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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 : 2024-09-30 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
Mortality rates in people presenting with a new diabetes-related foot ulcer: a cohort study with implications for management 新发糖尿病足溃疡患者的死亡率:一项队列研究及其对管理的影响
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-27 DOI: 10.1007/s00125-024-06262-w
Naomi Holman, Arthur C. Yelland, Bob Young, Jonathan Valabhji, William Jeffcoate, Fran Game

Aims/hypothesis

People with diabetes-related foot ulcers (DFUs) have high mortality rates. This analysis assesses the impact of selected risk factors on short-term mortality using a population registered in the National Diabetes Foot Care Audit (NDFA).

Methods

Mortality rates at 12, 26 and 52 weeks was assessed in people with a new DFU registered by a specialist diabetes footcare service in the NDFA in England and Wales between April 2017 and March 2022. Poisson regression models were created to explore risk factors for mortality.

Results

In 71,000 people registered with a new DFU, mortality rates at 12, 26 and 52 weeks was 4.2%, 8.2% and 14.4%, respectively. At 26 weeks, higher mortality rates was associated with older age (rate ratio 2.15; 95% CI 2.03, 2.28, for age ≥80 years vs age 65–79 years), certain ulcer characteristics (area ≥1 cm2 [1.50; 95% CI 1.42, 1.59], deep ulcers [1.26; 95% CI 1.18, 1.35] or hindfoot location [1.53; 95% CI 1.44, 1.62]) and recorded evidence of ischaemia in the lower limb (1.78; 95% CI 1.69, 1.88) and various comorbidities (heart failure [2.13; 95% CI 2.00, 2.26], myocardial infarction [1.45; 95% CI 1.29, 1.63], stroke [1.37; 95% CI 1.22, 1.53], renal replacement therapy [2.34; 95% CI 2.09, 2.61] and chronic kidney disease stage 3 or greater [1.20; 95% CI 1.12, 1.29]). The 26-week mortality rate exceeded 25% for 7.3% of all individuals, rising to 11.5% of those aged 65 years and older, and 22.1% of those aged 80 years and over.

Conclusions/interpretation

Short-term mortality rates in people with a DFU is high. Teams managing people with DFUs should consider modifying the burdensome interventions and care required to heal such ulcers so maximising the quality of residual life, rather than focusing exclusively on healing.

Graphical Abstract

目的/假设糖尿病足溃疡(DFU)患者的死亡率很高。本分析以全国糖尿病足护理审计(NDFA)中登记的人群为对象,评估了选定风险因素对短期死亡率的影响。方法对2017年4月至2022年3月期间英格兰和威尔士NDFA中糖尿病足护理专科服务机构登记的新发DFU患者在12周、26周和52周的死亡率进行评估。结果在7.1万名新登记的DFU患者中,12周、26周和52周的死亡率分别为4.2%、8.2%和14.4%。在 26 周时,死亡率较高与年龄较大(年龄≥80 岁与 65-79 岁的比率比为 2.15;95% CI 为 2.03,2.28)、某些溃疡特征(面积≥1 平方厘米 [1.50;95% CI 为 1.42,1.59],深溃疡 [1.26;95% CI 为 1.18,1.35] 或后足位置 [1.53;95% CI 为 1.44,1.62])和有记录的溃疡证据有关。62])以及下肢缺血的记录证据(1.78;95% CI 1.69,1.88)和各种合并症(心力衰竭[2.13;95% CI 2.00,2.26],心肌梗塞[1.45;95% CI 1.29,1.63]、中风[1.37;95% CI 1.22,1.53]、肾脏替代治疗[2.34;95% CI 2.09,2.61]和慢性肾脏病 3 期或以上[1.20;95% CI 1.12,1.29])。7.3%的患者在26周内的死亡率超过25%,65岁及以上的患者死亡率为11.5%,80岁及以上的患者死亡率为22.1%。管理 DFU 患者的团队应考虑改变治愈此类溃疡所需的繁重干预和护理,从而最大限度地提高残余生命的质量,而不是仅仅关注治愈。
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引用次数: 0
A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial 全食物、以植物为基础的强化生活方式干预可改善 2 型糖尿病患者的血糖控制并减少用药:随机对照试验
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-21 DOI: 10.1007/s00125-024-06272-8
Cody J. Hanick, Courtney M. Peterson, Brenda C. Davis, Joan Sabaté, John H. Kelly

Aims/hypothesis

We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes.

