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Microvascular insulin resistance with enhanced muscle glucose disposal in CD36 deficiency. CD36 缺乏症患者的微血管胰岛素抵抗与肌肉葡萄糖处置能力增强。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-01 Epub Date: 2024-11-06 DOI: 10.1007/s00125-024-06292-4
Cyndya A Shibao, Vivek S Peche, Terri A Pietka, Dmitri Samovski, Ian M Williams, Naji N Abumrad, Eric R Gamazon, Ira J Goldberg, David H Wasserman, Nada A Abumrad

Aims/hypothesis: Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal.

Methods: Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36-/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion.

Results: Insulin clamps showed that Cd36-/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal.

Conclusions/interpretation: CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism.

Trial registration: Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ).

目的/假设:微血管功能障碍会导致胰岛素抵抗。CD36是一种脂肪酸转运体和胰岛素信号调节器,在微血管内皮细胞中含量丰富。携带 CD36 编码变异 rs3211938 的小等位基因(G)的人类 CD36 表达减少 50%,并表现出内皮功能障碍。我们的目的是确定 G 等位基因携带者是否存在微血管对胰岛素的抵抗,如果有,这对葡萄糖处置有何影响:我们的多学科研究方法包括对 Cd36-/- 和野生型小鼠、CD36 缺乏 50% 的个体以及对照组进行高胰岛素血症-糖血症钳夹,此外还使用了有/无 CD36 缺失的原代人源性微血管内皮细胞:胰岛素钳夹显示,Cd36-/-小鼠在胰岛素刺激下的葡萄糖排出量增加,但血管顺应性和毛细血管灌注量减少。腓肠肌的肉眼显微镜检查显示,经毛细血管的胰岛素通量没有改变。CD36 基因缺陷的人类在胰岛素刺激下有更好的葡萄糖排出,但微血管血容量(MBV)对胰岛素无反应。缺失 CD36 的人体微血管细胞显示,胰岛素对 Akt、内皮 NO 合酶和 NO 生成的激活作用受损。因此,在 CD36 缺乏症中,微血管胰岛素抵抗与葡萄糖处置的胰岛素敏感性增强矛盾地联系在一起:CD36 缺乏症以前曾被证明会减少肌肉/心脏对脂肪酸的吸收,而在这里,我们发现它降低了血管顺应性和胰岛素增加 MBV 以优化葡萄糖和氧气输送的能力。肌肉和心脏通过转录重塑对这些能量挑战做出反应,使组织为胰岛素刺激的糖酵解通量做好准备。氧气输送量的减少会激活缺氧诱导因子、内皮细胞释放生长因子或细胞内小囊泡,这可能会介导这种适应。以 CD36 缺乏症患者的 NO 生物利用率为靶点,可能有益于微血管和肌肉/心脏的新陈代谢:Clinicaltrials.gov NCT03012386 数据可用性:本研究产生的 RNAseq 数据已存入 NCBI 基因表达总库 ( www.ncbi.nlm.nih.gov/geo/ ),加入代码为 GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 )。
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引用次数: 0
Cardiac arrhythmia and hypoglycaemia among individuals with and without diabetes receiving haemodialysis (the CADDY study): a Danish multicentre cohort study
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-28 DOI: 10.1007/s00125-025-06388-5
Dea H. Kofod, Søren Z. Diederichsen, Tobias Bomholt, Mads Ø. Andersen, Andreas Andersen, Ebba Mannheimer, Marianne Rix, Ylian S. Liem, Kristine Lindhard, Henrik P. Hansen, Casper Rydahl, Morten Lindhardt, Julie Brøsen, Kristine Schandorff, Theis Lange, Kirsten Nørgaard, Thomas P. Almdal, Jesper H. Svendsen, Bo Feldt-Rasmussen, Mads Hornum

Aims/hypothesis

We aimed to examine arrhythmias and hypoglycaemia among individuals with and without diabetes who are receiving haemodialysis and to investigate the association between arrhythmias and hypoglycaemia, hyperglycaemia and glycaemic variability.

Methods

This prospective multicentre cohort study included 70 participants on maintenance haemodialysis (35 with diabetes and 35 without diabetes). We employed implantable cardiac monitors for continuous heart rhythm monitoring in combination with periodic use of continuous glucose monitoring. Logistic-regression-type linear mixed models were used to examine associations between arrhythmias and glycaemic measures.

