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Racial and ethnic disparities in the uptake of SGLT2is and GLP-1RAs among Medicare beneficiaries with type 2 diabetes and heart failure, atherosclerotic cardiovascular disease and chronic kidney disease, 2013–2019 2013-2019年2型糖尿病合并心力衰竭、动脉粥样硬化性心血管疾病和慢性肾病的医疗保险受益人在服用SGLT2is和GLP-1RAs方面的种族和民族差异
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-08 DOI: 10.1007/s00125-024-06321-2
Eric Wang, Elisabetta Patorno, Farzin Khosrow-Khavar, Stephen Crystal, Chintan V. Dave

Aims/hypothesis

The aim of this study was to investigate racial and ethnic disparities in the use of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor antagonists (GLP-1RAs) among older adults with type 2 diabetes and cardiorenal conditions.

Methods

Using Medicare fee-for-service data (2013–2019), this retrospective cohort study identified older adults (≥65 years) with type 2 diabetes initiating second-line therapies (SGLT2is, GLP1-RAs, dipeptidyl peptidase-4 inhibitors [DPP4is] and sulfonylureas [SUs]) with (1) heart failure (HF), (2) atherosclerotic cardiovascular disease (ASCVD), (3) chronic kidney disease (CKD) and (4) no recorded cardiorenal conditions. Participants were classified as non-Hispanic White, non-Hispanic Black and Hispanic. Multinomial regressions, adjusting for sociodemographic, clinical and county-level characteristics, were used to model the odds of initiating SGLT2is or GLP-1RAs within each cohort.

Results

Black participants with HF, ASCVD, CKD or no recorded cardiorenal conditions had 35% (adjusted OR 0.65 [95% CI 0.61, 0.68]), 33% (0.67 [0.64, 0.69]), 32% (0.68 [0.64, 0.72]) and 24% (0.76 [0.74, 0.79]) lower odds of initiating SGLT2is, respectively, than White participants. Disparities ameliorated from 50–60% lower odds in 2013 to 17–18% in 2019. Similar patterns were observed for GLP-1RA uptake among Black participants. By contrast, Hispanic participants had similar odds of SGLT2i initiation in the HF and CKD cohorts as White participants, but 6% (0.94 [0.91, 0.98]) lower odds in the ASCVD cohort. Notable disparities for Hispanic participants compared with White participants were observed for GLP-1RA uptake in the HF, ASCVD, CKD and no cardiorenal conditions cohorts: 11% (0.89 [0.84, 0.94]), 16% (0.84 [0.81, 0.87]), 16% (0.84 [0.80, 0.89]) and 25% (0.75 [0.72, 0.78]) lower odds, respectively. Participants had greater odds than White participants of initiating DPP4is, which confer no cardiorenal benefits, across all cohorts (HF 1.25 [1.19, 1.31]; ASCVD 1.36 [1.32, 1.40]; CKD 1.32 [1.26, 1.38). Adjustment for social determinants of health did not meaningfully change the study findings.

Conclusions/interpretation

Compared with White participants, disparities in the uptake of SGLT2is were evident for Black participants, and in the uptake of GLP-1RAs for both Black and Hispanic participants. This study highlights how type 2 diabetes management is evolving, while underscoring historical imbalances that have shown signs of abatement.

Graphical Abstract

目的/假设本研究旨在调查患有 2 型糖尿病和心力衰竭的老年人使用钠-葡萄糖共转运体 2 抑制剂 (SGLT2is) 和胰高血糖素样肽-1 受体拮抗剂 (GLP-1RA) 的种族和民族差异。方法利用医疗保险付费服务数据(2013-2019 年),这项回顾性队列研究确定了开始接受二线疗法(SGLT2is、GLP1-RAs、二肽基肽酶-4 抑制剂 [DPP4is] 和磺脲类药物 [SUs])的 2 型糖尿病老年人(≥65 岁),同时患有 (1)心力衰竭 (HF)、(2) 动脉粥样硬化性心血管疾病 (ASCVD)、(3) 慢性肾脏疾病 (CKD) 和 (4) 无记录的心肾疾病。参与者分为非西班牙裔白人、非西班牙裔黑人和西班牙裔。在对社会人口学、临床和县级特征进行调整后,采用多项式回归法对每个队列中开始使用 SGLT2is 或 GLP-1RAs 的几率进行建模。结果患有高血压、ASCVD、慢性肾脏病或无心肾疾病记录的黑人参与者开始使用 SGLT2is 的几率分别比白人参与者低 35% (调整后 OR 0.65 [95% CI 0.61, 0.68])、33% (0.67 [0.64, 0.69])、32% (0.68 [0.64, 0.72])和 24% (0.76 [0.74, 0.79])。差距从 2013 年的 50-60% 下降到 2019 年的 17-18%。在黑人参与者中也观察到了类似的 GLP-1RA 摄入模式。相比之下,西班牙裔参与者在高血压和慢性肾脏病队列中开始使用 SGLT2i 的几率与白人参与者相似,但在 ASCVD 队列中几率要低 6% (0.94 [0.91, 0.98])。与白人参与者相比,西班牙裔参与者在高血压、ASCVD、慢性肾功能衰竭和无心肾疾病队列中摄入 GLP-1RA 的比例存在显著差异:分别低 11% (0.89 [0.84, 0.94])、16% (0.84 [0.81, 0.87])、16% (0.84 [0.80, 0.89])和 25% (0.75 [0.72, 0.78])。与白人参与者相比,所有组群的参与者开始服用 DPP4is 的几率更大,而 DPP4is 对心血管无益(HF 1.25 [1.19, 1.31];ASCVD 1.36 [1.32, 1.40];CKD 1.32 [1.26, 1.38])。结论/解释与白人参与者相比,黑人参与者在服用 SGLT2is 方面存在明显差异,黑人和西班牙裔参与者在服用 GLP-1RAs 方面也存在明显差异。这项研究突显了 2 型糖尿病管理的演变过程,同时也强调了历史上的不平衡现象,而这种不平衡现象已经出现了缓解的迹象。
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引用次数: 0
Increased risk of major adverse cardiovascular events in patients with deep and infected diabetes-related foot ulcers 深层感染性糖尿病足溃疡患者发生重大不良心血管事件的风险增加
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-07 DOI: 10.1007/s00125-024-06316-z
Nick S. R. Lan, Jonathan Hiew, Ivana Ferreira, J. Carsten Ritter, Laurens Manning, P. Gerry Fegan, Girish Dwivedi, Emma J. Hamilton

Aims/hypothesis

Diabetes-related foot ulceration (DFU) is associated with increased cardiovascular risk, but the mechanisms remain unclear. Inflammation and infection are mediators of CVD, which may be important in DFU.