Methods

We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18–75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA1c, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded.

Results

Compared with SMC (n=90 randomised; n=70 analysed), the PB+Ex (n=79 randomised; n=66 analysed) intervention decreased HbA1c by an additional 14 mmol/mol (1.3%) at week 12 (−22 vs −7 mmol/mol [−2.0% vs −0.7%]; p<0.0001) and 8 mmol/mol (0.7%) at week 24 (−16 vs −8 mmol/mol [−1.4% vs −0.7%]; p=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%; p=0.006), and 23% of PB+Ex participants with a baseline HbA1c <75 mmol/mol (<9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (−2.7 kg; p<0.0001), C-reactive protein (−11 nmol/l; p=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24.

Conclusions/interpretation

A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT03862963

Funding

This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).

Graphical Abstract

我们对马绍尔群岛 169 名 18-75 岁的 2 型糖尿病患者进行了为期 24 周的随机分组(平行臂;计算机化 1:1 随机分配比例),将他们分配到强化全食物、植物性干预和适度运动(PB+Ex)或标准医疗护理(SMC)中。PB+Ex 干预包括 12 周的膳食、运动课程和小组课程。主要结果是血糖控制(HbA1c、葡萄糖、胰岛素和 HOMA-IR)和降糖药物的使用。次要结果包括血脂、血压、心率和 C 反应蛋白。结果与 SMC(随机人数=90;分析人数=70)相比,PB+Ex(随机人数=79;分析人数=66)干预在第 12 周将 HbA1c 再降低 14 mmol/mol(1.3%),第 24 周时降低 8 mmol/mol (0.7%) (-16 vs -8 mmol/mol [-1.4% vs -0.7%]; p=0.01)。同时,63% 的 PB+Ex 参与者减少了降糖药物的服用(vs 24%;p=0.006),基线 HbA1c 为 75 mmol/mol (<9%) 的 PB+Ex 参与者中有 23% 实现了病情缓解。此外,与 SMC 相比,PB+Ex 干预措施降低了体重(-2.7 千克;p<0.0001)、C 反应蛋白(-11 毫摩尔/升;p=0.005)和心血管药物使用量。在中间时间点,它改善了血糖、胰岛素、HOMA-IR、胆固醇、甘油三酯和心率,但在第 24 周时没有改善。结论/解释与 SMC 相比,全食物、以植物为基础的生活方式干预对改善血糖控制更有效。它还减少了对糖尿病和心血管药物的需求,并使一些参与者的糖尿病得到缓解。因此,对于 2 型糖尿病患者来说,这是一种有效的、以证据为基础的生活方式选择。试验注册ClinicalTrials.gov NCT03862963资助本研究由陆军部(W81XWH-05-1-0547)资助。CJH获得了美国国立卫生研究院T32肥胖症博士前期奖学金(T32 HL105349)的资助。
{"title":"A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial","authors":"Cody J. Hanick, Courtney M. Peterson, Brenda C. Davis, Joan Sabaté, John H. Kelly","doi":"10.1007/s00125-024-06272-8","DOIUrl":"https://doi.org/10.1007/s00125-024-06272-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18–75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA<sub>1c</sub>, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Compared with SMC (<i>n</i>=90 randomised; <i>n</i>=70 analysed), the PB+Ex (<i>n</i>=79 randomised; <i>n</i>=66 analysed) intervention decreased HbA<sub>1c</sub> by an additional 14 mmol/mol (1.3%) at week 12 (−22 vs −7 mmol/mol [−2.0% vs −0.7%]; <i>p</i>&lt;0.0001) and 8 mmol/mol (0.7%) at week 24 (−16 vs −8 mmol/mol [−1.4% vs −0.7%]; <i>p</i>=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%; <i>p</i>=0.006), and 23% of PB+Ex participants with a baseline HbA<sub>1c</sub> &lt;75 mmol/mol (&lt;9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (−2.7 kg; <i>p</i>&lt;0.0001), C-reactive protein (−11 nmol/l; <i>p</i>=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Trial registration</h3><p>ClinicalTrials.gov NCT03862963</p><h3 data-test=\"abstract-sub-heading\">Funding</h3><p>This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"89 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276795","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
The DPP-4 inhibitor sitagliptin improves glycaemic control and early-stage diabetic nephropathy in adolescents with type 1 diabetes using the MiniMed 780G advanced hybrid closed-loop system: a randomised controlled trial 使用 MiniMed 780G 高级混合闭环系统,DPP-4 抑制剂西格列汀可改善 1 型糖尿病青少年的血糖控制和早期糖尿病肾病:随机对照试验
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-14 DOI: 10.1007/s00125-024-06265-7
Nancy S. Elbarbary, Eman A. Ismail, Manal H. El-Hamamsy, Marwa Z. Ibrahim, Amal A. Elkholy