Results

During 18 months of follow-up, clinically significant arrhythmias (bradyarrhythmia and ventricular tachycardia) were identified in 12 (34%) participants with diabetes and 11 (31%) without diabetes. Atrial fibrillation was detected in 13 (37%) participants with diabetes and 14 (40%) without, while other supraventricular tachycardia was detected in seven (20%) and 11 (31%) participants with and without diabetes, respectively. Hypoglycaemia (sensor glucose <3.9 mmol/l) was observed in 27 (77%) participants with diabetes and 32 (91%) without diabetes. Compared with euglycaemia, hypoglycaemia was associated with an increased rate of arrhythmias among participants without diabetes (incidence rate ratio [IRR] 3.13 [95% CI 1.49, 6.55]), while hyperglycaemia (sensor glucose >10.0 mmol/l) was associated with a decreased rate of arrhythmias among participants with diabetes (IRR 0.58 [95% CI 0.37, 0.92]). Glycaemic variability showed no association with arrhythmias regardless of the presence of diabetes.

Conclusions/interpretation

Arrhythmias and hypoglycaemia were common in those undergoing haemodialysis regardless of diabetes status. Our data suggest a temporal relationship between arrhythmias and glucose level in both individuals with and without diabetes.

Trial registration

Clinicaltrials.gov: NCT04841304.

Graphical Abstract

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引用次数: 0
Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes affirms markers of disease
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-28 DOI: 10.1007/s00125-025-06394-7
Robert Moulder, M. Karoliina Hirvonen, Tommi Välikangas, Tomi Suomi, Lut Overbergh, Mark Peakman, Søren Brunak, Chantal Mathieu, Mikael Knip, Laura L. Elo, Riitta Lahesmaa

Aims/hypothesis

While investigating markers for declining beta cell function in type 1 diabetes, we previously demonstrated 11 statistically significant protein associations with fasting C-peptide/glucose ratios in longitudinal serum samples from newly diagnosed (ND) individuals (n=86; 228 samples in total) participating in the INNODIA (Innovative approaches to understanding and arresting type 1 diabetes) study. Furthermore, comparison with protein measurements from age- and sex-matched autoantibody-negative unaffected family members (UFMs, n=194) revealed differences in the serum levels of 13 target proteins. To further evaluate these findings, we analysed longitudinal serum drawn during the first year after diagnosis from a new group of ND individuals subsequently enrolled in the study, together with samples from additional UFMs.

Methods

To validate the previously reported statistically significant protein associations with type 1 diabetes progression, selected reaction monitoring (SRM) MS analyses were carried out. Sera from individuals diagnosed with type 1 diabetes under the age of 18 years (n=146) were collected within 6 weeks of diagnosis and at 3, 6 and 12 months after diagnosis (560 samples in total). The resulting SRM data were compared with fasting C-peptide/glucose measurements, which were used as a proxy for beta cell function. The protein data were further compared with cross-sectional SRM measurements from age- and sex-matched UFMs (n=272).

Results

Our results confirmed the presence of significant (p<0.05) inverse associations between fasting C-peptide/glucose ratios and peptides from apolipoprotein B-100, apolipoprotein M and glutathione peroxidase 3 (GPX3) in ND individuals. Additionally, we observed consistent differences in the levels of ten of the 13 targeted proteins between individuals with type 1 diabetes and UFMs. These proteins included GPX3, transthyretin, prothrombin, apolipoprotein C1 and afamin.

Conclusions/interpretation

The validated results reflect the landscape of biological changes accompanying type 1 diabetes. For example, the association of the targeted apolipoproteins with fasting C-peptide/glucose ratios in the first year after diagnosis is likely to relate to lipid abnormalities observed in individuals with type 1 diabetes, and reiterates the connection of apolipoproteins with the underlying changes accompanying the disease. Further research is needed to explore the clinical value and relevance of these targets.

Graphical Abstract

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引用次数: 0
IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes IA-2A 阳性会增加 1 型糖尿病在既定阶段内和跨阶段进展的风险
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-28 DOI: 10.1007/s00125-025-06382-x
Emily K. Sims, David Cuthbertson, Lauric A. Ferrat, Emanuele Bosi, Carmella Evans-Molina, Linda A. DiMeglio, Brandon M. Nathan, Heba M. Ismail, Laura M. Jacobsen, Maria J. Redondo, Richard A. Oram, Jay M. Sosenko

Aims/hypothesis

Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study.

