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The effect of vitamin D3 supplementation on the incidence of type 2 diabetes in healthy older adults not at high risk for diabetes (FIND): a randomised controlled trial 维生素D3补充剂对非糖尿病高风险健康老年人2型糖尿病发病率的影响:一项随机对照试验
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-02 DOI: 10.1007/s00125-024-06336-9
Jyrki K. Virtanen, Sari Hantunen, Niko Kallio, Christel Lamberg-Allardt, JoAnn E. Manson, Tarja Nurmi, Jussi Pihlajamäki, Matti Uusitupa, Ari Voutilainen, Tomi-Pekka Tuomainen
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>Vitamin D insufficiency is associated with an elevated risk of type 2 diabetes, but evidence from randomised trials on the benefits of vitamin D supplementation is limited, especially for average-risk populations. The Finnish Vitamin D Trial (FIND) investigated the effects of vitamin D<sub>3</sub> supplementation at two different doses on the incidence of type 2 diabetes in a generally healthy older adult population.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>FIND was a 5 year randomised placebo-controlled, parallel-arm trial among 2271 male and female participants aged ≥60 years and ≥65 years, respectively, from a general Finnish population who were free of CVD or cancer and did not use diabetes medications. The study had three arms: placebo, 1600 IU/day of vitamin D<sub>3</sub> or 3200 IU/day of vitamin D<sub>3</sub>. A non-study group statistician carried out sex-stratified simple randomisation in a 1:1:1 ratio, based on computerised random number generation. The participants, investigators and study staff were masked to group assignment. National health registries were used to collect event data. A representative subcohort of 505 participants had more detailed in-person investigations at months 0, 6, 12 and 24.</p><h3 data-test="abstract-sub-heading">Results</h3><p>During the mean follow-up of 4.2 years, there were 38 (5.0%), 31 (4.2%) and 36 (4.7%) type 2 diabetes events in the placebo (<i>n</i>=760), 1600 IU/day vitamin D<sub>3</sub> (<i>n</i>=744; vs placebo: HR 0.81; 95% CI 0.50, 1.30) and 3200 IU/day vitamin D<sub>3</sub> (<i>n</i>=767; vs placebo: HR 0.92, 95% CI 0.58, 1.45) arms, respectively (<i>p</i>-trend=0.73). When the two vitamin D<sub>3</sub> arms were combined and compared with the placebo arm, the HR was 0.86 (95% CI 0.58, 1.29). In the analyses stratified by BMI (<25 kg/m<sup>2</sup> [<i>n</i>=813, number of type 2 diabetes events=12], 25–30 kg/m<sup>2</sup> [<i>n</i>=1032, number of events=38], ≥30 kg/m<sup>2</sup> [<i>n</i>=422, number of events=54]), the HRs in the combined vitamin D<sub>3</sub> arms vs the placebo were 0.43 (95% CI 0.14, 1.34), 0.97 (0.50, 1.91) and 1.00 (0.57, 1.75), respectively (<i>p</i>-interaction <0.001). In the subcohort, the mean (SD) baseline serum 25-hydroxyvitamin D<sub>3</sub> (25(OH)D<sub>3</sub>) concentration was 74.5 (18.1) nmol/l. After 12 months, the concentrations were 72.6 (17.7), 99.3 (20.8) and 120.9 (22.1) nmol/l in the placebo, 1600 IU/day vitamin D<sub>3</sub> and 3200 IU/day vitamin D<sub>3</sub> arms, respectively. In the subcohort, no differences were observed in changes in plasma glucose or insulin concentrations, BMI or waist circumference during the 24 month follow-up (<i>p</i> values ≥0.19).</p><h3 data-test="abstract-sub-heading">Conclusion/interpretation</h3><p>Among generally healthy older adults who are not at high risk for diabetes and who have serum 25(OH)D<sub>3</sub> levels that are suffic
目的/假设维生素D不足与2型糖尿病风险升高有关,但来自随机试验的证据表明补充维生素D的益处有限,特别是对于平均风险人群。芬兰维生素D试验(FIND)调查了两种不同剂量的维生素D3补充对一般健康老年人2型糖尿病发病率的影响。方法:find是一项为期5年的随机、安慰剂对照、平行组试验,研究对象分别为2271名年龄≥60岁和≥65岁的男性和女性,受试者均来自无心血管疾病或癌症且未使用糖尿病药物的芬兰普通人群。该研究分为三组:安慰剂组、每天1600国际单位维生素D3组和每天3200国际单位维生素D3组。非研究组统计学家根据计算机生成的随机数,按1:1:1的比例进行了性别分层的简单随机化。参与者、调查人员和研究人员按小组分配进行分组。使用国家卫生登记来收集事件数据。505名参与者的代表性亚队列在第0、6、12和24个月进行了更详细的亲自调查。结果在平均4.2年的随访中,安慰剂组(n=760)发生38例(5.0%)、31例(4.2%)和36例(4.7%)2型糖尿病事件,维生素D3组(n=744;与安慰剂相比:HR 0.81;95% CI 0.50, 1.30)和3200 IU/d维生素D3 (n=767;与安慰剂组相比:HR 0.92, 95% CI 0.58, 1.45)组(p-trend=0.73)。当两个维生素D3组联合使用并与安慰剂组比较时,风险比为0.86 (95% CI 0.58, 1.29)。在按BMI (25 kg/m2 [n=813, 2型糖尿病事件数=12],25 - 30 kg/m2 [n=1032,事件数=38],≥30 kg/m2 [n=422,事件数=54])分层的分析中,联合维生素D3组与安慰剂组的HRs分别为0.43 (95% CI 0.14, 1.34), 0.97(0.50, 1.91)和1.00 (0.57,1.75)(p-交互作用<;0.001)。在亚队列中,平均(SD)基线血清25(OH)D3 (25(OH)D3)浓度为74.5 (18.1)nmol/l。12个月后,安慰剂组、1600 IU/天维生素D3组和3200 IU/天维生素D3组的浓度分别为72.6(17.7)、99.3(20.8)和120.9 (22.1)nmol/l。在亚队列中,在24个月的随访期间,血浆葡萄糖或胰岛素浓度、BMI或腰围的变化均无差异(p值≥0.19)。结论/解释在一般健康的老年人中,没有糖尿病的高风险,血清25(OH)D3水平足以维持骨骼健康,补充维生素D3并没有显著降低患糖尿病的风险。临床试验注册:clinicaltrials .gov NCT01463813。图形抽象
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引用次数: 0
Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations. 鉴定不同种族和民族人群中与 2 型糖尿病风险相关的蛋白质。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 Epub Date: 2024-09-30 DOI: 10.1007/s00125-024-06277-3
Shuai Liu, Jingjing Zhu, Hua Zhong, Chong Wu, Haoran Xue, Burcu F Darst, Xiuqing Guo, Peter Durda, Russell P Tracy, Yongmei Liu, W Craig Johnson, Kent D Taylor, Ani W Manichaikul, Mark O Goodarzi, Robert E Gerszten, Clary B Clish, Yii-Der Ida Chen, Heather Highland, Christopher A Haiman, Christopher R Gignoux, Leslie Lange, David V Conti, Laura M Raffield, Lynne Wilkens, Loïc Le Marchand, Kari E North, Kristin L Young, Ruth J Loos, Steve Buyske, Tara Matise, Ulrike Peters, Charles Kooperberg, Alexander P Reiner, Bing Yu, Eric Boerwinkle, Quan Sun, Mary R Rooney, Justin B Echouffo-Tcheugui, Martha L Daviglus, Qibin Qi, Nicholas Mancuso, Changwei Li, Youping Deng, Alisa Manning, James B Meigs, Stephen S Rich, Jerome I Rotter, Lang Wu