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>Dipeptidyl peptidase-4 (DPP-4) inhibition has beneficial effects on various metabolic indicators in diabetes. Stromal cell-derived factor-1 (SDF-1) is expressed in diverse organs including the kidneys and is cleaved and inactivated by DPP-4 enzyme. The aim of this study was to conduct a randomised controlled trial to assess the effect of sitagliptin on diabetic nephropathy when used as an add-on therapy to the advanced hybrid closed-loop (AHCL) system in adolescents with type 1 diabetes and nephropathy.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>This open-label, parallel-group, randomised controlled trial took place at the Pediatric Diabetes Clinic, Ain Shams University, Egypt. Forty-six adolescents aged 14.13 ± 2.43 years on the MiniMed 780G system for at least 6 months before study, with HbA<sub>1c</sub> ≤69 mmol/mol (8.5%) and diabetic nephropathy in the form of microalbuminuria, were randomly assigned to two groups (<i>n</i>=23 for each) based on a computer-generated randomisation sequence. The intervention group received oral sitagliptin 50 mg for 3 months. The other group used AHCL only and served as a control group. The primary outcome measure was the change in urinary albumin/creatinine ratio (UACR) after 3 months of administration of sitagliptin. The key secondary outcome measure was the change from baseline in SDF-1 levels after treatment.</p><h3 data-test="abstract-sub-heading">Results</h3><p>Data for all participants were analysed. No significant difference was found between the groups as regards baseline clinical and laboratory characteristics as well as AHCL system settings (<i>p</i>>0.05). Serum SDF-1 levels were higher in all individuals with type 1 diabetes vs healthy control individuals (<i>p</i><0.001). After 3 months, sitagliptin resulted in a significant decrease of SDF-1 levels from 3.58 ± 0.73 to 1.99 ± 0.76 ng/ml (<i>p</i><0.001), together with improvement of UACR from 7.27 ± 2.41 to 1.32 ± 0.31 mg/mmol (<i>p</i><0.001). In addition, sitagliptin reduced postprandial glucose, sensor glucose, coefficient of variation and total daily dose of insulin, while time in range 3.9–10.0 mmol/l (70–180 mg/dl) and insulin-to-carbohydrate ratio were significantly increased. Sitagliptin was safe and well-tolerated without severe hypoglycaemia or diabetic ketoacidosis.</p><h3 data-test="abstract-sub-heading">Conclusions/interpretation</h3><p>Sitagliptin as an add-on therapy to AHCL had a reno-protective effect for individuals with type 1 diabetes and diabetic nephropathy, in addition to the improvement of time in range while reducing glycaemic variability and without compromising safety.</p><h3 data-test="abstract-sub-heading">Funding</h3><p>This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.</p><h3 data-test="abstract-sub-heading">Trial registration</h3><p>ClinicalTrials.gov NCT06115460.</p
目的/假说二肽基肽酶-4(DPP-4)抑制剂对糖尿病患者的各种代谢指标有益处。基质细胞衍生因子-1(SDF-1)在包括肾脏在内的多种器官中表达,并被DPP-4酶裂解和灭活。本研究旨在开展一项随机对照试验,评估西他列汀作为高级混合闭环(AHCL)系统的附加疗法,对患有 1 型糖尿病和肾病的青少年糖尿病肾病的影响。根据计算机生成的随机序列,将 46 名年龄为 14.13 ± 2.43 岁、使用 MiniMed 780G 系统至少 6 个月(研究前)、HbA1c ≤69 mmol/mol (8.5%) 和糖尿病肾病(微量白蛋白尿)的青少年随机分配到两组(每组 23 人)。干预组口服西格列汀 50 毫克,为期 3 个月。另一组仅使用 AHCL,作为对照组。主要结果指标是服用西格列汀 3 个月后尿白蛋白/肌酐比值(UACR)的变化。主要次要结果指标是治疗后 SDF-1 水平与基线相比的变化。在基线临床和实验室特征以及 AHCL 系统设置方面,各组之间无明显差异(p>0.05)。与健康对照组相比,所有 1 型糖尿病患者的血清 SDF-1 水平都更高(p<0.001)。3 个月后,西格列汀使 SDF-1 水平从 3.58 ± 0.73 ng/ml 显著降至 1.99 ± 0.76 ng/ml (p<0.001),同时使 UACR 从 7.27 ± 2.41 mg/mmol 降至 1.32 ± 0.31 mg/mmol (p<0.001)。此外,西他列汀还降低了餐后血糖、感应血糖、变异系数和每日胰岛素总剂量,而在 3.9-10.0 毫摩尔/升(70-180 毫克/分升)范围内的时间和胰岛素与碳水化合物的比率则显著增加。西他列汀安全且耐受性良好,未出现严重低血糖或糖尿病酮症酸中毒。结论/解释西他列汀作为 AHCL 的附加疗法,对 1 型糖尿病和糖尿病肾病患者具有肾脏保护作用,此外还能在降低血糖变异性的同时改善血糖在范围内的时间,且不影响安全性。本研究未从公共、商业或非营利部门的任何资助机构获得特定资助。试验注册ClinicalTrials.gov NCT06115460.Graphical abstract
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引用次数: 0
Genetic evidence for efficacy of targeting IL-2, IL-6 and TYK2 signalling in the prevention of type 1 diabetes: a Mendelian randomisation study 以 IL-2、IL-6 和 TYK2 信号为靶点预防 1 型糖尿病疗效的遗传学证据:孟德尔随机研究
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-13 DOI: 10.1007/s00125-024-06267-5
Tea E. Heikkilä, Emilia K. Kaiser, Jake Lin, Dipender Gill, Jaakko J. Koskenniemi, Ville Karhunen