Methods

Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (n=192) and autoantibody-positive (n=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages.

Results

Compared with IA-2A individuals, IA-2A+ individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A stage 1 individuals. Individuals at highest risk within the single-IA-2A+ category included children (HR 14.2 [95% CI 1.9, 103.1], p=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], p<0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], p<0.001) and individuals with HLA DR4-positive status (HR 3.7 [95% CI 1.6, 8.3], p=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A+ individuals and dysglycaemic IA-2A individuals.

Conclusions/interpretation

IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A. Approaches to incorporate IA-2A+ status into monitoring strategies for autoantibody-positive individuals should be considered.

Graphical Abstract

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引用次数: 0
Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease.
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-27 DOI: 10.1007/s00125-025-06385-8
Sheng Ding, Jin-Ling Xu, Jia-Yue Tong, Yang-Yang Cheng, Ling-Feng Shi, Wei Wei, Li-Ming Zhang, Jia-Jia Zhang, Bi-Ying Meng, Xiang-Yan Peng, Lin Xiang, Shu-Guang Li, Ling Yue, Zhong-Jing Wang, Guang-da Xiang

Aims/hypothesis: Brown adipose tissue (BAT) consumes excess energy through heat production by uncoupling protein 1 (UCP1) to regulate the metabolic profile, but the UCP1-independent mechanisms of BAT, such as in endocrine function, are largely unknown. Our previous study showed that BAT-derived neuregulin 4 (NRG4) displays anti-atherosclerotic properties. Thus, we hypothesised that BAT could regulate diabetic nephropathy, a diabetic microvascular complication, via NRG4.

Methods: To investigate the influence of NRG4 from BAT on podocyte apoptosis, both loss- and gain-of-function approaches were used in in vivo experiments. Diabetic nephropathy models were created using BAT-specific Nrg4-knockout (BKO) mice, global Nrg4-knockout (KO) mice and wild-type (WT) mice. In in vitro studies, podocytes (MPC5) were exposed to glucose and recombinant NRG4 (rNrg4). Additionally, brown adipocytes were co-cultured with MPC5 podocytes using a transwell system. The expression levels of proteins associated with podocyte apoptosis and signalling pathways were measured.

Results: BAT-specific NRG4 deficiency aggravated podocyte apoptosis (increased by 47.46%) and increased the urinary albumin/creatinine ratio (increased by 41.71%), decreased nephrin expression and increased desmin expression. As expected, these changes were reversed by NRG4 replenishment using adeno-associated virus-NRG4 interscapular BAT injection and BAT transplantation assays in KO mice. Additionally, co-culture experiments demonstrated that brown adipocytes from WT mice could alleviate high-glucose-induced podocyte apoptosis. In in vitro experiments, recombinant NRG4 inhibited high-glucose-induced podocyte apoptosis. Mechanistically, the Akt-glycogen synthase kinase 3 β (GSK-3β) pathway is crucial for the protection that BAT-derived NRG4 provides to podocytes in diabetic nephropathy.

Conclusions/interpretation: Our data show that BAT had a protective effect on podocyte apoptosis in diabetic nephropathy through BAT-derived NRG4, and the Akt-GSK‑3β signalling pathway may mediate the inhibition of BAT-derived NRG4 on podocyte apoptosis in diabetic nephropathy.

