health illness and mental health medication use were associated with increased perceived stress in mothers regardless of their child's autoantibody status.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"343-349"},"PeriodicalIF":10.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457760","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}
Pub Date : 2026-01-29DOI: 10.1007/s00125-026-06667-9
Ilyas F Mustafajev,Marijn S Hendriksz,Rinke Stienstra,Cees J Tack,Bastiaan E de Galan,Rick I Meijer
AIMS/HYPOTHESISHypoglycaemia induces an acute and sustained inflammatory response both in people with type 1 diabetes and in people without diabetes. To investigate the role of adrenaline (epinephrine) in this response, we measured the inflammatory effects of adrenaline in a concentration and timeframe comparable to that seen during hypoglycaemia, in people with type 1 diabetes and matched control participants without diabetes.METHODSAdults with type 1 diabetes and matched control participants received adrenaline intravenously at 0.04 µg kg-1 min-1 for 1 h. Blood was drawn at baseline, after 30, 60 and 180 min, and on days 1, 3 and 7 following start of adrenaline administration, to determine white blood cell counts, cytokine secretion using ex vivo stimulation of isolated monocytes and circulating inflammatory markers using the Olink inflammatory panel.RESULTSAdrenaline acutely increased neutrophil, lymphocyte and monocyte counts in both groups. While neutrophil and monocyte levels returned to baseline after 1 day, lymphocytes remained elevated for 7 days. Adrenaline acutely altered monocyte function towards a more inflammatory phenotype, reflected by increased secretion of cytokines after ex vivo stimulation with lipopolysaccharide in both groups. Adrenaline also increased circulating inflammatory proteins, including urokinase-type plasminogen activator, Fms-like tyrosine kinase 3 ligand, chemokine (C-X3-C motif) ligand 1 and fibroblast growth factor 21, after 7 days in both groups, with a more pronounced response in people with type 1 diabetes.CONCLUSIONS/INTERPRETATIONLevels of adrenaline similar to those seen in response to hypoglycaemia elicit an acute and prolonged inflammatory response in people with type 1 diabetes and matched control participants on a cellular, functional and protein level. These findings suggest that adrenaline is a prominent driver of inflammatory responses following hypoglycaemia.TRIAL REGISTRATIONClinicalTrials.gov NCT05990933.
{"title":"Adrenaline is a prominent driver of inflammatory responses following hypoglycaemia.","authors":"Ilyas F Mustafajev,Marijn S Hendriksz,Rinke Stienstra,Cees J Tack,Bastiaan E de Galan,Rick I Meijer","doi":"10.1007/s00125-026-06667-9","DOIUrl":"https://doi.org/10.1007/s00125-026-06667-9","url":null,"abstract":"AIMS/HYPOTHESISHypoglycaemia induces an acute and sustained inflammatory response both in people with type 1 diabetes and in people without diabetes. To investigate the role of adrenaline (epinephrine) in this response, we measured the inflammatory effects of adrenaline in a concentration and timeframe comparable to that seen during hypoglycaemia, in people with type 1 diabetes and matched control participants without diabetes.METHODSAdults with type 1 diabetes and matched control participants received adrenaline intravenously at 0.04 µg kg-1 min-1 for 1 h. Blood was drawn at baseline, after 30, 60 and 180 min, and on days 1, 3 and 7 following start of adrenaline administration, to determine white blood cell counts, cytokine secretion using ex vivo stimulation of isolated monocytes and circulating inflammatory markers using the Olink inflammatory panel.RESULTSAdrenaline acutely increased neutrophil, lymphocyte and monocyte counts in both groups. While neutrophil and monocyte levels returned to baseline after 1 day, lymphocytes remained elevated for 7 days. Adrenaline acutely altered monocyte function towards a more inflammatory phenotype, reflected by increased secretion of cytokines after ex vivo stimulation with lipopolysaccharide in both groups. Adrenaline also increased circulating inflammatory proteins, including urokinase-type plasminogen activator, Fms-like tyrosine kinase 3 ligand, chemokine (C-X3-C motif) ligand 1 and fibroblast growth factor 21, after 7 days in both groups, with a more pronounced response in people with type 1 diabetes.CONCLUSIONS/INTERPRETATIONLevels of adrenaline similar to those seen in response to hypoglycaemia elicit an acute and prolonged inflammatory response in people with type 1 diabetes and matched control participants on a cellular, functional and protein level. These findings suggest that adrenaline is a prominent driver of inflammatory responses following hypoglycaemia.TRIAL REGISTRATIONClinicalTrials.gov NCT05990933.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"82 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073270","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}