Aims/hypothesis

We aimed to investigate the genetic evidence that supports the repurposing of drugs already licensed or in clinical phases of development for prevention of type 1 diabetes.

Methods

We obtained genome-wide association study summary statistics for the risk of type 1 diabetes, whole-blood gene expression and serum protein levels and investigated genetic polymorphisms near seven potential drug target genes. We used co-localisation to examine whether the same genetic variants that are associated with type 1 diabetes risk were also associated with the relevant drug target genetic proxies and used Mendelian randomisation to evaluate the direction and magnitude of the associations. Furthermore, we performed Mendelian randomisation analysis restricted to functional variants within the drug target genes.

Results

Co-localisation revealed that the blood expression levels of IL2RA (encoding IL-2 receptor subunit α [IL2RA]), IL6R (encoding IL-6 receptor [IL6R]) and IL6ST (encoding IL-6 cytokine family signal transducer [IL6ST]) shared the same causal variant with type 1 diabetes liability near the corresponding genes (posterior probabilities 100%, 96.5% and 97.0%, respectively). The OR (95% CI) of type 1 diabetes per 1-SD increase in the genetically proxied gene expression of IL2RA, IL6R and IL6ST were 0.22 (0.17, 0.27), 1.98 (1.48, 2.65) and 1.90 (1.45, 2.48), respectively. Using missense variants, genetically proxied TYK2 (encoding tyrosine kinase 2) expression levels were associated with type 1 diabetes risk (OR 0.61 [95% CI 0.54, 0.69]).

Conclusions/interpretation

Our findings support the targeting of IL-2, IL-6 and TYK2 signalling in prevention of type 1 diabetes.

Data availability

The analysis code is available at https://github.com/jkoskenniemi/T1DSCREEN, which also includes instructions on how to download the original GWAS summary statistics.