Aims/hypothesis: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European.

Methods: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations.

Results: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development.

Conclusions/interpretation: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations.

Data availability: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub ( https://github.com/Arthur1021/MESA-1K-PWAS ).

目的/假设:有几项研究报告了欧洲人群中特定蛋白质与 2 型糖尿病风险之间的关联。为了更好地了解蛋白质在不同人群的 2 型糖尿病病因中扮演的角色,我们使用基因工具对四个种族和民族群体进行了一项大型蛋白质组关联研究:方法:多种族动脉粥样硬化研究(MESA)的基因组和血浆蛋白质组数据涉及居住在美国的 182 名非洲人、69 名亚洲人、284 名西班牙裔/拉丁美洲人和 409 名欧洲人,我们利用这些数据建立了蛋白质预测模型,并使用了可能相关的顺式和反式 SNPs。这些模型被应用于对来自不同种族和民族的 250 127 例 2 型糖尿病病例和 1 222 941 例对照的全基因组关联研究汇总统计:结果:我们在亚裔、欧裔和拉美裔人群中分别发现了 3 种、44 种和 1 种与 2 型糖尿病风险相关的蛋白质。元分析确定了 40 种蛋白质与不同人群的 2 型糖尿病风险有关,其中包括已经证实的蛋白质以及尚未与 2 型糖尿病发病有关的新型蛋白质:我们的研究增进了我们对不同人群 2 型糖尿病病因的了解:MVP、DIAMANTE、Biobank Japan 和其他研究的多种族 2 型糖尿病 GWAS 的汇总统计数据可从基因型与表型数据库(dbGaP)获取,数据库登录号为 phs001672.v3.p1。MESA 基因、蛋白质组和协变量数据可通过 dbGaP 访问,登录号为 phs000209.v13.p3。所有代码均可在 GitHub ( https://github.com/Arthur1021/MESA-1K-PWAS ) 上获取。
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引用次数: 0
GLP-1 receptor agonists in lean diabetes in racial and ethnic minority groups: closing the treatment gap. GLP-1 受体激动剂在少数种族和少数族裔瘦型糖尿病患者中的应用:缩小治疗差距。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 Epub Date: 2024-10-21 DOI: 10.1007/s00125-024-06297-z
Felix P Chilunga, George F Mkoma
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引用次数: 0
Addressing disparities in the long-term mortality risk in individuals with non-ST segment myocardial infarction (NSTEMI) by diabetes mellitus status: a nationwide cohort study. 解决非 ST 段心肌梗死 (NSTEMI) 患者的长期死亡风险因糖尿病状况而存在的差异:一项全国性队列研究。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 Epub Date: 2024-10-03 DOI: 10.1007/s00125-024-06281-7
Andrew Cole, Nicholas Weight, Shivani Misra, Julia Grapsa, Martin K Rutter, Zbigniew Siudak, Saadiq Moledina, Evangelos Kontopantelis, Kamlesh Khunti, Mamas A Mamas

Aims/hypothesis: The aim of this study was to investigate how diabetes mellitus affects longer term outcomes in individuals presenting to hospital with non-ST segment elevation myocardial infarction (NSTEMI).

Methods: We analysed data from 456,376 adults hospitalised between January 2005 and March 2019 with NSTEMI from the UK Myocardial Ischaemia National Audit Project (MINAP) registry, linked with Office for National Statistics death reporting. We compared outcomes and quality of care by diabetes status.

Results: Individuals with diabetes were older (median age 74 vs 73 years), were more often of Asian ethnicity (13% vs 4%) and underwent revascularisation (percutaneous coronary intervention or coronary artery bypass graft surgery) (38% vs 40%) less frequently than those without diabetes. The mortality risk for those with diabetes compared with those without was significantly higher at 30 days (HR 1.19, 95% CI 1.15, 1.23), 1 year (HR 1.28, 95% CI 1.26, 1.31), 5 years (HR 1.36, 95% CI 1.34, 1.38) and 10 years (HR 1.39, 95% CI 1.36, 1.42). In individuals with diabetes, higher quality inpatient care, assessed by opportunity-based quality indicator (OBQI) score category ('poor', 'fair', 'good' or 'excellent'), was associated with lower mortality rates compared with poor care (good: HR 0.74, 95% CI 0.73, 0.76; excellent: HR 0.69, 95% CI 0.68, 0.71). In addition, compared with poor care, excellent care in the diabetes group was associated with the lowest mortality rates in the diet-treated and insulin-treated subgroups (diet-treated: HR 0.64, 95% CI 0.61, 0.68; insulin-treated: HR 0.69, CI 0.66, 0.72).

