Diabetologia最新文献_第4页

Systematic analysis of loss-of-function variants across MODY genes demonstrates gene-specific effects and expands the spectrum of INS variants causing MODY. 对MODY基因中功能丧失变异的系统分析显示了基因特异性效应，并扩大了导致MODY的INS变异的范围。

IF 8.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-03-03 DOI: 10.1007/s00125-026-06685-7

Thomas W Laver,Aparajita Sriram,Matthew N Wakeling,Zeynep Şiklar,Farah Kobaisi,Oguzhan Kalyon,Andrew T Hattersley,Michael N Weedon,Sarah E Flanagan,Elisa De Franco,Kevin Colclough,Kashyap A Patel

AIMS/HYPOTHESISAccurate interpretation of loss-of-function (LOF) variants in MODY genes is essential for diagnosis but remains challenging, particularly for variants that are predicted to escape nonsense-mediated decay (NMD). We aimed to systematically evaluate the pathogenicity of LOF variants, stratified by NMD-triggering and NMD-escape status, across all known MODY genes.METHODSWe analysed ultra-rare LOF variants (minor allele frequency <1 in 10,000) in 5171 individuals of European ancestry with suspected MODY, compared with 155,501 population-based control individuals from UK Biobank. LOF variants in ABCC8, GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, NEUROD1, PDX1 and RFX6 were classified as NMD-triggering or NMD-escape. We tested for gene-level enrichment in cases vs controls. For novel associations, we performed replication in additional MODY patients, assessed familial co-segregation, and undertook in silico protein modelling.RESULTSLOF variants were significantly enriched in all MODY genes except ABCC8 and KCNJ11. Both NMD-triggering and NMD-escape variants were enriched in GCK, HNF1A and HNF4A, consistent with haploinsufficiency (all p<10-3). HNF1B and RFX6 showed enrichment only for NMD-triggering variants, while NEUROD1 and PDX1 were enriched only for NMD-escape variants. A novel finding was the significant enrichment of only NMD-escape LOF variants in INS (OR=181, p<10-5). Including replication in additional MODY patients, we identified eight families with 17 affected individuals carrying INS variants. These variants co-segregated with diabetes (logarithm of the odds score=3), included one de novo case, and were absent from >800,000 population control individuals. Individuals presented with diabetes at a median age of 19 years, had median BMI of 22.9 kg/m2, were negative for islet autoantibodies, and had low type 1 diabetes genetic risk scores. Compared with INS missense MODY, diagnosis occurred approximately 10 years later in individuals with NMD-escape LOF variants. Protein modelling suggested that INS NMD-escape variants produce aberrant proinsulin molecules with unpaired B-chain cysteines, leading to milder misfolding.CONCLUSIONS/INTERPRETATIONThe pathogenicity of LOF variants in MODY genes depends on gene context and NMD status. Heterozygous NMD-escape LOF variants in INS are a novel cause of MODY. These findings provide systematic gene-level evidence to inform variant interpretation guidelines and improve the accuracy of MODY diagnosis in clinical practice.

目的/假设对MODY基因中功能丧失（LOF）变异的准确解释对于诊断至关重要，但仍然具有挑战性，特别是对于预测可以逃脱无义介导的衰变（NMD）的变异。我们的目的是系统地评估LOF变异的致病性，根据nmd触发和nmd逃逸状态对所有已知的MODY基因进行分层。方法对80万对照人群进行超罕见LOF变异（次要等位基因频率）分析。糖尿病患者中位年龄为19岁，中位BMI为22.9 kg/m2，胰岛自身抗体呈阴性，1型糖尿病遗传风险评分较低。与INS错义MODY相比，nmd逃逸型LOF变异患者的诊断时间大约晚10年。蛋白质模型表明，INS nmd -逸出变体产生异常的胰岛素原分子，其中含有未配对的b链半胱氨酸，导致较轻微的错误折叠。结论/解释MODY基因中LOF变异的致病性取决于基因背景和NMD状态。INS中的杂合nmd逃逸型LOF变异是引起MODY的新原因。这些发现为变异解释指南提供了系统的基因水平证据，并提高了临床实践中MODY诊断的准确性。

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引用次数: 0

A diabetes-induced change of MDM2 SNP309T→G contributes to aberrant retinal angiogenesis. 糖尿病引起的MDM2 SNP309T→G的改变导致视网膜血管生成异常。

IF 10.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-03-02 DOI: 10.1007/s00125-026-06695-5

Gaoen Ma, Wenyi Wu, Yajian Duan, Yanhui Yang, Xionggao Huang, Zhuo Pang, Heng Jiang, Junkai Ma, Fang Yuan, Guohong Zhou, Bart Vanhaesebroeck, Jing Luo, Xiaohe Yan, Hetian Lei