Graphical Abstract

目的/假设我们旨在调查支持将已获许可或处于临床开发阶段的药物重新用于预防 1 型糖尿病的基因证据。方法我们获得了 1 型糖尿病风险、全血基因表达和血清蛋白水平的全基因组关联研究汇总统计,并调查了七个潜在药物靶基因附近的基因多态性。我们使用共定位法检测与 1 型糖尿病风险相关的基因变异是否也与相关的药物靶点基因代理相关,并使用孟德尔随机法评估关联的方向和程度。结果共同定位显示,IL2RA(编码IL-2受体亚基α [IL2RA])、IL6R(编码IL-6受体[IL6R])和IL6ST(编码IL-6细胞因子家族信号转导子[IL6ST])的血液表达水平与相应基因附近的1型糖尿病责任具有相同的因果变异(后验概率分别为100%、96.5%和97.0%)。IL2RA、IL6R和IL6ST的基因代理基因表达量每增加1-SD,1型糖尿病的OR值(95% CI)分别为0.22(0.17,0.27)、1.98(1.48,2.65)和1.90(1.45,2.48)。结论/解释我们的研究结果支持以 IL-2、IL-6 和 TYK2 信号为靶点预防 1 型糖尿病。数据提供分析代码可在 https://github.com/jkoskenniemi/T1DSCREEN 上获取,其中还包括如何下载原始 GWAS 统计摘要的说明。图表摘要
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引用次数: 0
Metabolic health in people living with type 1 diabetes in Belgium: a repeated cross-sectional study 比利时 1 型糖尿病患者的代谢健康:重复横断面研究
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-13 DOI: 10.1007/s00125-024-06273-7
Astrid Lavens, Christophe De Block, Philippe Oriot, Laurent Crenier, Jean-Christophe Philips, Michel Vandenbroucke, An-Sofie Vanherwegen, Frank Nobels, Chantal Mathieu
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>Metabolic abnormalities such as central obesity, insulin resistance, dyslipidaemia and hypertension, often referred to as ‘the metabolic syndrome’ (or ‘combined metabolic abnormalities’), are increasingly being identified in people living with type 1 diabetes, accelerating the risk for CVD. As a result, in recent years, treatment in people living with type 1 diabetes has shifted to improving overall metabolic health rather than glucose control alone. In Belgium, diabetes care for people living with type 1 diabetes is centrally organised. The Initiative for Quality Improvement and Epidemiology in Diabetes, imposed by the Belgian health insurance system, has systematically collected data from patients on intensive insulin therapy treated in all 101 diabetes clinics in Belgium since 2001. The aim of this real-world study is to describe the evolution of treatment and metabolic health, including the prevalence of obesity and combined metabolic abnormalities, in people living with type 1 diabetes over the past 20 years, and to compare the treatment and prevalence of complications between those with and without combined metabolic abnormalities.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>We analysed data on adults (≥16 years old) living with type 1 diabetes, who were diagnosed at age ≤45 years and who had a diabetes duration ≥1 year, collected between 2001 and 2022. The evolution of HbA<sub>1c</sub>, BMI, LDL-cholesterol, systolic BP, lipid-lowering therapy and antihypertensive therapy over time was analysed. The prevalence of individual and multiple metabolic abnormalities according to various definitions of the metabolic syndrome/combined metabolic abnormalities was analysed, and the association between combined metabolic abnormalities and metabolic health indicators, complications and treatment was investigated in the 2022 data.