Methods

Prospectively collected data from patients attending a multidisciplinary DFU service were analysed. A deep ulcer was defined as one that reached muscle, tendon or deeper structures. Patients were categorised into four DFU groups: not deep and no infection (D−/I−), not deep but infected (D−/I+), deep with no infection (D+/I−) or deep with infection (D+/I+). Incident major adverse cardiovascular events (MACE) were defined as hospitalisation for myocardial infarction, stroke or transient ischaemic attack, or heart failure. Survival analyses were performed using the logrank test and multivariate Cox regression.

Results

Of 513 patients, 241 (47.0%) were in the D−/I− group, 110 (21.4%) were in the D−/I+ group, 35 (6.8%) were in the D+/I− group and 127 (24.8%) were in the D+/I+ group. MACE or all-cause mortality occurred in 75 patients (14.6%), and MACE alone occurred in 46 patients (9.0%) after median follow-up of 381 days (IQR 220–551) and 404 days (IQR 228–576), respectively. Infection was associated with significantly higher MACE or all-cause mortality (21.5% vs 8.7%; p<0.001) and MACE alone (13.5% vs 5.1%; p=0.003). MACE or all-cause mortality was significantly higher in the D+/I+ group (D−/I− 7.9%; D−/I+ 15.5%; D+/I− 14.3%; D+/I+ 26.8%; p<0.001), as was MACE alone (D−/I− 5.0%; D−/I+ 10.9%; D+/I− 5.7%; D+/I+ 15.7%; p=0.017). Infection and a deep ulcer were independent predictors of adverse outcomes.

Conclusions/interpretation

Deep and/or infected DFUs are associated with increased cardiovascular risk compared with DFUs that are not deep or infected. These findings provide a potential mechanistic explanation that requires investigation.

Graphical Abstract

目的/假设糖尿病相关足部溃疡(DFU)与心血管风险增加有关,但其机制仍不清楚。炎症和感染是心血管疾病的介质,可能在 DFU 中起重要作用。方法分析了从接受多学科 DFU 服务的患者处收集的数据。深部溃疡的定义是溃疡达到肌肉、肌腱或深层结构。患者被分为四组:不深且无感染(D-/I-)、不深但有感染(D-/I+)、深且无感染(D+/I-)或深且有感染(D+/I+)。重大不良心血管事件(MACE)是指因心肌梗死、中风或短暂性脑缺血发作或心力衰竭而住院。结果 在513名患者中,D-/I-组241人(47.0%),D-/I+组110人(21.4%),D+/I-组35人(6.8%),D+/I+组127人(24.8%)。中位随访时间分别为 381 天(IQR 220-551)和 404 天(IQR 228-576)后,75 例患者(14.6%)发生了 MACE 或全因死亡,46 例患者(9.0%)仅发生了 MACE。感染与较高的 MACE 或全因死亡率(21.5% vs 8.7%;p<0.001)和单纯 MACE(13.5% vs 5.1%;p=0.003)明显相关。D+/I+组的MACE或全因死亡率明显更高(D-/I- 7.9%; D-/I+ 15.5%; D+/I- 14.3%; D+/I+ 26.8%; p<0.001),单纯MACE也明显更高(D-/I- 5.0%; D-/I+ 10.9%; D+/I- 5.7%; D+/I+ 15.7%; p=0.017)。感染和深部溃疡是不良结局的独立预测因素。结论/解释与不深或未感染的 DFU 相比,深部和/或感染的 DFU 与心血管风险增加有关。这些发现提供了一种潜在的机制解释,需要进行研究。
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引用次数: 0
NT-proBNP improves prediction of cardiorenal complications in type 2 diabetes: the Hong Kong Diabetes Biobank NT-proBNP可提高对2型糖尿病心肾并发症的预测能力:香港糖尿病生物数据库
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-07 DOI: 10.1007/s00125-024-06299-x
Ronald C. W. Ma, Claudia H. T. Tam, Yong Hou, Eric S. H. Lau, Risa Ozaki, Juliana N. M. Lui, Elaine Chow, Alice P. S. Kong, Chuiguo Huang, Alex C. W. Ng, Erik G. Fung, Andrea O. Y. Luk, Wing Yee So, Cadmon K. P. Lim, Juliana C. N. Chan

Aims/hypothesis

N-terminal pro B-type natriuretic peptide (NT-proBNP) is a natriuretic peptide that is strongly associated with congestive heart failure (CHF). The utility of NT-proBNP for prediction of cardiovascular events and renal endpoints, compared with clinical risk factors, has not been evaluated in detail. We hypothesise that NT-proBNP can improve risk stratification and prediction of cardiorenal events in type 2 diabetes, beyond that provided by clinical risk factors.

Methods

NT-proBNP was measured in 1993 samples from the Hong Kong Diabetes Biobank, a multicentre prospective diabetes cohort and biobank. A cut-off of ≥125 pg/ml was used to define elevated NT-proBNP. Associations between elevated NT-proBNP and incident cardiovascular and renal endpoints were examined using Cox regression, adjusted for sex, age and duration of diabetes, as well as other covariates. Prognostic and incremental predictive values of NT-proBNP in diabetes cardiorenal complications, compared with those of the Joint Asia Diabetes Evaluation risk equations for CHD, CHF and kidney failure, were evaluated using the concordance index (C index), net reclassification improvement index, integrated discrimination improvement index and relative integrated discrimination improvement index.