Aims/hypothesis: The 309G SNP in the second promoter of the gene encoding mouse double minute 2 (MDM2) has been implicated in multiple human diseases. The aims of this study were to determine whether MDM2 SNP309G is associated with proliferative diabetic retinopathy (PDR), and whether it contributes to pathological angiogenesis.Methods: Sanger DNA sequencing was used to determine the MDM2 SNP309 status in peripheral blood and fibrovascular membranes (FVMs) from individuals with PDR, as well as in epiretinal membranes from individuals with proliferative vitreoretinopathy (PVR). An ELISA was used to quantify the levels of the oxidative DNA damage biomarker 8-oxo-2'-deoxyguanosine in vitreous humour samples from individuals with PDR or PVR. Prime editing was employed to introduce MDM2 SNP309G into primary human retinal microvascular endothelial cells (HRECs), which were then assessed for in vitro angiogenic activities, including proliferation, migration and tube formation. A mouse model of oxygen-induced retinopathy (OIR) was used to evaluate pathological retinal neovascularisation in humanised mice carrying MDM2 SNP309T or SNP309G. Quantitative RT-PCR and western blot analyses were performed to assess gene and protein expression related to MDM2-mediated signalling pathways.Results: An association between MDM2 SNP309G and PDR was identified. Among 110 individuals with PDR, 60.1% harboured MDM2 SNP309G in their FVMs, and 20.9% exhibited a T→G substitution at position 309 in FVMs compared with matched blood samples. The vitreous humour from individuals with PDR contained significantly higher levels of 8-oxo-2'-deoxyguanosine (7.8±1.2-fold) compared with PVR control participants. Chronic exposure of primary HRECs to vitreous humour containing a high concentration of D-glucose suppressed expression of 8-oxoguanine DNA glycosylase, promoted conversion of MDM2 SNP309T to G (36.1%), and increased MDM2 protein levels. Prime editing-mediated conversion of MDM2 SNP309T to G in HRECs (51.6%) further enhanced high-glucose-induced MDM2 expression and angiogenic responses in vitro. In vivo, humanised C57BL/6J mice carrying MDM2 SNP309G exhibited increased retinal levels of MDM2, hypoxia-inducible factor-1α (HIF-1α), phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2), phosphorylated Erk1/2 and phosphorylated specificity protein 1 (Sp1), together with elevated vascular endothelial growth factor (VEGF) in the vitreous humour, and exacerbated pathological retinal angiogenesis in the OIR model, compared with mice harbouring MDM2 SNP309T.Conclusions/interpretation: These findings suggest that MDM2 SNP309G drives a positive feedback loop involving MDM2 and VEGF signalling in vascular endothelial cells, thereby promoting pathological angiogenesis. Targeting the second promoter of MDM2 may represent a novel therapeutic strategy for preventing aberrant angiogenesi

目的/假设：编码小鼠双分钟2 （MDM2）基因的第二个启动子309G SNP与多种人类疾病有关。本研究的目的是确定MDM2 SNP309G是否与增殖性糖尿病视网膜病变（PDR）相关，以及它是否有助于病理性血管生成。方法：采用Sanger DNA测序方法检测MDM2 SNP309在PDR患者外周血和纤维血管膜（fvm）以及增生性玻璃体视网膜病变（PVR）患者视网膜前膜中的状态。采用ELISA法定量测定PDR或PVR患者玻璃体样本中氧化DNA损伤生物标志物8-氧-2′-脱氧鸟苷的水平。采用引体编辑将MDM2 SNP309G导入原代人视网膜微血管内皮细胞（HRECs），然后评估其体外血管生成活性，包括增殖、迁移和成管。采用小鼠氧致视网膜病变（OIR）模型来评估携带MDM2 SNP309T或SNP309G的人源化小鼠的病理性视网膜新生血管。采用定量RT-PCR和western blot分析评估与mdm2介导的信号通路相关的基因和蛋白表达。结果：MDM2 SNP309G与PDR之间存在关联。在110名PDR患者中，60.1%的人在fvm中携带MDM2 SNP309G， 20.9%的人在fvm中309位出现T→G替换。与PVR对照组相比，PDR患者的玻璃体体液中8-氧-2′-脱氧鸟苷含量显著升高（7.8±1.2倍）。原发性HRECs长期暴露于含高浓度d -葡萄糖的玻璃体中，可抑制8-氧鸟嘌呤DNA糖基化酶的表达，促进MDM2 SNP309T向G的转化（36.1%），并增加MDM2蛋白水平。引物编辑介导的MDM2 SNP309T在HRECs中转化为G（51.6%）进一步增强了高糖诱导的MDM2表达和体外血管生成反应。在体内，与携带MDM2 SNP309T的小鼠相比，携带MDM2 SNP309G的人源化C57BL/6J小鼠在OIR模型中表现出视网膜MDM2、缺氧诱导因子-1α (HIF-1α)、磷酸化血管内皮生长因子受体2 （VEGFR2）、磷酸化Erk1/2和磷酸化特异性蛋白1 （Sp1）水平升高，玻璃体中血管内皮生长因子（VEGF）水平升高，病理性视网膜血管生成加剧。结论/解释：这些发现提示MDM2 SNP309G在血管内皮细胞中驱动涉及MDM2和VEGF信号的正反馈循环，从而促进病理性血管生成。靶向MDM2的第二启动子可能是预防PDR异常血管生成的一种新的治疗策略。