Pub Date : 2026-01-29DOI: 10.1007/s00125-025-06665-3
Guillaume Giudicelli,Nicerine Krause,Victoire Turin-Huet,Maud Robert,Berenice Segrestin,Christian Toso,Monika E Hagen,Arnaud Dupuis,Giacomo Gastaldi,Alend Saadi,Minoa K Jung
AIMS/HYPOTHESISTimely metabolic surgery improves glycaemic control and reduces cardiovascular risk for patients with type 2 diabetes. Young age is a known predictor of favourable metabolic outcome, but Roux-en-Y gastric bypass (RYGB) is often delayed owing to reported surgical and psychological risks in young adults. We hypothesised that use of RYGB in adults aged 18-35 years would result in higher rates of diabetes remission compared with older individuals, without an associated increase in morbidity.METHODSWe analysed prospective registry data from three expert centres where young adults (29.5±5 years) and older adults (48±6.8 years) (means ± SD) who were living with non-insulin-dependent type 2 diabetes underwent RYGB. Younger adults were matched in a 1:2 ratio to their older counterparts for duration of preoperative diabetes, sex, BMI and American Society of Anesthesiologists physical status score. The rates of diabetes remission and adverse events in both groups were compared five years postoperatively.RESULTSA total of 79.1% (53/67) of the young adults and 76.9% (103/134) of the older adults attended the 5 year follow-up. Diabetes remission occurred earlier and more frequently in the young adult group, with an HR of 2.92 (95% CI 1.13, 7.59; p=0.027) and a median time to remission of 6 months (95% CI 3.1, 8.9), compared with 24 months (95% CI 10.9, 37.1) for older adults (p=0.001). There were no significant differences in all-cause adverse events, percentage weight change or loss to follow-up between groups.CONCLUSIONS/INTERPRETATIONDiabetes remission occurred earlier and more frequently in young adults within the first 5 years after RYGB. Surgical complications, nutritional deficiency or suboptimal weight loss were not different in the investigated young adult group compared with the older adults.
目的/假设及时的代谢手术可以改善2型糖尿病患者的血糖控制并降低心血管风险。年轻是一个已知的有利代谢结果的预测因子，但Roux-en-Y胃旁路术（RYGB）通常由于报道的手术和心理风险而延迟。我们假设，与老年人相比，18-35岁的成年人使用RYGB会导致更高的糖尿病缓解率，而不会导致发病率的增加。方法：我们分析了来自三个专家中心的前瞻性登记数据，这些非胰岛素依赖型2型糖尿病患者（29.5±5岁）和老年人（48±6.8岁）（mean±SD）接受了RYGB治疗。在术前糖尿病持续时间、性别、身体质量指数和美国麻醉医师协会身体状况评分方面，年轻人与老年人按1:2的比例进行匹配。比较两组患者术后5年糖尿病缓解率和不良事件发生率。结果参加5年随访的青壮年和老年人的tsa分别为79.1%（53/67）和76.9%（103/134）。糖尿病缓解在青壮年组发生得更早、更频繁，风险比为2.92 (95% CI 1.13, 7.59; p=0.027)，中位缓解时间为6个月（95% CI 3.1, 8.9），而老年人的中位缓解时间为24个月（95% CI 10.9, 37.1） （p=0.001）。两组之间的全因不良事件、体重变化百分比或随访体重下降百分比无显著差异。结论/解释：在RYGB后的前5年内，年轻人糖尿病的缓解发生得更早、更频繁。手术并发症、营养缺乏或体重下降不理想在被调查的年轻人组与老年人组没有什么不同。
{"title":"Type 2 diabetes remission and metabolic outcomes 5 years after Roux-en-Y gastric bypass in young vs older adults: a multicentre matched cohort study.","authors":"Guillaume Giudicelli,Nicerine Krause,Victoire Turin-Huet,Maud Robert,Berenice Segrestin,Christian Toso,Monika E Hagen,Arnaud Dupuis,Giacomo Gastaldi,Alend Saadi,Minoa K Jung","doi":"10.1007/s00125-025-06665-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06665-3","url":null,"abstract":"AIMS/HYPOTHESISTimely metabolic surgery improves glycaemic control and reduces cardiovascular risk for patients with type 2 diabetes. Young age is a known predictor of favourable metabolic outcome, but Roux-en-Y gastric bypass (RYGB) is often delayed owing to reported surgical and psychological risks in young adults. We hypothesised that use of RYGB in adults aged 18-35 years would result in higher rates of diabetes remission compared with older individuals, without an associated increase in morbidity.METHODSWe analysed prospective registry data from three expert centres where young adults (29.5±5 years) and older adults (48±6.8 years) (means ± SD) who were living with non-insulin-dependent type 2 diabetes underwent RYGB. Younger adults were matched in a 1:2 ratio to their older counterparts for duration of preoperative diabetes, sex, BMI