Results

A total of 24.7% of participants had elevated NT-proBNP. Participants with elevated NT-proBNP at baseline had a more adverse cardiometabolic profile, with 2–4-fold higher frequency of complications at baseline. Adjusting for age at baseline, sex and duration of diabetes, elevated NT-proBNP was associated with incident atrial fibrillation (HR 4.64 [95% CI 2.44, 8.85]), CHD (HR 4.21 [2.46, 7.21]), CVD (HR 3.32 [2.20, 5.01]) and CHF (HR 4.18 [2.18, 8.03]; all p<0.001). All these associations remained significant after further adjustment for additional covariates. Elevated NT-proBNP had good discriminative ability for various cardiorenal endpoints, with C index of 0.83 (95% CI 0.76, 0.90) for CHD, 0.88 (0.81, 0.94) for atrial fibrillation, 0.89 (0.83, 0.95) for CHF, 0.81 (0.77, 0.84) for 40% drop in eGFR and 0.88 (0.84, 0.92) for kidney failure. Models incorporating NT-proBNP had improved prediction compared with established clinical risk models. Sensitivity analyses including alternative cut-off of NT-proBNP, as well as use of other risk engines of CHD, yielded similar results.

Conclusions/interpretation

NT-proBNP demonstrated a promising ability to serve as a prognostic marker for a variety of cardiorenal complications in type 2 diabetes. Considering NT-proBNP in clinical assessments could potentially help identify high-risk individuals who may benefit from more intensive therapies.

Graphical Abstract

目的/假设N-末端前 B 型利钠肽 (NT-proBNP) 是一种与充血性心力衰竭 (CHF) 密切相关的利钠肽。与临床风险因素相比,NT-proBNP 在预测心血管事件和肾脏终点方面的作用尚未得到详细评估。我们假设,NT-proBNP 可改善 2 型糖尿病患者的风险分层和心肾事件预测,而临床风险因素则无法提供这样的预测结果。方法NT-proBNP 是在香港糖尿病生物库(一个多中心前瞻性糖尿病队列和生物库)1993 年的样本中测定的。NT-proBNP≥125 pg/ml是NT-proBNP升高的界值。在对性别、年龄和糖尿病持续时间以及其他协变量进行调整后,采用 Cox 回归法检测了 NT-proBNP 升高与心血管和肾脏终点事件之间的关系。使用一致性指数(C 指数)、净再分类改进指数、综合鉴别改进指数和相对综合鉴别改进指数,评估了 NT-proBNP 与亚洲糖尿病联合评估风险方程对糖尿病心肾并发症的预测价值和增量预测价值。基线时NT-proBNP升高的参试者的心脏代谢情况更差,基线时并发症的发生率高出2-4倍。对基线年龄、性别和糖尿病病程进行调整后,NT-proBNP 升高与心房颤动(HR 4.64 [95% CI 2.44, 8.85])、冠心病(HR 4.21 [2.46, 7.21])、心血管疾病(HR 3.32 [2.20, 5.01])和冠心病心房颤动(HR 4.18 [2.18, 8.03];所有 p<0.001)的发生率相关。在对其他协变量进行进一步调整后,所有这些相关性仍然显著。NT-proBNP 升高对各种心肾终点具有良好的鉴别能力,CHD 的 C 指数为 0.83 (95% CI 0.76, 0.90),心房颤动为 0.88 (0.81, 0.94),CHF 为 0.89 (0.83, 0.95),eGFR 下降 40% 为 0.81 (0.77, 0.84),肾衰竭为 0.88 (0.84, 0.92)。与已建立的临床风险模型相比,纳入 NT-proBNP 的模型具有更好的预测效果。结论/解释NT-proBNP显示了作为2型糖尿病患者各种心肾并发症预后标志物的良好能力。在临床评估中考虑NT-proBNP可能有助于识别可能从更多强化治疗中获益的高危人群。
{"title":"NT-proBNP improves prediction of cardiorenal complications in type 2 diabetes: the Hong Kong Diabetes Biobank","authors":"Ronald C. W. Ma, Claudia H. T. Tam, Yong Hou, Eric S. H. Lau, Risa Ozaki, Juliana N. M. Lui, Elaine Chow, Alice P. S. Kong, Chuiguo Huang, Alex C. W. Ng, Erik G. Fung, Andrea O. Y. Luk, Wing Yee So, Cadmon K. P. Lim, Juliana C. N. Chan","doi":"10.1007/s00125-024-06299-x","DOIUrl":"https://doi.org/10.1007/s00125-024-06299-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>N-terminal pro B-type natriuretic peptide (NT-proBNP) is a natriuretic peptide that is strongly associated with congestive heart failure (CHF). The utility of NT-proBNP for prediction of cardiovascular events and renal endpoints, compared with clinical risk factors, has not been evaluated in detail. We hypothesise that NT-proBNP can improve risk stratification and prediction of cardiorenal events in type 2 diabetes, beyond that provided by clinical risk factors.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>NT-proBNP was measured in 1993 samples from the Hong Kong Diabetes Biobank, a multicentre prospective diabetes cohort and biobank. A cut-off of ≥125 pg/ml was used to define elevated NT-proBNP. Associations between elevated NT-proBNP and incident cardiovascular and renal endpoints were examined using Cox regression, adjusted for sex, age and duration of diabetes, as well as other covariates. Prognostic and incremental predictive values of NT-proBNP in diabetes cardiorenal complications, compared with those of the Joint Asia Diabetes Evaluation risk equations for CHD, CHF and kidney failure, were evaluated using the concordance index (C index), net reclassification improvement index, integrated discrimination improvement index and relative integrated discrimination improvement index.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 24.7% of participants had elevated NT-proBNP. Participants with elevated NT-proBNP at baseline had a more adverse cardiometabolic profile, with 2–4-fold higher frequency of complications at baseline. Adjusting for age at baseline, sex and duration of diabetes, elevated NT-proBNP was associated with incident atrial fibrillation (HR 4.64 [95% CI 2.44, 8.85]), CHD (HR 4.21 [2.46, 7.21]), CVD (HR 3.32 [2.20, 5.01]) and CHF (HR 4.18 [2.18, 8.03]; all <i>p</i>&lt;0.001). All these associations remained significant after further adjustment for additional covariates. Elevated NT-proBNP had good discriminative ability for various cardiorenal endpoints, with C index of 0.83 (95% CI 0.76, 0.90) for CHD, 0.88 (0.81, 0.94) for atrial fibrillation, 0.89 (0.83, 0.95) for CHF, 0.81 (0.77, 0.84) for 40% drop in eGFR and 0.88 (0.84, 0.92) for kidney failure. Models incorporating NT-proBNP had improved prediction compared with established clinical risk models. Sensitivity analyses including alternative cut-off of NT-proBNP, as well as use of other risk engines of CHD, yielded similar results.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>NT-proBNP demonstrated a promising ability to serve as a prognostic marker for a variety of cardiorenal complications in type 2 diabetes. Considering NT-proBNP in clinical assessments could potentially help identify high-risk individuals who may benefit from more intensive therapies.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"9 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594912","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}
引用次数: 0
Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models 非β胰岛细胞转录组异质性与小鼠模型中 2 型糖尿病的发生有关
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-07 DOI: 10.1007/s00125-024-06301-6
Pascal Gottmann, Thilo Speckmann, Mandy Stadion, Prateek Chawla, Judith Saurenbach, Nikolay Ninov, Heiko Lickert, Annette Schürmann