Conclusion/interpretation: Individuals with diabetes experience disparities during inpatient care following NSTEMI. They have a higher risk of long-term mortality than those without diabetes, and higher quality inpatient care may lead to better long-term survival.

目的/假设:本研究旨在探讨糖尿病如何影响非ST段抬高型心肌梗死(NSTEMI)住院患者的长期预后:我们分析了2005年1月至2019年3月期间因NSTEMI住院的456376名成人的数据,这些数据来自英国心肌缺血国家审计项目(MINAP)登记处,并与国家统计局死亡报告相关联。我们比较了糖尿病患者的治疗结果和护理质量:糖尿病患者年龄较大(中位年龄为 74 岁对 73 岁),多为亚裔(13% 对 4%),接受血管重建(经皮冠状动脉介入治疗或冠状动脉旁路移植手术)(38% 对 40%)的频率低于非糖尿病患者。糖尿病患者与非糖尿病患者相比,30 天(HR 1.19,95% CI 1.15,1.23)、1 年(HR 1.28,95% CI 1.26,1.31)、5 年(HR 1.36,95% CI 1.34,1.38)和 10 年(HR 1.39,95% CI 1.36,1.42)的死亡风险明显更高。在糖尿病患者中,以机会质量指标(OBQI)评分类别("差"、"一般"、"好 "或 "优")评估的较高质量住院护理与较差护理相比,死亡率更低(好:HR 0.74,95% CI 0.73,0.76;优:HR 0.69,95% CI 0.68,0.71)。此外,与不良护理相比,糖尿病组中的优秀护理与饮食治疗亚组和胰岛素治疗亚组的最低死亡率相关(饮食治疗:HR 0.64,95% CI 0.73,95% CI 0.68,0.71;胰岛素治疗:HR 0.69,95% CI 0.68,0.71):HR为0.64,95% CI为0.61,0.68;胰岛素治疗组:HR为0.69,95% CI为0.68:结论/解释:结论/解释:糖尿病患者在 NSTEMI 后的住院治疗过程中存在差异。与非糖尿病患者相比,糖尿病患者的长期死亡风险更高,而更高质量的住院治疗可提高长期生存率。
{"title":"Addressing disparities in the long-term mortality risk in individuals with non-ST segment myocardial infarction (NSTEMI) by diabetes mellitus status: a nationwide cohort study.","authors":"Andrew Cole, Nicholas Weight, Shivani Misra, Julia Grapsa, Martin K Rutter, Zbigniew Siudak, Saadiq Moledina, Evangelos Kontopantelis, Kamlesh Khunti, Mamas A Mamas","doi":"10.1007/s00125-024-06281-7","DOIUrl":"10.1007/s00125-024-06281-7","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The aim of this study was to investigate how diabetes mellitus affects longer term outcomes in individuals presenting to hospital with non-ST segment elevation myocardial infarction (NSTEMI).</p><p><strong>Methods: </strong>We analysed data from 456,376 adults hospitalised between January 2005 and March 2019 with NSTEMI from the UK Myocardial Ischaemia National Audit Project (MINAP) registry, linked with Office for National Statistics death reporting. We compared outcomes and quality of care by diabetes status.</p><p><strong>Results: </strong>Individuals with diabetes were older (median age 74 vs 73 years), were more often of Asian ethnicity (13% vs 4%) and underwent revascularisation (percutaneous coronary intervention or coronary artery bypass graft surgery) (38% vs 40%) less frequently than those without diabetes. The mortality risk for those with diabetes compared with those without was significantly higher at 30 days (HR 1.19, 95% CI 1.15, 1.23), 1 year (HR 1.28, 95% CI 1.26, 1.31), 5 years (HR 1.36, 95% CI 1.34, 1.38) and 10 years (HR 1.39, 95% CI 1.36, 1.42). In individuals with diabetes, higher quality inpatient care, assessed by opportunity-based quality indicator (OBQI) score category ('poor', 'fair', 'good' or 'excellent'), was associated with lower mortality rates compared with poor care (good: HR 0.74, 95% CI 0.73, 0.76; excellent: HR 0.69, 95% CI 0.68, 0.71). In addition, compared with poor care, excellent care in the diabetes group was associated with the lowest mortality rates in the diet-treated and insulin-treated subgroups (diet-treated: HR 0.64, 95% CI 0.61, 0.68; insulin-treated: HR 0.69, CI 0.66, 0.72).</p><p><strong>Conclusion/interpretation: </strong>Individuals with diabetes experience disparities during inpatient care following NSTEMI. They have a higher risk of long-term mortality than those without diabetes, and higher quality inpatient care may lead to better long-term survival.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2711-2725"},"PeriodicalIF":8.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11604752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364772","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}
引用次数: 0
Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C. 利用启动子聚焦捕获-C 在相关代谢细胞模型中揭示 2 型糖尿病效应基因。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 Epub Date: 2024-09-06 DOI: 10.1007/s00125-024-06261-x
Nicholas A Wachowski, James A Pippin, Keith Boehm, Sumei Lu, Michelle E Leonard, Elisabetta Manduchi, Ursula W Parlin, Martin Wabitsch, Alessandra Chesi, Andrew D Wells, Struan F A Grant, Matthew C Pahl