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引用次数: 0

Atypical diabetes subtypes in Black African populations. 非洲黑人人群中的非典型糖尿病亚型。

IF 10.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-03-02 DOI: 10.1007/s00125-026-06697-3

Jean Claude Katte, Charlotte Bavuma, Sarah H Wild, Meredith Hawkins, Nihal Thomas, Eugene Sobngwi, Moffat J Nyirenda, Davis Kibirige

Atypical diabetes subtypes and presentations are disproportionately prevalent in populations of African and Asian ancestry. This review discusses the epidemiology, clinical presentation, aetiopathogenesis and management of four atypical diabetes subtypes commonly reported in Black African populations. These are ketosis-prone diabetes (KPD), fibrocalculous pancreatic diabetes (FCPD), type 2 diabetes in individuals without overweight or obesity, and malnutrition-related diabetes (MRD). The review summarises current insights into these atypical diabetes subtypes in Black African populations and provides practical recommendations to guide their precision diagnosis and management in the African region. These four atypical diabetes subtypes exhibit phenotypic features that diverge from those of classical type 1 and type 2 diabetes. KPD is characterised by unprovoked, transient, index episodes of diabetic ketoacidosis, often in the absence of markers of islet cell autoimmunity, with frequent subsequent insulin independence and diabetes remission. FCPD typically presents in young lean individuals, with a strong male preponderance and with radiological evidence of pancreatic calcifications, reduced beta cell reserve and severe hyperglycaemia without ketosis. Type 2 diabetes in individuals without overweight or obesity is characterised by normal BMI with a trend towards low levels of markers of visceral adiposity, insulin resistance and an exaggerated beta cell secretory dysfunction. MRD is associated with a previous and persistent history of undernutrition, with features of undernutrition such as stunting and BMI <18.5 kg/m², resistance to diabetic ketoacidosis, no evidence of visceral or ectopic adiposity, and severe beta cell secretory dysfunction. The high prevalence and heterogeneous presentation of these atypical forms of diabetes in African populations highlight the urgent need for enhanced collaborative research to better define their epidemiology, improve diagnostic accuracy and develop context-appropriate management strategies tailored to diverse African populations.

非典型糖尿病亚型和表现在非洲和亚洲血统人群中不成比例地普遍。本文综述了非洲黑人人群中常见的四种非典型糖尿病亚型的流行病学、临床表现、发病机制和治疗方法。这些是酮症易感性糖尿病（KPD）、纤维结石性胰腺糖尿病（FCPD）、非超重或肥胖个体的2型糖尿病和营养不良相关糖尿病（MRD）。这篇综述总结了目前对非洲黑人人群中这些非典型糖尿病亚型的见解，并提供了实用的建议，以指导非洲地区对这些亚型的精确诊断和管理。这四种非典型糖尿病亚型表现出与经典1型和2型糖尿病不同的表型特征。KPD的特征是无端的、短暂的、糖尿病酮症酸中毒的指数发作，通常在缺乏胰岛细胞自身免疫标志物的情况下，随后经常出现胰岛素依赖性和糖尿病缓解。FCPD通常出现在年轻、瘦弱的个体中，男性居多，影像学表现为胰腺钙化、β细胞储备减少和严重的高血糖，但无酮症。没有超重或肥胖的2型糖尿病患者的特征是BMI正常，但内脏脂肪、胰岛素抵抗和β细胞分泌功能障碍的指标水平较低。MRD与既往和持续的营养不良史有关，营养不良的特征包括发育迟缓和BMI 2，对糖尿病酮症酸中毒的抵抗，无内脏或异位性肥胖的证据，以及严重的β细胞分泌功能障碍。非洲人群中这些非典型糖尿病的高患病率和异质性突出了加强合作研究的迫切需要，以更好地确定其流行病学，提高诊断准确性，并制定适合不同非洲人群的管理策略。

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引用次数: 0

Fully closed-loop systems: can people with type 1 diabetes just do it? Insights from open-source systems. 全闭环系统：1型糖尿病患者能做到吗？来自开源系统的见解。

IF 10.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-03-01 Epub Date: 2026-01-19 DOI: 10.1007/s00125-025-06644-8

Rayhan Lal, Katarina Braune, Dana M Lewis, Lenka Petruzelkova, Martin de Bock, Sufyan Hussain