Aims/hypothesis

The aim of this work was to understand the role of non-beta cells in pancreatic islets at early stages of type 2 diabetes pathogenesis.

Methods

Specific clustering was employed to single-cell transcriptome data from islet cells of obese mouse strains differing in their diabetes susceptibility (diabetes-resistant B6.V.Lepob/ob [OB] and diabetes-susceptible New Zealand Obese [NZO] mice) on a diabetogenic diet.

Results

Refined clustering analysis revealed several heterogeneous subpopulations for alpha cells, delta cells and macrophages, of which 133 mapped to human diabetes genes identified by genome-wide association studies. Importantly, a similar non-beta cell heterogeneity was found in a dataset of human islets from donors at different stages of type 2 diabetes. The predominant alpha cell cluster in NZO mice displayed signs of cellular stress and lower mitochondrial capacity (97 differentially expressed genes [DEGs]), whereas delta cells from these mice exhibited higher expression levels of maturation marker genes (Hhex and Sst) but lower somatostatin secretion than OB mice (184 DEGs). Furthermore, a cluster of macrophages was almost twice as abundant in islets of OB mice, and displayed extensive cell–cell communication with beta cells of OB mice. Treatment of beta cells with IL-15, predicted to be released by macrophages, activated signal transducer and activator of transcription (STAT3), which may mediate anti-apoptotic effects. Similar to mice, humans without diabetes possess a greater number of macrophages than those with prediabetes (39 mmol/mol [5.7%] < HbA1c < 46 mmol/mol [6.4%]) and diabetes.

Conclusions/interpretation

Our study indicates that the transcriptional heterogeneity of non-beta cells has an impact on intra-islet crosstalk and participates in beta cell (dys)function.

Data availability

scRNA-seq data from the previous study are available in gene expression omnibus under gene accession number GSE159211 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211).