Aims/hypothesis: Genome-wide association studies (GWAS) have identified hundreds of type 2 diabetes loci, with the vast majority of signals located in non-coding regions; as a consequence, it remains largely unclear which 'effector' genes these variants influence. Determining these effector genes has been hampered by the relatively challenging cellular settings in which they are hypothesised to confer their effects.

Methods: To implicate such effector genes, we elected to generate and integrate high-resolution promoter-focused Capture-C, assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq datasets to characterise chromatin and expression profiles in multiple cell lines relevant to type 2 diabetes for subsequent functional follow-up analyses: EndoC-BH1 (pancreatic beta cell), HepG2 (hepatocyte) and Simpson-Golabi-Behmel syndrome (SGBS; adipocyte).

Results: The subsequent variant-to-gene analysis implicated 810 candidate effector genes at 370 type 2 diabetes risk loci. Using partitioned linkage disequilibrium score regression, we observed enrichment for type 2 diabetes and fasting glucose GWAS loci in promoter-connected putative cis-regulatory elements in EndoC-BH1 cells as well as fasting insulin GWAS loci in SGBS cells. Moreover, as a proof of principle, when we knocked down expression of the SMCO4 gene in EndoC-BH1 cells, we observed a statistically significant increase in insulin secretion.

Conclusions/interpretation: These results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings.

Data availability: Raw and processed next-generation sequencing data for EndoC-BH1, HepG2, SGBS_undiff and SGBS_diff cells are deposited in GEO under the Superseries accession GSE262484. Promoter-focused Capture-C data are deposited under accession GSE262496. Hi-C data are deposited under accession GSE262481. Bulk ATAC-seq data are deposited under accession GSE262479. Bulk RNA-seq data are deposited under accession GSE262480.