and American Society of Anesthesiologists physical status score. The rates of diabetes remission and adverse events in both groups were compared five years postoperatively.RESULTSA total of 79.1% (53/67) of the young adults and 76.9% (103/134) of the older adults attended the 5 year follow-up. Diabetes remission occurred earlier and more frequently in the young adult group, with an HR of 2.92 (95% CI 1.13, 7.59; p=0.027) and a median time to remission of 6 months (95% CI 3.1, 8.9), compared with 24 months (95% CI 10.9, 37.1) for older adults (p=0.001). There were no significant differences in all-cause adverse events, percentage weight change or loss to follow-up between groups.CONCLUSIONS/INTERPRETATIONDiabetes remission occurred earlier and more frequently in young adults within the first 5 years after RYGB. Surgical complications, nutritional deficiency or suboptimal weight loss were not different in the investigated young adult group compared with the older adults.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"11 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073267","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}
Pub Date : 2026-01-29DOI: 10.1007/s00125-025-06664-4
Rafael Simó,Cristina Hernández,Simona Frontoni,Paolo Sbraccia,Reinier Schlingemann,Xavier Valldeperas,Stela Vujosevic,Inês Marques,José Cunha-Vaz,Jakob Grauslund,Frederik N Pedersen,María-José Barahona,Natasa Popovic,Gianpaolo Zerbini,Andreea Ciudin,Santiago Perez-Hoyos,Lieza Exalto,Geert Jan Biessels,Noemi Lois
AIMS/HYPOTHESISThere are no robust, reliable and easy to administer tests to screen for mild cognitive impairment (MCI) in people living with diabetes. Since the retina is ontogenically brain-derived, we hypothesised that retinal biomarkers could be used, alone or in combination with other simple tests, to screen for MCI in people with diabetes.METHODSBaseline data from participants screened for RECOGNISED, a Horizon 2020-funded European project, were analysed. Main eligibility criteria for RECOGNISED included age ≥65 years, type 2 diabetes of over 5 years standing, no previous history of stroke or neurodegenerative disease, and no overt diabetic retinopathy or only mild-to-moderate non-proliferative diabetic retinopathy. Baseline characteristics of participants, including scores from the Montreal Cognitive Assessment test (MoCA) and Self-Administered Gerocognitive Examination, the Diabetes Specific Dementia Risk Score (DSDRS) and ophthalmological endpoints gathered from standardised seven field colour fundus photography, spectral domain optical coherence tomography, microperimetry and a hand-held portable electroretinography device (RETeval), were obtained and used in the work presented here as potential screening predictors for presence of MCI. MCI and normocognition (NC) were determined based on a full neuropsychological test battery and the Clinical Dementia Rating score. A stepwise selection of variables, based on Akaike's information criterion, and logistic regression models for predicting MCI were undertaken. Area under the receiver-operating characteristic curve analyses were used to predict the probability of the presence of MCI as well as sensitivity and specificity cut-off points.RESULTSA total of 313 people living with diabetes (128 with NC and 185 with MCI) were included. People with diabetes with MCI were older (p=0.006) and had fewer years of education (p<0.001), lower retinal sensitivity (p=0.01) and less capacity of gaze fixation (p≤0.001) than those with NC. Statistically significant differences in pupillary area ratio (p=0.002) and photopic b-wave amplitude (p=0.03) were detected between people with diabetes with NC and with MCI. Multivariable logistic regression showed that the best model to identify people with diabetes with MCI was that combining retinal sensitivity, gaze fixation, photopic b-wave amplitude and pupillary size change following stimulation, years of education, DSDRS and MoCA score, with an AUC of 0.84 (sensitivity 79.9, specificity 79.0). The visuo-construction domain was the most affected in people with diabetes with MCI and its impairment was independently related to retinal sensitivity and gaze fixation.CONCLUSIONS/INTERPRETATIONThe assessment of retinal neurodysfunction in combination with simple clinical variables appears useful to identify people with diabetes with MCI. This strategy could optimise current screening of MCI in people living with diabetes.