Automated insulin delivery (AID) systems have significantly advanced diabetes management, progressively reducing user interactions required for optimal glucose management. This review evaluates the current landscape and future potential of AID systems without meal announcement, particularly focusing on real-world insights from open-source AID (OS-AID) technologies. Although commercial AID systems operating in hybrid closed-loop (HCL) mode have improved glycaemic outcomes, they remain dependent on manual meal announcement and user-driven actions, limiting their real-world utility. Current versions of OS-AID systems, developed by the diabetes community, can allow operation without meal announcements, presenting an opportunity to move closer to truly automated diabetes management. Recent clinical trials suggest that OS-AID systems can effectively manage glucose levels without meal announcements, achieving glucose levels comparable with those obtained by AID systems in HCL mode, with the potential of reduced management burden for users. However, practical challenges persist, including the need for expert configuration and handling of rapid changes in insulin sensitivity, such as during exercise or rapid glucose fluctuations following predicted low-glucose. This review synthesises insights from user and healthcare professional experiences, and emerging clinical evidence. It highlights the fact that successful implementation of AID without meal announcement requires advanced algorithmic responsiveness, user personalisation and ongoing clinician engagement. Looking forward, integrating adjunctive therapies, artificial intelligence and enhanced physiological modelling will likely enhance system performance to drive the next generation of diabetes care towards wider adoption and true 'set-and-forget' functionality.

自动胰岛素输送（AID）系统具有显著先进的糖尿病管理，逐步减少最佳葡萄糖管理所需的用户交互。本文评估了AID系统的现状和未来潜力，但没有正式宣布，特别关注开源AID （OS-AID）技术的现实见解。尽管以混合闭环（HCL）模式运行的商用AID系统改善了血糖结果，但它们仍然依赖于手动膳食公告和用户驱动的操作，限制了它们在现实世界中的效用。由糖尿病社区开发的OS-AID系统的当前版本可以在没有用餐通知的情况下进行操作，这为真正的自动化糖尿病管理提供了机会。最近的临床试验表明，OS-AID系统可以在没有用餐通知的情况下有效地管理血糖水平，达到与AID系统在HCL模式下获得的血糖水平相当的水平，并有可能减轻用户的管理负担。然而，实际的挑战仍然存在，包括需要专家配置和处理胰岛素敏感性的快速变化，例如在运动期间或预测低血糖后的快速血糖波动。这篇综述综合了来自用户和医疗保健专业经验以及新出现的临床证据的见解。它强调了这样一个事实，即成功实施无餐公告的艾滋病需要先进的算法响应能力、用户个性化和持续的临床医生参与。展望未来，整合辅助疗法、人工智能和增强的生理建模可能会提高系统性能，推动下一代糖尿病护理走向更广泛的采用和真正的“设置和遗忘”功能。

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引用次数: 0

David Ross Laybutt, 1969-2026. David Ross Laybutt, 1969-2026。

IF 10.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-02-27 DOI: 10.1007/s00125-026-06704-7

Melkam A Kebede, Trevor Biden

引用次数: 0

GlucoseGo: a simple tool to predict hypoglycaemia during exercise in type 1 diabetes GlucoseGo：预测1型糖尿病患者运动期间低血糖的简单工具

IF 8.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-02-25 DOI: 10.1007/s00125-026-06692-8

Catherine L. Russon, Michael J. Allen, Emma Cockcroft, John S. Pemberton, Anne-Marie Frohock, Neil Vaughan, Richard M. Pulsford, Robert C. Andrews

Aims/hypothesis This study aimed to develop an accessible tool, derived using machine learning, to predict hypoglycaemia risk at the start of exercise and to provide clear, rapid risk assessment to support safer participation in exercise. Methods Data from four diverse studies were combined, encompassing 16,430 exercise sessions from 834 participants aged 12–80 years using various insulin delivery methods. The XGBoost algorithm was used to develop two models: a comprehensive model and a simplified model for predicting hypoglycaemia during exercise. Results The comprehensive model (406 variables) achieved a mean ROC AUC of 0.89. The simplified model, using only starting glucose, exercise duration and glucose trend arrows, achieved a comparable ROC AUC of 0.87. The simplified model performed consistently across exercise types and insulin delivery methods. In collaboration with individuals with type 1 diabetes, this model was translated into GlucoseGo, a user-friendly traffic-light heatmap displaying hypoglycaemia risk based on the three variables. Conclusions/interpretation The GlucoseGo heatmap provides a practical, accessible tool for predicting hypoglycaemia risk immediately before exercise. It may empower individuals with type 1 diabetes to exercise more safely, reduce hypoglycaemic episodes, and increase engagement in physical activity. Graphical