Graphical Abstract

目的/假设这项工作的目的是了解非β细胞在 2 型糖尿病发病早期阶段在胰岛中的作用。方法对肥胖小鼠品系(糖尿病耐药 B6.V.Lepob/ob [OB]和糖尿病易感新西兰肥胖 [NZO] 小鼠)的胰岛细胞的单细胞转录组数据进行了特异性聚类分析。结果细化聚类分析发现了多个不同的α细胞、δ细胞和巨噬细胞亚群,其中 133 个亚群与全基因组关联研究确定的人类糖尿病基因相对应。重要的是,在一个来自处于 2 型糖尿病不同阶段的供体的人类胰岛数据集中也发现了类似的非贝塔细胞异质性。NZO小鼠的主要α细胞集群显示出细胞压力和线粒体能力降低的迹象(97个差异表达基因[DEGs]),而这些小鼠的δ细胞显示出较高的成熟标志基因(Hhex和Sst)表达水平,但体泌素分泌却低于OB小鼠(184个差异表达基因)。此外,OB 小鼠胰岛中巨噬细胞群的数量几乎是 OB 小鼠的两倍,并与 OB 小鼠的 beta 细胞进行广泛的细胞间交流。用预计由巨噬细胞释放的 IL-15 处理β细胞,可激活信号转导和转录激活因子(STAT3),从而起到抗凋亡的作用。与小鼠类似,与糖尿病前期(39 mmol/mol [5.7%] <HbA1c<46mmol/mol[6.4%])和糖尿病患者相比,未患糖尿病的人类拥有更多的巨噬细胞。结论/解释我们的研究表明,非β细胞的转录异质性对胰岛内串联有影响,并参与了β细胞(功能障碍)。先前研究的scRNA-seq数据可在基因表达总库中查阅,基因登录号为GSE159211 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211)。图文摘要
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引用次数: 0
Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of type 1 diabetes β细胞胞外囊泡 PD-L1 是 CD8+ T 细胞活性的新型调节因子和 1 型糖尿病演变过程中的生物标记物
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-07 DOI: 10.1007/s00125-024-06313-2
Chaitra Rao, Daniel T. Cater, Saptarshi Roy, Jerry Xu, Andre G. De Oliveira, Carmella Evans-Molina, Jon D. Piganelli, Decio L. Eizirik, Raghavendra G. Mirmira, Emily K. Sims
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death protein 1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesised that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry and ELISA. EV PD-L1 binding to PD-1 was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8<sup>+</sup> T cells. Plasma EV and soluble PD-L1 were assayed in the plasma of islet autoantibody-positive (Ab<sup>+</sup>) individuals or individuals with recent-onset type 1 diabetes and compared with levels in non-diabetic control individuals.</p><h3 data-test="abstract-sub-heading">Results</h3><p>PD-L1 protein co-localised with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. Treatment with IFN-α or IFN-γ for 24 h induced a twofold increase in EV PD-L1 cargo without a corresponding increase in the number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8<sup>+</sup> T cells. Plasma EV PD-L1 levels were increased in Ab<sup>+</sup>individuals, particularly in those positive for a single autoantibody. Additionally, in Ab<sup>+</sup> individuals or those who had type 1 diabetes, but not in control individuals, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV PD-L1 could be protective for residual beta cell function.</p><h3 data-test="abstract-sub-heading">Conclusions/interpretation</h3><p>IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8<sup>+</sup> T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in Ab<sup>+</sup> individuals than in control individuals. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit
目的/假说1型糖尿病中存活的β细胞通过上调程序性死亡配体1(PD-L1)来应对炎症,从而与免疫细胞程序性死亡蛋白1(PD-1)结合,限制自我反应免疫细胞的破坏。细胞外囊泡 (EV) 及其载体可作为β细胞健康的生物标志物,并有助于胰岛细胞间的交流。我们假设 1 型糖尿病的炎症环境会增加贝塔细胞 EV 货物中的 PD-L1,而 EV PD-L1 可保护贝塔细胞免受免疫介导的细胞死亡。使用超速离心法或尺寸排阻色谱法分离 EV,并通过免疫印迹、流式细胞术和 ELISA 进行分析。使用竞争性结合试验和体外功能试验评估了EV PD-L1与PD-1的结合情况,测试了EV PD-L1抑制NOD CD8+ T细胞的能力。在胰岛自身抗体阳性(Ab+)者或新近发病的1型糖尿病患者的血浆中检测血浆EV和可溶性PD-L1,并与非糖尿病对照者的水平进行比较。用 IFN-α 或 IFN-γ 处理 24 小时后,诱导 EV PD-L1 货物增加了两倍,但 EV 的数量没有相应增加。IFN暴露主要增加了β细胞EV表面的PD-L1表达,β细胞EV PD-L1显示出与PD-1结合的剂量依赖性能力。功能实验证明,β细胞 EV PD-L1 有抑制小鼠 CD8+ T 细胞增殖和细胞毒性的特殊作用。血浆 EV PD-L1 水平在抗体阳性者中升高,尤其是在单一自身抗体阳性者中。此外,在Ab+个体或1型糖尿病患者中,血浆EV PD-L1与循环C肽呈正相关,而在对照个体中则没有,这表明较高的EV PD-L1可能对残留的β细胞功能具有保护作用。Beta 细胞 EV PD-L1 与 PD1 结合,抑制 CD8+ T 细胞增殖和细胞毒性。Ab+患者的循环EV PD-L1高于对照组。在 1 型糖尿病进展的不同阶段,循环中的 EV PD-L1 水平与残留的 C 肽相关。这些研究结果表明,EV PD-L1可能是导致1型糖尿病进展和残留β细胞功能异质性的原因之一,并提出了利用EV PD-L1抑制免疫介导的β细胞死亡的可能性。
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引用次数: 0
Comment on the role of interferons in the pathology of beta cell destruction in type 1 diabetes. 评论干扰素在 1 型糖尿病β细胞破坏病理学中的作用。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-01 Epub Date: 2024-09-07 DOI: 10.1007/s00125-024-06264-8
Sigurd Lenzen
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引用次数: 0
Genetic relations between type 1 diabetes, coronary artery disease and leukocyte counts. 1 型糖尿病、冠状动脉疾病和白细胞计数之间的遗传关系。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-01 Epub Date: 2024-08-14 DOI: 10.1007/s00125-024-06247-9
Jolade Adebekun, Ajay Nadig, Priscilla Saarah, Samira Asgari, Linda Kachuri, David A Alagpulinsa
<p><strong>Aims/hypothesis: </strong>Type 1 diabetes is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of haematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between type 1 diabetes, CAD and leukocyte counts.</p><p><strong>Methods: </strong>Genome-wide association study summary statistics were used to perform pairwise linkage disequilibrium score regression and heritability estimation from summary statistics (ρ-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomisation to estimate the causal relationships between leukocyte counts (335,855 healthy individuals), type 1 diabetes (18,942 cases, 501,638 control individuals) and CAD (122,733 cases, 424,528 control individuals). A latent causal variable (LCV) model was performed to estimate the genetic causality proportion of the genetic correlation between type 1 diabetes and CAD.</p><p><strong>Results: </strong>There was significant genome-wide genetic correlation (r<sub>g</sub>) between type 1 diabetes and CAD (r<sub>g</sub>=0.088, p=8.60 × 10<sup>-3</sup>) and both diseases shared significant genome-wide genetic determinants with eosinophil count (r<sub>g</sub> for type 1 diabetes [r<sub>g(T1D)</sub>]=0.093, p=7.20 × 10<sup>-3</sup>, r<sub>g</sub> for CAD [r<sub>g(CAD)</sub>]=0.092, p=3.68 × 10<sup>-6</sup>) and lymphocyte count (r<sub>g(T1D)</sub>=-0.052, p=2.76 × 10<sup>-2</sup>, r<sub>g(CAD)</sub>=0.176, p=1.82 × 10<sup>-15</sup>). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, type 1 diabetes and/or CAD. Cis-genetic regulation of the expression levels of genes within shared loci between type 1 diabetes and CAD was associated with both diseases as well as leukocyte counts, including SH2B3, CTSH, MORF4L1, CTRB1, CTRB2, CFDP1 and IFIH1. Genetically predicted lymphocyte, neutrophil and eosinophil counts were associated with type 1 diabetes and CAD (lymphocyte OR for type 1 diabetes [OR<sub>T1D</sub>]=0.67, p=2.02<sup>-19</sup>, OR<sub>CAD</sub>=1.09, p=2.67 × 10<sup>-6</sup>; neutrophil OR<sub>T1D</sub>=0.82, p=5.63 × 10<sup>-5</sup>, OR<sub>CAD</sub>=1.17, p=5.02 × 10<sup>-14</sup>; and eosinophil OR<sub>T1D</sub>=1.67, p=5.45 × 10<sup>-25</sup>, OR<sub>CAD</sub>=1.07, p=2.03 × 10<sup>-4</sup>. The genetic causality proportion between type 1 diabetes and CAD was 0.36 ± 0.16 (p<sub>LCV</sub>=1.30 × 10<sup>-2</sup>), suggesting a possible intermediary causal variable.</p><p><strong>Conclusions/interpretation: </strong>This study sheds light on shared genetic mechanisms underlying type 1 diabetes and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts and identifies cellular and molecular targets for fur