目的/假设:全基因组关联研究(GWAS)发现了数百个 2 型糖尿病基因位点,其中绝大多数信号位于非编码区;因此,这些变异对哪些 "效应 "基因产生影响在很大程度上仍不清楚。确定这些效应基因的工作受到了相对困难的细胞环境的阻碍:为了确定这些效应基因,我们选择生成并整合高分辨率启动子聚焦捕获-C、转座酶可接触染色质测序(ATAC-seq)和 RNA-seq 数据集,以描述与 2 型糖尿病相关的多个细胞系的染色质和表达谱,以便进行后续功能跟踪分析:这些细胞系包括:EndoC-BH1(胰腺β细胞)、HepG2(肝细胞)和辛普森-戈拉比-贝赫默综合征(SGBS;脂肪细胞):结果:随后进行的变异到基因分析在 370 个 2 型糖尿病风险基因位点上发现了 810 个候选效应基因。通过分区连锁不平衡得分回归,我们观察到 EndoC-BH1 细胞中与启动子连接的推定顺式调节元件富集了 2 型糖尿病和空腹血糖 GWAS 基因位点,SGBS 细胞中也富集了空腹胰岛素 GWAS 基因位点。此外,作为原理证明,当我们敲除 EndoC-BH1 细胞中 SMCO4 基因的表达时,我们观察到胰岛素分泌有显著的统计学增长:与相对具有挑战性的原代细胞设置相比,这些结果为在可控的细胞模型中比较组织特异性数据提供了资源:EndoC-BH1、HepG2、SGBS_undiff和SGBS_diff细胞的原始和处理过的新一代测序数据存放在GEO的Superseries accession GSE262484中。Promoter-focused Capture-C 数据以 GSE262496 编号保存。Hi-C 数据以登录号 GSE262481 保存。批量 ATAC-seq 数据以登录号 GSE262479 保存。批量 RNA-seq 数据以登录号 GSE262480 保存。
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引用次数: 0
Deletion of RFX6 impairs iPSC-derived islet organoid development and survival, with no impact on PDX1+/NKX6.1+ progenitors. RFX6的缺失会影响iPSC衍生的胰岛器官发育和存活,但对PDX1+/NKX6.1+祖细胞没有影响。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 Epub Date: 2024-07-30 DOI: 10.1007/s00125-024-06232-2
Noura Aldous, Ahmed K Elsayed, Bushra Memon, Sadaf Ijaz, Sikander Hayat, Essam M Abdelalim

Aims/hypothesis: Homozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6's known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6.

Methods: We examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs).

Results: RFX6 expression was detected in PDX1+ cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets.

Conclusions/interpretation: These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+/NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes.

Data availability: RNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891 ).