目的/假设本研究旨在开发一种可访问的工具，使用机器学习来预测运动开始时的低血糖风险，并提供清晰，快速的风险评估，以支持更安全的运动参与。方法将来自四项不同研究的数据结合起来，包括来自834名年龄在12-80岁之间的参与者的16,430次锻炼，使用各种胰岛素给药方法。利用XGBoost算法建立了运动期间低血糖预测的综合模型和简化模型。结果综合模型（406个变量）的平均ROC AUC为0.89。简化模型仅使用起始葡萄糖、运动持续时间和葡萄糖趋势箭头，其可比ROC AUC为0.87。简化的模型在不同的运动类型和胰岛素输送方法中表现一致。在与1型糖尿病患者的合作中，该模型被转化为GlucoseGo，这是一个用户友好的红绿灯热图，显示基于三个变量的低血糖风险。结论/解释GlucoseGo热图为在运动前预测低血糖风险提供了一个实用、方便的工具。它可以使1型糖尿病患者更安全地锻炼，减少低血糖发作，并增加体力活动。图形化的

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引用次数: 0

The diabetes-associated K⁺ channel TALK-2 controls human beta cell endoplasmic reticulum Ca²⁺ handling, which promotes basal insulin release and limits glucose-stimulated insulin secretion. 糖尿病相关的K+通道TALK-2控制人β细胞内质网Ca2+处理，促进基础胰岛素释放并限制葡萄糖刺激的胰岛素分泌。

IF 10.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-02-25 DOI: 10.1007/s00125-026-06683-9

Jordyn R Dobson, Prasanna K Dadi, Matthew T Dickerson, Arya Y Nakhe, Soma Behera, Shannon E Gibson, Spencer J Peachee, Anthony Piron, Miriam Cnop, David A Jacobson

Aims/hypothesis: The two-pore domain K+ channel TWIK1-related alkalinisation-activated K+ channel 2 (TALK-2) is encoded by KCNK17, which is one of the most abundant beta cell K+ channel transcripts that also shows high islet expression specificity. Polymorphisms that increase islet KNCK17 expression or result in TALK-2 gain-of-function are associated with a predisposition for developing type 2 diabetes. However, there is a gap in knowledge of the beta cell function(s) of TALK-2. As K+ channels typically control beta cell Ca2+ handling, we aimed to examine the TALK-2 channel control of beta cell Ca2+ homeostasis and the resulting impact on insulin secretion.Methods: Localisation of TALK-2 was evaluated with immunofluorescent staining as well as TALK-2-GFP construct co-expressed with intracellular markers. TALK-2 function was evaluated by measuring changes in cytoplasmic Ca2+ (Ca2+C), endoplasmic reticulum Ca2+ (Ca2+ER), ER membrane potential (Vm), K+ currents and insulin secretion in a TALK-2 inducible cell line and/or primary human beta cells with adenoviral-mediated shRNA knockdown (KD) of TALK-2 or scramble shRNA.Results: TALK-2 protein localised to the plasma membrane and ER membrane, and formed functional channels on the ER membrane. Ca2+ER release was accelerated by TALK-2 (slope for TALK-2-expressing cells vs controls: 14.8 ± 0.7 vs 8.9 ± 1.3, respectively, shown as mean ± SE), which reduced Ca2+ER storage (ΔCa2+ER amplitude: TALK-2-expressing cells reduced by 25 ± 5%) and increased basal relative Ca2+C (fold increase by 12 ± 2%). Furthermore, TALK-2 diminished ER membrane hyperpolarisation following Ca2+ER release (Accelerated Sensor of Action Potentials [ASAP3ER] amplitude decreased by 20 ± 0.8% in TALK-2-expressing cells), suggesting that TALK-2 strengthens the electrical driving force for Ca2+ER leak. In human beta cells, TALK-2-KD increased Ca2+ER stores by reducing Ca2+ER leak (2.30 ± 0.12 vs controls 2.65 ± 0.14). Moreover, TALK-2-KD reduced beta cell Ca2+C at euglycaemic conditions (2.88 ± 0.36 vs controls 3.16 ± 0.36) and increased beta cell Ca2+C influx in response to hyperglycaemic conditions (4.07 ± 0.55 vs controls 3.45 ± 0.48). Human pseudoislets with beta cell-specific TALK-2-KD displayed reduced basal insulin secretion (0.266 ± 0.065 vs controls 0.432 ± 0.073) and enhanced glucose-stimulated insulin secretion (GSIS; 85.01 ± 13.96 vs controls 42.53 ± 5.52).Conclusions/interpretation: These data support the notion that TALK-2 functions on the human beta cell