目的/假设:即使考虑了已知的心血管风险因素,1 型糖尿病仍与过高的冠状动脉疾病(CAD)风险相关。改变白细胞生成的造血基因扰动是冠心病风险的一个新的独立调节因素。我们研究了 1 型糖尿病、CAD 和白细胞数量之间是否存在共同的遗传决定因素和因果关系:方法:利用全基因组关联研究汇总统计进行配对连锁不平衡得分回归和遗传率估计汇总统计(ρ-HESS),分别估计全基因组和局部遗传相关性,并利用双样本孟德尔随机化估计白细胞计数(335,855 名健康个体)、1 型糖尿病(18,942 例,501,638 名对照个体)和 CAD(122,733 例,424,528 名对照个体)之间的因果关系。通过潜在因果变量(LCV)模型估算了1型糖尿病与CAD之间遗传相关性的遗传因果关系比例:结果:1 型糖尿病和 CAD 之间存在明显的全基因组遗传相关性(rg)(rg=0.088,p=8.60 × 10-3),这两种疾病与嗜酸性粒细胞计数共享明显的全基因组遗传决定因素(1 型糖尿病的 rg [rg(T1D)]=0.093,p=7.20 × 10-3)。093,p=7.20×10-3;CAD的rg[rg(CAD)]=0.092,p=3.68×10-6)和淋巴细胞计数(rg(T1D)=-0.052,p=2.76×10-2;rg(CAD)=0.176,p=1.82×10-15)。16个独立位点显示白细胞计数、1型糖尿病和/或CAD之间存在严格的Bonferroni显着局部遗传相关性。1 型糖尿病和 CAD 之间共享位点内基因表达水平的顺式遗传调控与这两种疾病以及白细胞计数相关,包括 SH2B3、CTSH、MORF4L1、CTRB1、CTRB2、CFDP1 和 IFIH1。基因预测的淋巴细胞、中性粒细胞和嗜酸性粒细胞计数与 1 型糖尿病和 CAD 相关(1 型糖尿病的淋巴细胞 OR [ORT1D]=0.67, p=2.02-19,ORCAD=1.09,p=2.67 × 10-6;中性粒细胞 ORT1D=0.82,p=5.63 × 10-5,ORCAD=1.17,p=5.02 × 10-14;嗜酸性粒细胞 ORT1D=1.67,p=5.45 × 10-25,ORCAD=1.07,p=2.03 × 10-4。1型糖尿病与CAD之间的遗传因果关系比例为0.36 ± 0.16(pLCV=1.30 × 10-2),表明可能存在中间因果变量:本研究揭示了 1 型糖尿病和 CAD 的共同遗传机制,这些机制可能通过调控基因表达和白细胞数量导致这两种疾病的同时发生,并确定了细胞和分子靶点,以便进一步研究疾病预测和潜在药物的发现。
{"title":"Genetic relations between type 1 diabetes, coronary artery disease and leukocyte counts.","authors":"Jolade Adebekun, Ajay Nadig, Priscilla Saarah, Samira Asgari, Linda Kachuri, David A Alagpulinsa","doi":"10.1007/s00125-024-06247-9","DOIUrl":"10.1007/s00125-024-06247-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims/hypothesis: &lt;/strong&gt;Type 1 diabetes is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of haematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between type 1 diabetes, CAD and leukocyte counts.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Genome-wide association study summary statistics were used to perform pairwise linkage disequilibrium score regression and heritability estimation from summary statistics (ρ-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomisation to estimate the causal relationships between leukocyte counts (335,855 healthy individuals), type 1 diabetes (18,942 cases, 501,638 control individuals) and CAD (122,733 cases, 424,528 control individuals). A latent causal variable (LCV) model was performed to estimate the genetic causality proportion of the genetic correlation between type 1 diabetes and CAD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;There was significant genome-wide genetic correlation (r&lt;sub&gt;g&lt;/sub&gt;) between type 1 diabetes and CAD (r&lt;sub&gt;g&lt;/sub&gt;=0.088, p=8.60 × 10&lt;sup&gt;-3&lt;/sup&gt;) and both diseases shared significant genome-wide genetic determinants with eosinophil count (r&lt;sub&gt;g&lt;/sub&gt; for type 1 diabetes [r&lt;sub&gt;g(T1D)&lt;/sub&gt;]=0.093, p=7.20 × 10&lt;sup&gt;-3&lt;/sup&gt;, r&lt;sub&gt;g&lt;/sub&gt; for CAD [r&lt;sub&gt;g(CAD)&lt;/sub&gt;]=0.092, p=3.68 × 10&lt;sup&gt;-6&lt;/sup&gt;) and lymphocyte count (r&lt;sub&gt;g(T1D)&lt;/sub&gt;=-0.052, p=2.76 × 10&lt;sup&gt;-2&lt;/sup&gt;, r&lt;sub&gt;g(CAD)&lt;/sub&gt;=0.176, p=1.82 × 10&lt;sup&gt;-15&lt;/sup&gt;). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, type 1 diabetes and/or CAD. Cis-genetic regulation of the expression levels of genes within shared loci between type 1 diabetes and CAD was associated with both diseases as well as leukocyte counts, including SH2B3, CTSH, MORF4L1, CTRB1, CTRB2, CFDP1 and IFIH1. Genetically predicted lymphocyte, neutrophil and eosinophil counts were associated with type 1 diabetes and CAD (lymphocyte OR for type 1 diabetes [OR&lt;sub&gt;T1D&lt;/sub&gt;]=0.67, p=2.02&lt;sup&gt;-19&lt;/sup&gt;, OR&lt;sub&gt;CAD&lt;/sub&gt;=1.09, p=2.67 × 10&lt;sup&gt;-6&lt;/sup&gt;; neutrophil OR&lt;sub&gt;T1D&lt;/sub&gt;=0.82, p=5.63 × 10&lt;sup&gt;-5&lt;/sup&gt;, OR&lt;sub&gt;CAD&lt;/sub&gt;=1.17, p=5.02 × 10&lt;sup&gt;-14&lt;/sup&gt;; and eosinophil OR&lt;sub&gt;T1D&lt;/sub&gt;=1.67, p=5.45 × 10&lt;sup&gt;-25&lt;/sup&gt;, OR&lt;sub&gt;CAD&lt;/sub&gt;=1.07, p=2.03 × 10&lt;sup&gt;-4&lt;/sup&gt;. The genetic causality proportion between type 1 diabetes and CAD was 0.36 ± 0.16 (p&lt;sub&gt;LCV&lt;/sub&gt;=1.30 × 10&lt;sup&gt;-2&lt;/sup&gt;), suggesting a possible intermediary causal variable.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions/interpretation: &lt;/strong&gt;This study sheds light on shared genetic mechanisms underlying type 1 diabetes and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts and identifies cellular and molecular targets for fur","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2518-2529"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975269","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}
引用次数: 0
Publisher Correction: EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summary. 出版商更正:EASL-EASD-EASO关于代谢功能障碍相关性脂肪性肝病(MASLD)管理的临床实践指南:执行摘要。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-01 DOI: 10.1007/s00125-024-06258-6
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引用次数: 0
Dietary patterns during pregnancy and maternal and birth outcomes in women with type 1 diabetes: the Environmental Determinants of Islet Autoimmunity (ENDIA) study. 妊娠期饮食模式与 1 型糖尿病妇女的母婴结局:胰岛自身免疫的环境决定因素 (ENDIA) 研究。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-01 Epub Date: 2024-09-02 DOI: 10.1007/s00125-024-06259-5
Rebecca L Thomson, James D Brown, Helena Oakey, Kirsten Palmer, Pat Ashwood, Megan A S Penno, Kelly J McGorm, Rachel Battersby, Peter G Colman, Maria E Craig, Elizabeth A Davis, Tony Huynh, Leonard C Harrison, Aveni Haynes, Richard O Sinnott, Peter J Vuillermin, John M Wentworth, Georgia Soldatos, Jennifer J Couper