目的/假设:RFX6 的同基因突变会导致新生儿糖尿病,并伴有胰腺发育不全,而杂基因突变则会导致 MODY。最近的研究还显示 RFX6 变异与 2 型糖尿病有关。尽管 RFX6 在胰岛发育中的功能众所周知,但其在糖尿病发病机制中的具体作用仍不清楚。在此,我们旨在了解 RFX6 功能缺失突变导致的胰岛发育障碍和随后的胰岛发育不良的机制:我们检测了人类胚胎干细胞(hESC)分化成胰岛过程中调节因子X6(RFX6)的表达,并重新分析了单细胞RNA-seq数据集,以确定胰岛发育过程中RFX6特异性细胞群。此外,还利用 CRISPR/Cas9 生成了缺乏 RFX6 的诱导多能干细胞(iPSC)系。然后,我们采用了多种方法来探索 RFX6 缺失在不同发育阶段的后果。随后,我们通过对胰腺祖细胞(PPs)和内分泌祖细胞(EPs)进行RNA-seq分析,评估了RFX6缺失导致的转录变化:结果:在hESC衍生的后前肠(PF)的PDX1+细胞中检测到了RFX6的表达。然而,在后前肠(PPs)中,RFX6 并未与胰腺和十二指肠同工酶 1(PDX1)或 NK 同工酶 1(NKX6.1)共定位,而是与神经原蛋白 3、NK2 同工酶 2 以及 EPs 和胰岛激素共定位。单细胞分析显示,在不同的 hESC 衍生胰腺分化阶段,内分泌簇中的 RFX6 表达水平都很高。将缺乏 RFX6 的 iPSCs 分化成胰岛后,在 PF 阶段观察到 PDX1 表达显著下降,但这并不影响共同表达 PDX1 和 NKX6.1 的 PPs。RNA-seq 分析显示,RFX6 缺乏导致参与胰腺内分泌分化、胰岛素分泌和离子转运的重要基因下调。此外,由于细胞凋亡增加,RFX6 缺乏会导致形成较小的胰岛器官组织,这与过氧化氢酶表达减少有关,意味着 RFX6 具有保护作用。RFX6的过表达逆转了RFX6基因敲除的胰岛细胞、胰岛素细胞和胰岛的缺陷表型:这些研究结果表明,与 RFX6 基因突变相关的胰腺发育不良和胰岛细胞形成减少并非由于 PDX1+/NKX6.1+ PPs 的改变,而是细胞凋亡和胰腺内分泌基因下调的结果:RNA-seq数据集已存入Zenodo资源库,并附有加入链接(DOI: https://doi.org/10.5281/zenodo.10656891 )。
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引用次数: 0
Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study. IMI-DIRECT 研究发现的人体血浆代谢物在糖尿病前期和 2 型糖尿病中的作用。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 Epub Date: 2024-09-30 DOI: 10.1007/s00125-024-06282-6
Sapna Sharma, Qiuling Dong, Mark Haid, Jonathan Adam, Roberto Bizzotto, Juan J Fernandez-Tajes, Angus G Jones, Andrea Tura, Anna Artati, Cornelia Prehn, Gabi Kastenmüller, Robert W Koivula, Paul W Franks, Mark Walker, Ian M Forgie, Giuseppe Giordano, Imre Pavo, Hartmut Ruetten, Manolis Dermitzakis, Mark I McCarthy, Oluf Pedersen, Jochen M Schwenk, Konstantinos D Tsirigos, Federico De Masi, Soren Brunak, Ana Viñuela, Andrea Mari, Timothy J McDonald, Tarja Kokkola, Jerzy Adamski, Ewan R Pearson, Harald Grallert
<p><strong>Aims/hypothesis: </strong>Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes.</p><p><strong>Methods: </strong>As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively.</p><p><strong>Results: </strong>In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA<sub>1c</sub> progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes.</p><p><strong>Conclusions/interpretation: </strong>Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, signific
目的/假设:2 型糖尿病是一种由高血糖引起的慢性疾病。我们的目的是描述代谢组学的特征,找出它们与血糖谱的关联,并找出代谢物与 2 型糖尿病之间的因果关系:作为创新药物倡议--糖尿病患者分层研究(IMI-DIRECT)联盟的一部分,我们使用 Biocrates AbsoluteIDQ p150 试剂盒和 Metabolon 分析仪测量了 3000 份血浆样本。共有 911 个代谢物(132 个靶向代谢组学、779 个非靶向代谢组学)通过了质量控制。以每种代谢物的浓度/峰面积为解释变量,以血糖状况为因变量,计算出多变量线性回归和逻辑回归分析估计值。该分析在基本模型中对年龄、性别、体重指数和研究中心进行了调整,在完整模型中对酒精、吸烟、血压、空腹高密度脂蛋白胆固醇和空腹三酰甘油进行了调整。统计显著性均经过 Bonferroni 校正。除了关联之外,我们还研究了中介效应和因果效应,分别采用了因果中介检验和双样本孟德尔随机化(2SMR)方法:在靶向代谢组学中,我们分别观察到 4 个(15 个)、34 个(99 个)和 50 个(108 个)代谢物(括号内为非靶向代谢组学中观察到的代谢物数量)在比较正常血糖调节与受损血糖调节/糖尿病、正常血糖调节与 2 型糖尿病、受损血糖调节与 2 型糖尿病时存在显著差异。重要的代谢物主要是支链氨基酸(BCAAs),还有一些衍生的支链氨基酸、脂类、异生物体和一些未知物。C17:0 的溶血磷脂酰胆碱、六糖总和、BCAA 代谢产生的氨基酸(包括亮氨酸、异亮氨酸、缬氨酸、N-乳酰缬氨酸、N-乳酰亮氨酸和甲脒谷氨酸)和乳酸盐等代谢物以及一种未知代谢物(X-24295)与 HbA1c 进展率有关,并且是 2 型糖尿病从基线到 18 个月和 48 个月随访期间的重要介质。2SMR 是利用英国生物库全基因组关联研究的汇总统计来估计暴露对结果的因果效应。我们发现,2 型糖尿病对三种代谢物(己糖、谷氨酸和己酸[脂肪酸 (FA) 6:0])的水平有因果效应,而脂质,如特定的磷脂酰胆碱(PC)(即 PC aa C36:2、PC aa C36:5、PC ae C36:3和PC ae C34:3)以及两种n-3脂肪酸硬脂酸酯(18:4n3)和二十二碳五烯酸酯(22:5n3)可能在2型糖尿病的发病中起着诱因作用。结论/解释:我们的研究结果确定了已知的 BCAAs 和脂类,以及新型 N-乳酰氨基酸代谢物,它们与糖尿病前期和糖尿病有显著相关性,从基线到随访(18 个月和 48 个月)都能介导糖尿病的影响。利用基因变异进行的因果推断显示,脂质代谢和 n-3 脂肪酸是代谢物对 2 型糖尿病的因果关系,而六糖总和则是 2 型糖尿病对代谢物的因果关系。已确定的代谢物标记物有助于根据个人的风险进展对其进行分层,并应能采取有针对性的干预措施。
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引用次数: 0
Cardiovascular autonomic neuropathy in diabetes: an update with a focus on management. 糖尿病的心血管自主神经病变:以管理为重点的最新进展。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 Epub Date: 2024-08-09 DOI: 10.1007/s00125-024-06242-0
Aikaterini Eleftheriadou, Vincenza Spallone, Abd A Tahrani, Uazman Alam