目的/假设：双孔域K+通道twik1相关碱化激活K+通道2 （TALK-2）由KCNK17编码，KCNK17是β细胞中最丰富的K+通道转录本之一，也具有较高的胰岛表达特异性。增加胰岛KNCK17表达或导致TALK-2功能获得的多态性与患2型糖尿病的易感性相关。然而，对TALK-2的β细胞功能的了解还存在空白。由于K+通道通常控制β细胞Ca2+处理，我们旨在研究TALK-2通道控制β细胞Ca2+稳态及其对胰岛素分泌的影响。方法：采用免疫荧光染色及与细胞内标记共表达的TALK-2- gfp构建物评价TALK-2的定位。通过测量TALK-2诱导细胞系和/或原代人β细胞中细胞质Ca2+ (Ca2+C)、内质网Ca2+ (Ca2+ER)、ER膜电位（Vm）、K+电流和胰岛素分泌的变化来评估TALK-2功能，腺病毒介导的TALK-2 shRNA敲低（KD）或scramble shRNA。结果：TALK-2蛋白定位于质膜和内质膜，并在内质膜上形成功能通道。TALK-2加速了Ca2+ER的释放（表达TALK-2的细胞与对照组的斜率分别为14.8±0.7 vs 8.9±1.3，用平均值±SE表示），从而减少了Ca2+ER的储存（ΔCa2+ER振幅：表达TALK-2的细胞减少了25±5%）并增加了基础相对Ca2+C（增加了12±2%）。此外，在Ca2+ER释放后，TALK-2降低了ER膜的超极化（在表达TALK-2的细胞中，ASAP3ER的振幅下降了20±0.8%），表明TALK-2增强了Ca2+ER泄漏的电驱动力。在人β细胞中，TALK-2-KD通过减少Ca2+ER泄漏增加Ca2+ER储存（2.30±0.12 vs对照组2.65±0.14）。此外，TALK-2-KD在高血糖状态下降低β细胞Ca2+C(2.88±0.36 vs对照组3.16±0.36)，在高血糖状态下增加β细胞Ca2+C内流（4.07±0.55 vs对照组3.45±0.48）。具有β细胞特异性TALK-2-KD的人假胰岛显示基础胰岛素分泌减少（0.266±0.065 vs对照组0.432±0.073），葡萄糖刺激胰岛素分泌增强（GSIS; 85.01±13.96 vs对照组42.53±5.52）。结论/解释：这些数据支持了TALK-2在人β细胞ER膜上的功能，以增加β细胞Ca2+ER释放的电驱动力，减少葡萄糖刺激的Ca2+内流并限制GSIS。此外，talk -2介导的Ca2+ER泄漏的扩增可能通过增加Ca2+C来增强基础胰岛素分泌。因此，增加TALK-2活性或表达的KCNK17多态性可以通过减弱β细胞葡萄糖刺激的Ca2+内流、限制GSIS、促进Ca2+ER泄漏和提高基础胰岛素分泌来增加2型糖尿病的风险。

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引用次数: 0

Canagliflozin attenuates CMR-quantified myocardial fibrosis in individuals with type 2 diabetes mellitus at high cardiovascular risk: a randomised open-label controlled trial. canag列净减轻心血管高危2型糖尿病患者cmr量化心肌纤维化：一项随机开放标签对照试验

IF 10.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-02-24 DOI: 10.1007/s00125-026-06682-w

Hongmei Yan, Jiaojiao Liu, Zhitian Zhang, Shuangshuang Chen, Xinxia Chang, Hang Jin, Xiaoying Li, Yinyin Chen, Ying Chen, Mengsu Zeng

Aims/hypothesis: We aimed to investigate canagliflozin's effects on myocardial fibrosis, cardiac structure and function, and microcirculation in high-cardiovascular-risk type 2 diabetes mellitus through cardiac magnetic resonance (CMR) quantification, while investigating the cardiovascular protective mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibitors.Methods: This open-label parallel RCT recruited 45 high-risk participants (18-75 years) with type 2 diabetes (HbA1c 53.0-91.3 mmol/mol [7.0-10.5%]) and left ventricular ejection fraction (LVEF) >50% from the Endocrinology Outpatient Clinic of Zhongshan Hospital, Fudan University (August 2022 to November 2024). Participants were 1:1 randomised via a computer-generated sequence through the centralised iClinicalStation system (allocation concealed, performed by independent personnel not involved in outcome assessment). They received canagliflozin 100 mg/day (n=23) or sitagliptin 100 mg/day (n=22) for 26 weeks. Consistent with the open-label design, participants and care providers were aware of treatment assignments; however, outcome assessors (radiologists, sonographers) and data analysts remained blinded to group allocation to minimise bias. The primary endpoint was CMR-quantified extracellular volume (ECV) change. Secondary outcomes included ventricular structure and function parameters, for example, left ventricular end-diastolic volume, left ventricular end-diastolic diameter, LVEF, etc. RESULTS: Among 67 individuals screened, 45 completed the intention-to-treat analysis (age 60.4 ± 9.7 years, BMI 26.4 ± 2.6 kg/m2, HbA1c 63.0 ± 8.7 mmol/mol [7.9 ± 0.8%]). At 26 weeks, compared with sitagliptin, canagliflozin significantly reduced the primary outcome of ECV (adjusted mean difference [AMD]: -3.67%; 95% CI -5.33, -2.01; p<0.001). Significant improvements were also observed in cardiac structure, including left ventricular end-diastolic volume (AMD: -20.72 ml; 95% CI -36.30, -5.14; p=0.010) and echocardiography-derived end-diastolic diameter (AMD: -2.82 mm; 95% CI -4.95, -0.70; p=0.010). Both groups showed comparable reductions in HbA1c (both Δ 0.7%, inter-group p=0.972).Conclusions/interpretation: This study demonstrates that 26 weeks of canagliflozin significantly reduces myocardial fibrosis, as assessed by CMR-derived ECV, in individuals with type 2 diabetes at high cardiovascular risk, providing imaging evidence for SGLT2 inhibitor cardiovascular protection mechanisms.Trial registration: ClinicalTrials.gov NCT05367063 FUNDING: This study was financially supported by the National Key Research and Development programme (2023YFA1802000), the National Natural Science Foundation of China (Youth Fund 82200909), the Young and Middle-aged Diabetes project from the Bethune Foundation (Z04JKM2022E002), the Joint Research Development project between Shenkang and Un