{"title":"Relationship between retinal neurodysfunction and cognitive impairment in type 2 diabetes: results of the RECOGNISED cross-sectional study.","authors":"Rafael Simó,Cristina Hernández,Simona Frontoni,Paolo Sbraccia,Reinier Schlingemann,Xavier Valldeperas,Stela Vujosevic,Inês Marques,José Cunha-Vaz,Jakob Grauslund,Frederik N Pedersen,María-José Barahona,Natasa Popovic,Gianpaolo Zerbini,Andreea Ciudin,Santiago Perez-Hoyos,Lieza Exalto,Geert Jan Biessels,Noemi Lois","doi":"10.1007/s00125-025-06664-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06664-4","url":null,"abstract":"AIMS/HYPOTHESISThere are no robust, reliable and easy to administer tests to screen for mild cognitive impairment (MCI) in people living with diabetes. Since the retina is ontogenically brain-derived, we hypothesised that retinal biomarkers could be used, alone or in combination with other simple tests, to screen for MCI in people with diabetes.METHODSBaseline data from participants screened for RECOGNISED, a Horizon 2020-funded European project, were analysed. Main eligibility criteria for RECOGNISED included age ≥65 years, type 2 diabetes of over 5 years standing, no previous history of stroke or neurodegenerative disease, and no overt diabetic retinopathy or only mild-to-moderate non-proliferative diabetic retinopathy. Baseline characteristics of participants, including scores from the Montreal Cognitive Assessment test (MoCA) and Self-Administered Gerocognitive Examination, the Diabetes Specific Dementia Risk Score (DSDRS) and ophthalmological endpoints gathered from standardised seven field colour fundus photography, spectral domain optical coherence tomography, microperimetry and a hand-held portable electroretinography device (RETeval), were obtained and used in the work presented here as potential screening predictors for presence of MCI. MCI and normocognition (NC) were determined based on a full neuropsychological test battery and the Clinical Dementia Rating score. A stepwise selection of variables, based on Akaike's information criterion, and logistic regression models for predicting MCI were undertaken. Area under the receiver-operating characteristic curve analyses were used to predict the probability of the presence of MCI as well as sensitivity and specificity cut-off points.RESULTSA total of 313 people living with diabetes (128 with NC and 185 with MCI) were included. People with diabetes with MCI were older (p=0.006) and had fewer years of education (p<0.001), lower retinal sensitivity (p=0.01) and less capacity of gaze fixation (p≤0.001) than those with NC. Statistically significant differences in pupillary area ratio (p=0.002) and photopic b-wave amplitude (p=0.03) were detected between people with diabetes with NC and with MCI. Multivariable logistic regression showed that the best model to identify people with diabetes with MCI was that combining retinal sensitivity, gaze fixation, photopic b-wave amplitude and pupillary size change following stimulation, years of education, DSDRS and MoCA score, with an AUC of 0.84 (sensitivity 79.9, specificity 79.0). The visuo-construction domain was the most affected in people with diabetes with MCI and its impairment was independently related to retinal sensitivity and gaze fixation.CONCLUSIONS/INTERPRETATIONThe assessment of retinal neurodysfunction in combination with simple clinical variables appears useful to identify people with diabetes with MCI. This strategy could optimise current screening of MCI in people living with diabetes.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"281 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073050","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}
Aims/hypothesis Dermal fibroblasts have emerged as potential contributors to chronic pain, yet their role in diabetic polyneuropathy (DPN) and neuropathic pain remains poorly defined. Mitochondrial dysfunction and low-grade inflammation have been implicated in different pain conditions, but whether fibroblast mitochondrial health and cytokine secretion contribute to painful DPN is unknown. Methods We conducted an integrated cellular and molecular profiling of dermal fibroblasts and skin biopsies from 30 participants, grouped into control participants ( n =5), diabetes without DPN ( n =7), pain-free DPN ( n =7) and painful DPN ( n =11). Fibroblast cultures ( n =24) were evaluated for morphology, growth rate, phenotype, inflammatory mediator secretion and mitochondrial function. Immunohistochemistry of skin biopsies was used