Cardiovascular autonomic neuropathy (CAN) is an under-recognised yet highly prevalent microvascular complication of diabetes. CAN affects approximately 20% of people with diabetes, with recent studies highlighting the presence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose), indicating early involvement of the autonomic nervous system. Understanding of the pathophysiology of CAN continues to evolve, with emerging evidence supporting a potential link between lipid metabolites, mitochondrial dysfunction and genetics. Recent advancements, such as streamlining CAN detection through wearable devices and monitoring of heart rate variability, present simplified and cost-effective approaches for early CAN detection. Further research on the optimal use of the extensive data provided by such devices is required. Despite the lack of specific pharmacological interventions targeting the underlying pathophysiology of autonomic neuropathy, several studies have suggested a favourable impact of newer glucose-lowering agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, where there is a wealth of clinical trial data on the prevention of cardiovascular events. This review delves into recent developments in the area of CAN, with emphasis on practical guidance to recognise and manage this underdiagnosed condition, which significantly increases the risk of cardiovascular events and mortality in diabetes.

心血管自主神经病变(CAN)是一种未被充分认识但却非常普遍的糖尿病微血管并发症。约有 20% 的糖尿病患者会受到心血管自主神经病变的影响,最近的研究强调,糖尿病前期(糖耐量受损和/或空腹血糖受损)患者也会出现心血管自主神经病变,这表明自主神经系统已提前受到影响。人们对 CAN 病理生理学的认识在不断发展,新出现的证据支持脂质代谢物、线粒体功能障碍和遗传之间的潜在联系。最近的进步,如通过可穿戴设备和心率变异性监测简化 CAN 检测,为早期 CAN 检测提供了简化且具有成本效益的方法。我们需要进一步研究如何优化使用这些设备提供的大量数据。尽管缺乏针对自主神经病变潜在病理生理学的特异性药物干预措施,但一些研究表明,钠-葡萄糖共转运体 2 抑制剂和胰高血糖素样肽-1 受体激动剂等新型降糖药物对预防心血管事件有积极影响,这些药物在预防心血管事件方面有丰富的临床试验数据。本综述深入探讨了 CAN 领域的最新进展,重点是如何识别和管理这种未得到充分诊断的疾病的实用指南,这种疾病会显著增加糖尿病患者发生心血管事件和死亡的风险。
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引用次数: 0
Up Front. 在前面
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-12-01 DOI: 10.1007/s00125-024-06305-2
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引用次数: 0
Correction: Quantifying beta cell function in the preclinical stages of type 1 diabetes 更正:量化 1 型糖尿病临床前期的β细胞功能
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-27 DOI: 10.1007/s00125-024-06335-w
Alfonso Galderisi, Alice L. J. Carr, Mariangela Martino, Peter Taylor, Peter Senior, Colin Dayan
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引用次数: 0
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Diabetologia
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