Aims/hypothesis: Dietary patterns characterised by high intakes of vegetables may lower the risk of pre-eclampsia and premature birth in the general population. The effect of dietary patterns in women with type 1 diabetes, who have an increased risk of complications in pregnancy, is not known. The aim of this study was to investigate the relationship between dietary patterns and physical activity during pregnancy and maternal complications and birth outcomes in women with type 1 diabetes. We also compared dietary patterns in women with and without type 1 diabetes.

Methods: Diet was assessed in the third trimester using a validated food frequency questionnaire in participants followed prospectively in the multi-centre Environmental Determinants of Islet Autoimmunity (ENDIA) study. Dietary patterns were characterised by principal component analysis. The Pregnancy Physical Activity Questionnaire was completed in each trimester. Data for maternal and birth outcomes were collected prospectively.

Results: Questionnaires were completed by 973 participants during 1124 pregnancies. Women with type 1 diabetes (n=615 pregnancies with dietary data) were more likely to have a 'fresh food' dietary pattern than women without type 1 diabetes (OR 1.19, 95% CI 1.07, 1.31; p=0.001). In women with type 1 diabetes, an increase equivalent to a change from quartile 1 to 3 in 'fresh food' dietary pattern score was associated with a lower risk of pre-eclampsia (OR 0.37, 95% CI 0.17, 0.78; p=0.01) and premature birth (OR 0.35, 95% CI 0.20, 0.62, p<0.001). These associations were mediated in part by BMI and HbA1c. The 'processed food' dietary pattern was associated with an increased birthweight (β coefficient 56.8 g, 95% CI 2.8, 110.8; p=0.04). Physical activity did not relate to outcomes.

Conclusions/interpretation: A dietary pattern higher in fresh foods during pregnancy was associated with sizeable reductions in risk of pre-eclampsia and premature birth in women with type 1 diabetes.