to assess fibroblast density, mitochondrial markers and immune cell infiltration. Results Fibroblast morphology and proliferation did not differ significantly between groups. Flow cytometric profiling revealed no significant differences in fibroblast subtype distributions across groups. Inflammatory mediator secretion was limited. Mitochondrial mass, membrane potential, reactive oxygen species production and bioenergetic parameters were not different across groups. Skin biopsy analyses confirmed comparable fibroblast density and mitochondrial profiles across groups, regardless of neuropathy or pain. Notably, dermal macrophage infiltration was significantly elevated in the painful DPN group (mean ~8%; ANOVA p =0.02; painful DPN vs control participants p =0.02; painful DPN vs pain-free DPN p =0.07), consistent with prior findings from the same cohort, while Langerhans cell area fraction did not differ between groups. Conclusions/interpretation Fibroblasts from participants with painful DPN did not differ in inflammatory and mitochondrial profiles compared with those from pain-free DPN. However, persistent dermal macrophage infiltration in painful DPN suggests a stable immune-activated microenvironment, potentially contributing to pain maintenance. Our results suggest that immune-related, rather than fibroblast-intrinsic, mechanisms could play a role in sustaining neuropathic pain in painful DPN. Graphical
{"title":"Dermal fibroblast mitochondrial profiles in painful diabetic neuropathy","authors":"Julie Mie Mølgaard Bentzen, Peter Kolind Brask-Thomsen, Maiken Krogsbæk, Xiaoli Hu, Jens Randel Nyengaard, Sandra Sif Gylfadottir, Pall Karlsson, Nanna Brix Finnerup, Rikke Katrine Jentoft Olsen, Zahra Nochi","doi":"10.1007/s00125-025-06660-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06660-8","url":null,"abstract":"Aims/hypothesis Dermal fibroblasts have emerged as potential contributors to chronic pain, yet their role in diabetic polyneuropathy (DPN) and neuropathic pain remains poorly defined. Mitochondrial dysfunction and low-grade inflammation have been implicated in different pain conditions, but whether fibroblast mitochondrial health and cytokine secretion contribute to painful DPN is unknown. Methods We conducted an integrated cellular and molecular profiling of dermal fibroblasts and skin biopsies from 30 participants, grouped into control participants ( <jats:italic>n</jats:italic> =5), diabetes without DPN ( <jats:italic>n</jats:italic> =7), pain-free DPN ( <jats:italic>n</jats:italic> =7) and painful DPN ( <jats:italic>n</jats:italic> =11). Fibroblast cultures ( <jats:italic>n</jats:italic> =24) were evaluated for morphology, growth rate, phenotype, inflammatory mediator secretion and mitochondrial function. Immunohistochemistry of skin biopsies was used to assess fibroblast density, mitochondrial markers and immune cell infiltration. Results Fibroblast morphology and proliferation did not differ significantly between groups. Flow cytometric profiling revealed no significant differences in fibroblast subtype distributions across groups. Inflammatory mediator secretion was limited. Mitochondrial mass, membrane potential, reactive oxygen species production and bioenergetic parameters were not different across groups. Skin biopsy analyses confirmed comparable fibroblast density and mitochondrial profiles across groups, regardless of neuropathy or pain. Notably, dermal macrophage infiltration was significantly elevated in the painful DPN group (mean ~8%; ANOVA <jats:italic>p</jats:italic> =0.02; painful DPN vs control participants <jats:italic>p</jats:italic> =0.02; painful DPN vs pain-free DPN <jats:italic>p</jats:italic> =0.07), consistent with prior findings from the same cohort, while Langerhans cell area fraction did not differ between groups. Conclusions/interpretation Fibroblasts from participants with painful DPN did not differ in inflammatory and mitochondrial profiles compared with those from pain-free DPN. However, persistent dermal macrophage infiltration in painful DPN suggests a stable immune-activated microenvironment, potentially contributing to pain maintenance. Our results suggest that immune-related, rather than fibroblast-intrinsic, mechanisms could play a role in sustaining neuropathic pain in painful DPN. Graphical","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"7 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048501","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}
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