</p><h3 data-test="abstract-sub-heading">Results</h3><p>The final dataset consisted of 26,791 registrations of adults living with type 1 diabetes collected between 2001 and 2022. Although glycaemic and lipid control generally improved over time, the prevalence of obesity strongly increased (12.1% in 2001 vs 21.7% in 2022, <i>p</i><0.0001), as did the presence of combined metabolic abnormalities (WHO criteria: 26.9% in 2001 vs 42.9% in 2022 in women, <i>p</i><0.0001; 30.4% in 2001 vs 52.1% in 2022 in men, <i>p</i><0.0001; WHO criteria without albuminuria: 22.3% in 2001 vs 40.6% in 2022 in women, <i>p</i><0.0001; 25.1% in 2001 vs 49.2% in 2022 in men, <i>p</i><0.0001; NCEP-ATPIII criteria: 39.9% in 2005 vs 57.2% in 2022 in women, <i>p</i><0.0001; 40.8% in 2005 vs 60.9% in 2022 in men, <i>p</i><0.0001; IDF criteria: 43.9% in 2005 vs 59.3% in 2022 in women, <i>p</i><0.001; 33.7% in 2005 vs 50.0% in 2022 in men, <i>p</i><0.0001). People with combined metabolic abnormalities had higher glucose levels compared to those without combined m
目的/假设1 型糖尿病患者中越来越多地出现代谢异常,如中心性肥胖、胰岛素抵抗、血脂异常和高血压,通常被称为 "代谢综合征"(或 "合并代谢异常"),从而增加了心血管疾病的风险。因此,近年来对 1 型糖尿病患者的治疗已转向改善整体代谢健康,而不仅仅是控制血糖。在比利时,1 型糖尿病患者的糖尿病治疗是集中组织的。自2001年以来,比利时医疗保险系统实施的糖尿病质量改进和流行病学计划系统地收集了比利时所有101家糖尿病诊所中接受胰岛素强化治疗的患者的数据。这项真实世界的研究旨在描述过去20年中1型糖尿病患者的治疗和代谢健康状况的变化,包括肥胖和合并代谢异常的患病率,并比较有合并代谢异常和没有合并代谢异常的患者的治疗情况和并发症的患病率。方法我们分析了2001年至2022年期间收集的1型糖尿病成年患者(≥16岁)的数据,这些患者确诊时年龄≤45岁,糖尿病病程≥1年。分析了 HbA1c、BMI、低密度脂蛋白胆固醇、收缩压、降脂治疗和降压治疗随时间的变化情况。根据代谢综合征/合并代谢异常的不同定义,分析了单个和多个代谢异常的患病率,并在 2022 年的数据中调查了合并代谢异常与代谢健康指标、并发症和治疗之间的关联。虽然随着时间的推移,血糖和血脂控制情况普遍有所改善,但肥胖症的发病率却大幅上升(2001 年为 12.1%,2022 年为 21.7%,p<0.0001),合并代谢异常的比例也有所上升(根据世界卫生组织的标准,2001 年为 26.9%,2022 年为 42%):WHO标准:女性2001年为26.9%,2022年为42.9%,p<0.0001;男性2001年为30.4%,2022年为52.1%,p<0.0001;WHO标准(无白蛋白尿):女性2001年为22.3%,2022年为40.6%,p<0.0001;男性2001年为25.1%,2022年为49.2%,p<0.0001;NCEP-ATPIII标准:2005年女性为39.9%,2022年为57.2%,p<0.0001;2005年男性为40.8%,2022年为60.9%,p<0.0001;IDF标准:2005年女性为43.9%,2022年为59.3%,p<0.001;2005年男性为33.7%,2022年为50.0%,p<0.0001)。与没有合并代谢异常的人相比,合并代谢异常的人血糖水平更高(男性 HbA1c >58 mmol:48.9% vs 36.9%;女性 HbA1c >58 mmol:53.3% vs 41.1%,p<0.0001)。合并代谢异常的患者更常接受二甲双胍、钠-葡萄糖转运蛋白 2 抑制剂和胰高血糖素样肽-1 受体激动剂等辅助疗法。在男性和女性中,合并代谢异常与眼部并发症、周围神经病变、慢性肾病和心血管疾病的发生密切相关,并对年龄、糖尿病病程和 HbA1c 进行了校正。结论/解释超重、肥胖和合并代谢异常在 1 型糖尿病患者中的发现越来越多,这进一步增加了微血管和大血管并发症的风险。及早发现合并代谢异常应能使治疗干预措施向多因素方法转变,除了严格控制血糖和加强使用降压药和他汀类药物外,还应注意避免超重的教育(如饮食咨询)。应更深入地探讨在这一人群中使用辅助疗法作为降低并发症风险的工具。
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引用次数: 0
Up Front 在前面
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-13 DOI: 10.1007/s00125-024-06263-9
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引用次数: 0
Risk factors for Charcot foot development in individuals with diabetes mellitus 糖尿病患者出现夏科氏足的风险因素
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-13 DOI: 10.1007/s00125-024-06271-9
Georgios Tsatsaris, Neda Rajamand Ekberg, Tove Fall, Sergiu-Bogdan Catrina

Aims/hypothesis

Charcot foot is a complication of diabetes mellitus that has potentially disastrous consequences. Although it was first described in 1868 and found to be associated with diabetes in 1936, there is still uncertainty about the risk factors affecting the development of the condition. Here, we aim to identify risk factors for Charcot foot in a nationwide cohort study.