目的/假设:蔬菜摄入量高的膳食模式可降低普通人群先兆子痫和早产的风险。对于妊娠并发症风险增加的 1 型糖尿病妇女,饮食模式的影响尚不清楚。本研究旨在调查 1 型糖尿病妇女孕期饮食模式和体力活动与产妇并发症和分娩结果之间的关系。我们还比较了患有和未患有 1 型糖尿病妇女的饮食模式:方法:在胰岛自身免疫环境决定因素(ENDIA)多中心研究的前瞻性跟踪调查中,我们使用经过验证的食物频率问卷对参加者怀孕三个月的饮食进行了评估。通过主成分分析确定饮食模式的特征。妊娠期体力活动问卷在每个孕期完成。前瞻性地收集了孕产妇和分娩结果的数据:共有 973 名参与者在 1124 次妊娠中填写了问卷。与未患 1 型糖尿病的妇女相比,患 1 型糖尿病的妇女(n=615 名有饮食数据的孕妇)更有可能采用 "新鲜食物 "饮食模式(OR 1.19,95% CI 1.07,1.31;p=0.001)。在患有 1 型糖尿病的妇女中,"新鲜食物 "膳食模式得分从 1 分位数到 3 分位数的增加与较低的先兆子痫风险(OR 0.37,95% CI 0.17,0.78;p=0.01)和早产风险(OR 0.35,95% CI 0.20,0.62,p1c)相关。加工食品 "饮食模式与出生体重增加有关(β系数 56.8 g,95% CI 2.8,110.8;p=0.04)。体育锻炼与结果无关:怀孕期间多吃新鲜食物的饮食模式与大幅降低 1 型糖尿病妇女的先兆子痫和早产风险有关。
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引用次数: 0
Assessing the influence of insulin type (ultra-rapid vs rapid insulin) and exercise timing on postprandial exercise-induced hypoglycaemia risk in individuals with type 1 diabetes: a randomised controlled trial. 评估胰岛素类型(超快速胰岛素与快速胰岛素)和运动时间对 1 型糖尿病患者餐后运动诱发低血糖风险的影响:随机对照试验。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-01 Epub Date: 2024-07-29 DOI: 10.1007/s00125-024-06234-0
Joséphine Molveau, Étienne Myette-Côté, Sémah Tagougui, Nadine Taleb, Roxane St-Amand, Corinne Suppère, Valérie Bourdeau, Elsa Heyman, Rémi Rabasa-Lhoret

Aims/hypothesis: The relationship between pre-meal insulin type, exercise timing and the risk of postprandial exercise-induced hypoglycaemia in people living with type 1 diabetes is unknown. We aimed to evaluate the effects of exercise timing (60 vs 120 min post meal) and different insulin types (aspart vs ultra-rapid aspart) on hypoglycaemic risk.

Methods: This was a four-way crossover randomised trial including 40 individuals with type 1 diabetes using multiple daily injections (mean HbA1c 56 mmol/mol [7.4%]). Participants, who were recruited from the Montreal Clinical Research Institute, undertook 60 min cycling sessions (60% of V ˙ O 2 peak ) after breakfast (60 min [EX60min] or 120 min [EX120min] post meal) with 50% of their usual insulin dose (aspart or ultra-rapid aspart). Eligibility criteria included age ≥18 years old, clinical diagnosis of type 1 diabetes for at least 1 year and HbA1c ≤80 mmol/mol (9.5%). Participants were allocated using sequentially numbered, opaque sealed envelopes. Participants were masked to their group assignment, and each participant was allocated a unique identification number to ensure anonymisation. The primary outcome was change in blood glucose levels between exercise onset and nadir.

Results: Prior to exercise onset, time spent in hyperglycaemia was lower for EX60min vs EX120min (time >10.0 mmol/l: 56.6% [1.2-100%] vs 78.0% [52.7-97.9%]; p<0.001). The glucose reduction between exercise onset and nadir was less pronounced with EX60min vs EX120min (-3.8±2.7 vs -4.7±2.5 mmol/l; p<0.001). A similar number of hypoglycaemic events occurred during both exercise timings. Blood glucose between exercise onset and nadir decreased less with ultra-rapid aspart compared with aspart (-4.1±2.3 vs -4.4±2.8 mmol/l; p=0.037). While a similar number of hypoglycaemic events during exercise were observed, less post-exercise hypoglycaemia occurred with ultra-rapid aspart (n=0, 0%, vs n=15, 38%; p=0.003). No interactions between insulin types and exercise timings were found.

Conclusions/interpretation: EX60min blunted the pre-exercise glucose increase following breakfast and was associated with a smaller glucose reduction during exercise. Ultra-rapid aspart led to a smaller blood glucose reduction during exercise and might be associated with diminished post-exercise hypoglycaemia.

Trial registration: ClinicalTrials.gov NCT03659799 FUNDING: This study was funded by Novo Nordisk Canada.

目的/假设:1 型糖尿病患者餐前胰岛素类型、运动时间与餐后运动诱发低血糖风险之间的关系尚不清楚。我们旨在评估运动时间(餐后 60 分钟 vs 餐后 120 分钟)和不同胰岛素类型(天冬胰岛素 vs 超快速天冬胰岛素)对低血糖风险的影响:这是一项四向交叉随机试验,包括 40 名每日多次注射的 1 型糖尿病患者(平均 HbA1c 56 mmol/mol [7.4%])。参与者从蒙特利尔临床研究所招募,在早餐后(餐后 60 分钟 [EX60min] 或 120 分钟 [EX120min])进行 60 分钟的自行车运动(V˙O 2 峰值的 60%),胰岛素剂量为平时的 50%(天冬胰岛素或超快速天冬胰岛素)。资格标准包括年龄≥18 岁,临床诊断为 1 型糖尿病至少 1 年,HbA1c ≤80 mmol/mol (9.5%)。参试者使用按顺序编号的不透明密封信封进行分配。参与者的组别分配均不公开,每位参与者都有一个唯一的识别号码,以确保匿名性。主要结果是运动开始和最低点之间血糖水平的变化:结果:在运动开始前,EX60min 与 EX120min 的高血糖时间较短(时间 >10.0 mmol/l:56.6% [1.2-100%] vs 78.0% [52.7-97.9%];p结论/解释:EX60min减弱了早餐后运动前血糖的升高,与运动中血糖降低幅度较小有关。超快速阿斯巴甜可使运动中的血糖降低幅度更小,可能与运动后低血糖症的减少有关:试验注册:ClinicalTrials.gov NCT03659799 资助:本研究由诺和诺德加拿大公司资助。
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Diabetologia
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