目的/假设：我们旨在通过心脏磁共振（CMR）定量研究卡格列净对高心血管风险2型糖尿病患者心肌纤维化、心脏结构功能和微循环的影响，同时探讨钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂的心血管保护机制。方法：本开放标签平行随机对照试验从复旦大学中山医院内分泌科门诊（2022年8月至2024年11月）招募45例2型糖尿病（HbA1c 53.0-91.3 mmol/mol[7.0-10.5%]）、左室射血分数（LVEF） bbb50 %)高危受试者（18-75岁）。参与者通过中央iClinicalStation系统通过计算机生成的序列进行1:1随机分配（分配隐藏，由不参与结果评估的独立人员执行）。他们接受卡格列净100 mg/天（n=23）或西格列汀100 mg/天（n=22），持续26周。与开放标签设计一致，参与者和护理提供者都知道治疗任务；然而，结果评估者（放射科医生、超声医师）和数据分析师仍然对分组分配不知情，以尽量减少偏见。主要终点是cmr量化的细胞外体积（ECV）变化。次要结局包括左室结构和功能参数，如左室舒张末期容积、左室舒张末期内径、LVEF等。结果：筛选的67例患者中，45例完成意向治疗分析（年龄60.4±9.7岁，BMI 26.4±2.6 kg/m2, HbA1c 63.0±8.7 mmol/mol[7.9±0.8%]）。在26周时，与西格列汀相比，卡格列净显著降低了ECV的主要结局(校正平均差[AMD]: -3.67%; 95% CI: -5.33, -2.01; p1c（均为Δ 0.7%，组间p=0.972）。结论/解释：本研究表明，cmr衍生的ECV评估显示，26周坎格列净可显著减少心血管高危2型糖尿病患者的心肌纤维化，为SGLT2抑制剂心血管保护机制提供影像学证据。试验注册：ClinicalTrials.gov NCT05367063国家重点研发计划项目（2023YFA1802000）、国家自然科学基金项目（青年基金82200909）、白求恩基金中青年糖尿病项目（Z04JKM2022E002）、申康与联合影像临床研究与转化联合研发项目（SKLY2022CRT201）资助。2024年上海市“探索者计划”（第二批）项目（24TS1411000）和上海浦江计划（21PJD012）。

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引用次数: 0

Maternal pre-pregnancy BMI differentially regulates intracellular pH in human umbilical vein endothelium from gestational diabetes mellitus pregnancies, with alkalinisation-associated reduction of adenosine transport in normal weight pregnancies. 孕妇孕前BMI差异调节妊娠期糖尿病妊娠人脐静脉内皮细胞内pH值，与正常体重妊娠中碱化相关的腺苷转运减少。

IF 10.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-02-24 DOI: 10.1007/s00125-026-06679-5

Gonzalo Fuentes, Paola Valero, Marcelo Cornejo, Katherin Silva, Marco A Ramírez, Daniel R González, Jan-Luuk Hillebrands, Harry van Goor, Luis Sobrevia

Aims/hypothesis: Gestational diabetes mellitus (GDM) is associated with fetoplacental endothelial dysfunction, including impaired extracellular clearance of adenosine, a vasodilator, in HUVECs. This study investigated the regulation of intracellular pH (pHi) and its impact on adenosine membrane transport in HUVECs. The hypothesis of this study was that Na⁺/H⁺ exchanger (NHE) isoform 1 (NHE1)-dependent pHi regulation differs between normal and GDM pregnancies depending on maternal pre-pregnancy BMI, leading to differential human equilibrative nucleoside transporters-mediated adenosine transport.