Methods

A retrospective register-based cohort study was performed for the period 2001–2016, using nationwide registries. Individuals with diabetes and Charcot foot were identified and matched by diabetes type and with similar diabetes duration with individuals with diabetes but not Charcot foot. Logistic regression analyses were used to identify risk factors.

Results

A total of 3397 participants with diabetes mellitus and Charcot foot and 27,662 control participants with diabetes but without Charcot foot were included. HbA1c, duration of diabetes, micro- and macroalbuminuria, retinopathy and atherosclerosis (general and peripheral) were identified as risk factors for Charcot foot in participants with type 1 diabetes and participants with type 2 diabetes.

Conclusions/interpretation

In the most extensive study on Charcot foot to date, we identified distinctive and common risk factors associated with the development of Charcot foot in individuals with type 1 diabetes and type 2 diabetes.

Graphical Abstract

目的/假说恰克脚是糖尿病的一种并发症,具有潜在的灾难性后果。虽然该病于 1868 年首次被描述,并于 1936 年被发现与糖尿病有关,但目前仍不确定影响该病发生的风险因素。在此,我们旨在通过一项全国性的队列研究来确定夏科足的风险因素。方法利用全国性的登记资料,对 2001-2016 年期间进行了一项基于登记资料的回顾性队列研究。根据糖尿病类型和相似的糖尿病持续时间,将患有糖尿病和夏科氏足的患者与患有糖尿病但未患有夏科氏足的患者进行配对。结果 共纳入了 3397 名患有糖尿病和夏科脚的参与者,以及 27662 名患有糖尿病但没有夏科脚的对照参与者。HbA1c、糖尿病持续时间、微量和大量白蛋白尿、视网膜病变和动脉粥样硬化(全身和外周)被确定为1型糖尿病患者和2型糖尿病患者发生夏科脚的风险因素。结论/解释在迄今为止最广泛的夏科脚研究中,我们确定了与1型糖尿病患者和2型糖尿病患者发生夏科脚相关的独特和常见风险因素。
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引用次数: 0
60th EASD Annual Meeting of the European Association for the Study of Diabetes 欧洲糖尿病研究协会第 60 届年会
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-12 DOI: 10.1007/s00125-024-06226-0
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引用次数: 0
An antifibrotic compound that ameliorates hyperglycaemia and fat accumulation in cell and HFD mouse models 一种抗纤维化化合物,可改善细胞和高密度脂蛋白胆固醇(HFD)小鼠模型中的高血糖和脂肪堆积状况
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-09 DOI: 10.1007/s00125-024-06260-y
Tsugumasa Toma, Nobukazu Miyakawa, Yuiichi Arakaki, Takuro Watanabe, Ryosei Nakahara, Taha F. S. Ali, Tanima Biswas, Mikio Todaka, Tatsuya Kondo, Mikako Fujita, Masami Otsuka, Eiichi Araki, Hiroshi Tateishi

Aims/hypothesis

Appropriate management of blood glucose levels and the prevention of complications are important in the treatment of diabetes. We have previously reported on a compound named HPH-15 that is not only antifibrotic but also AMP-activated protein kinase (AMPK)-activating. In this study, we evaluated whether HPH-15 is useful as a therapeutic medication for diabetes.

Methods

We examined the effects of HPH-15 on AMPK activation, glucose uptake, fat accumulation and lactic acid production in L6-GLUT4, HepG2 and 3T3-L1 cells, as a model of muscle, liver and fat tissue, respectively. Additionally, we investigated the glucose-lowering, fat-accumulation-suppressing, antifibrotic and AMPK-activating effect of HPH-15 in mice fed a high-fat diet (HFD).