Methods: HUVECs were isolated from 43 women with normal pregnancies and 23 with type A1 GDM and further stratified by maternal pre-pregnancy BMI into subgroups with normal weight, overweight and obesity. Data were also analysed as pooled groups (BMI ≥20 kg/m²). pHi and dpHi/dt were assessed in cells preloaded with the pH-sensitive fluorescent probe 2,7-bicarboxyethyl-5,6-carboxyfluorescein acetoxymethyl ester (12 µmol/l), in the absence or presence of 20 mmol/l NH₄Cl (acid pulse), the general NHEs inhibitor 5-N,N-hexamethylene amiloride (5 µmol/l) or the NHE1-selective inhibitor zoniporide (100 nmol/l). Intrinsic buffering capacity and H⁺ flux were calculated. NHE1 protein abundance was quantified by western blotting, and adenosine transport kinetics (0-500 µmol/l, 10 s) were determined.

Results: GDM was linked to intracellular alkalinisation (~0.6 pHi units vs normal pregnancies), increased activity of NHE1 and NHE isoforms 2 and 3 and reduced buffering capacity, with these effects varying by pre-pregnancy maternal BMI. Increased pHi recovery (~3.8-fold) and NHE1 activity (~4.8-fold) were observed in cells from women with GDM and pre-pregnancy overweight, while those with obesity (i.e. gestational diabesity) showed unaltered NHE1-mediated pHi recovery. Buffering capacity was reduced across most GDM groups, except in the overweight group. The GDM-reduced adenosine transport maximal capacity via human equilibrative nucleoside transporter isoform 2 was restored by intracellular acidification in GDM.

Conclusions/interpretation: Pre-pregnancy maternal metabolic status influences endothelial adaptation or maladaptation to GDM. Stratifying GDM cases by pre-pregnancy maternal BMI uncovers subgroup-specific physiological responses, highlighting the importance of tailored approaches in understanding GDM pathophysiology.

目的/假设：妊娠期糖尿病（GDM）与胎儿胎盘内皮功能障碍有关，包括HUVECs中腺苷（一种血管扩张剂）的细胞外清除受损。本研究探讨了HUVECs细胞内pH （pHi）的调节及其对腺苷膜转运的影响。本研究的假设是，Na+/H+交换器（NHE）异构体1 （NHE1）依赖的pHi调节在正常妊娠和GDM妊娠之间存在差异，这取决于母体孕前BMI，导致人类平衡核苷转运体介导的腺苷转运的差异。方法：从43例正常妊娠妇女和23例A1型GDM妇女中分离huvec，并根据孕妇孕前BMI分为正常体重、超重和肥胖亚组。数据也按合并组（BMI≥20 kg/m2）进行分析。在不含或存在20 mmol/l NH4Cl（酸脉冲）、一般NHEs抑制剂5- n -六亚甲基酰胺（5 µmol/l）或nhe1选择性抑制剂zoniporide（100 nmol/l）的情况下，预载ph敏感荧光探针2,7-二羧基乙基-5,6-羧基荧光素乙酰氧基甲酯（12 µmol/l）的细胞中，评估pHi和dpHi/dt。计算了H +的固有缓冲容量和通量。western blotting测定NHE1蛋白丰度，测定腺苷转运动力学（0-500 µmol/l, 10 s）。结果：GDM与细胞内碱化有关（与正常妊娠相比约0.6 pHi单位），NHE1和NHE亚型2和3活性增加，缓冲能力降低，这些影响因孕前母亲BMI而异。在GDM和孕前超重妇女的细胞中，观察到pHi恢复（~3.8倍）和NHE1活性（~4.8倍）增加，而肥胖（即妊娠期糖尿病）妇女的细胞中，NHE1介导的pHi恢复没有改变。除超重组外，大多数GDM组的缓冲能力降低。GDM通过人平衡核苷转运蛋白异构体2减少的腺苷转运最大能力通过GDM细胞内酸化恢复。结论/解释：孕前母体代谢状态影响内皮细胞对GDM的适应或不适应。通过孕前母亲BMI对GDM病例进行分层，揭示了亚组特异性生理反应，强调了定制方法在理解GDM病理生理中的重要性。

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引用次数: 0

Subtypes of newly diagnosed type 2 diabetes and risk of complications: analysis of electronic health records in the USA 新诊断的2型糖尿病亚型和并发症风险：美国电子健康记录分析

IF 8.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia

Pub Date : 2026-02-21 DOI: 10.1007/s00125-026-06687-5

Zhongyu Li, Star Liu, Joyce C. Ho, K. M. Venkat Narayan, Mohammed K. Ali, Jithin Sam Varghese

引用次数: 0