Results

HPH-15 at a concentration of 10 µmol/l increased AMPK activation, glucose uptake and membrane translocation of GLUT4 in each cell model to the same extent as metformin at 2 mmol/l. The production of lactic acid (which causes lactic acidosis) in HPH-15-treated cells was equal to or less than that observed in metformin-treated cells. In HFD-fed mice, HPH-15 lowered blood glucose from 11.1±0.3 mmol/l to 8.2±0.4 mmol/l (10 mg/kg) and 7.9±0.4 mmol/l (100 mg/kg) and improved insulin resistance. The HPH-15 (10 mg/kg) group showed the same level of AMPK activation as the metformin (300 mg/kg) group in all organs. The HPH-15-treated HFD-fed mice also showed suppression of fat accumulation and fibrosis in the liver and fat tissue; these effects were more significant than those obtained with metformin. Mice treated with high doses of HPH-15 also exhibited a 44% reduction in subcutaneous fat.

Conclusions/interpretation

HPH-15 activated AMPK at lower concentrations than metformin in vitro and in vivo and improved blood glucose levels and insulin resistance in vivo. In addition, HPH-15 was more effective than metformin at ameliorating fatty liver and adipocyte hypertrophy in HFD-fed mice. HPH-15 could be effective in preventing fatty liver, a common complication in diabetic individuals. Additionally, in contrast to metformin, high doses of HPH-15 reduced subcutaneous fat in HFD-fed mice. Presumably, HPH-15 has a stronger inhibitory effect on fat accumulation and fibrosis than metformin, accounting for the reduction of subcutaneous fat. Therefore, HPH-15 is potentially a glucose-lowering medication that can lower blood glucose, inhibit fat accumulation and ameliorate liver fibrosis.

Graphical Abstract

目的/假设适当控制血糖水平和预防并发症是治疗糖尿病的重要手段。我们曾报道过一种名为 HPH-15 的化合物,它不仅能抗纤维化,还能激活 AMP 激活蛋白激酶 (AMPK)。我们研究了 HPH-15 对分别作为肌肉、肝脏和脂肪组织模型的 L6-GLUT4、HepG2 和 3T3-L1 细胞中 AMPK 激活、葡萄糖摄取、脂肪积累和乳酸生成的影响。此外,我们还研究了 HPH-15 在高脂饮食(HFD)小鼠体内的降糖、抑制脂肪积累、抗纤维化和 AMPK 激活作用。结果 HPH-15 浓度为 10 µmol/l 时,在每种细胞模型中都能增加 AMPK 激活、葡萄糖摄取和 GLUT4 的膜转位,其增加程度与二甲双胍浓度为 2 mmol/l 时相同。经 HPH-15 处理的细胞产生的乳酸(导致乳酸酸中毒)与二甲双胍处理的细胞相同或更少。在高密度脂蛋白喂养的小鼠中,HPH-15可将血糖从11.1±0.3毫摩尔/升降至8.2±0.4毫摩尔/升(10毫克/千克)和7.9±0.4毫摩尔/升(100毫克/千克),并改善胰岛素抵抗。HPH-15(10毫克/千克)组与二甲双胍(300毫克/千克)组在所有器官中的AMPK激活水平相同。经 HPH-15 处理的高密度脂蛋白胆固醇喂养小鼠还显示出抑制肝脏和脂肪组织中脂肪堆积和纤维化的作用;这些作用比二甲双胍的作用更为显著。结论/解释HPH-15在体外和体内激活AMPK的浓度低于二甲双胍,并能改善体内血糖水平和胰岛素抵抗。此外,HPH-15 比二甲双胍更有效地改善高密度脂蛋白胆固醇喂养小鼠的脂肪肝和脂肪细胞肥大。HPH-15可有效预防糖尿病患者常见的并发症--脂肪肝。此外,与二甲双胍相反,高剂量的HPH-15可减少高密度脂蛋白喂养小鼠的皮下脂肪。据推测,HPH-15 对脂肪堆积和纤维化的抑制作用比二甲双胍更强,这也是皮下脂肪减少的原因。因此,HPH-15是一种潜在的降糖药物,可以降低血糖、抑制脂肪堆积和改善肝纤维化。 图文摘要
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Diabetologia
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