{"title":"Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease.","authors":"Sheng Ding, Jin-Ling Xu, Jia-Yue Tong, Yang-Yang Cheng, Ling-Feng Shi, Wei Wei, Li-Ming Zhang, Jia-Jia Zhang, Bi-Ying Meng, Xiang-Yan Peng, Lin Xiang, Shu-Guang Li, Ling Yue, Zhong-Jing Wang, Guang-da Xiang","doi":"10.1007/s00125-025-06385-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06385-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Brown adipose tissue (BAT) consumes excess energy through heat production by uncoupling protein 1 (UCP1) to regulate the metabolic profile, but the UCP1-independent mechanisms of BAT, such as in endocrine function, are largely unknown. Our previous study showed that BAT-derived neuregulin 4 (NRG4) displays anti-atherosclerotic properties. Thus, we hypothesised that BAT could regulate diabetic nephropathy, a diabetic microvascular complication, via NRG4.</p><p><strong>Methods: </strong>To investigate the influence of NRG4 from BAT on podocyte apoptosis, both loss- and gain-of-function approaches were used in in vivo experiments. Diabetic nephropathy models were created using BAT-specific Nrg4-knockout (BKO) mice, global Nrg4-knockout (KO) mice and wild-type (WT) mice. In in vitro studies, podocytes (MPC5) were exposed to glucose and recombinant NRG4 (rNrg4). Additionally, brown adipocytes were co-cultured with MPC5 podocytes using a transwell system. The expression levels of proteins associated with podocyte apoptosis and signalling pathways were measured.</p><p><strong>Results: </strong>BAT-specific NRG4 deficiency aggravated podocyte apoptosis (increased by 47.46%) and increased the urinary albumin/creatinine ratio (increased by 41.71%), decreased nephrin expression and increased desmin expression. As expected, these changes were reversed by NRG4 replenishment using adeno-associated virus-NRG4 interscapular BAT injection and BAT transplantation assays in KO mice. Additionally, co-culture experiments demonstrated that brown adipocytes from WT mice could alleviate high-glucose-induced podocyte apoptosis. In in vitro experiments, recombinant NRG4 inhibited high-glucose-induced podocyte apoptosis. Mechanistically, the Akt-glycogen synthase kinase 3 β (GSK-3β) pathway is crucial for the protection that BAT-derived NRG4 provides to podocytes in diabetic nephropathy.</p><p><strong>Conclusions/interpretation: </strong>Our data show that BAT had a protective effect on podocyte apoptosis in diabetic nephropathy through BAT-derived NRG4, and the Akt-GSK‑3β signalling pathway may mediate the inhibition of BAT-derived NRG4 on podocyte apoptosis in diabetic nephropathy.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515043","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
Beyond the loss of beta cells: a quantitative analysis of islet architecture in adults with and without type 1 diabetes
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-26 DOI: 10.1007/s00125-025-06376-9
Nicolás Verschueren van Rees, Peter Ashwin, Conor McMullan, Lars Krogvold, Knut Dahl-Jørgensen, Noel G. Morgan, Pia Leete, Kyle C. A. Wedgwood
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>The organisation and cellular architecture of islets of Langerhans are critical to the physiological regulation of hormone secretion but it is debated whether human islets adhere to the characteristic mantle–core (M-C) structure seen in rodents. It is also unclear whether inherent architectural changes contribute to islet dysfunction in type 1 diabetes, aside from the loss of beta cells. Therefore, we have exploited advances in immunostaining, spatial biology and machine learning to undertake a detailed, systematic analysis of adult human islet architecture in health and type 1 diabetes, by a quantitative analysis of a dataset of >250,000 endocrine cells in >3500 islets from ten individuals.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>Formalin-fixed paraffin-embedded pancreatic sections (4 μm) from organ donors without diabetes and living donors with recent-onset type 1 diabetes were stained for all five islet hormones and imaged prior to analysis, which employed a novel automated pipeline using QuPath software, capable of running on a standard laptop. Whole-slide image analysis involved segmentation classifiers, cell detection and phenotyping algorithms to identify islets, specific cell types and their locations as (<i>x,y</i>)-coordinates in regions of interest. Each endocrine cell was categorised into binary variables for cell type (i.e. beta or non-beta) and position (mantle or core). A χ<sup>2</sup> test for independence of these properties was performed and the OR was considered to estimate the effect size of the potential association between position and cell type. A quantification of the M-C structure at islet level was performed by computing the probability, <i>r</i>, that the observed number of non-beta cells in the mantle is due to a random arrangement. The distribution of the <i>r</i> values for the islets in the study was contrasted against the <i>r</i> values of a digital population of equivalent randomly arranged islets, termed digital siblings. Both distributions of <i>r</i> values were compared using the earth mover’s distance (EMD), a mathematical tool employed to describe differences in distribution patterns. The EMD was also used to contrast the distribution of islet size and beta cell fraction between type 1 diabetes and control islets.</p><h3 data-test="abstract-sub-heading">Results</h3><p>The χ<sup>2</sup> test supports the existence of a significant (<i>p</i><0.001) relationship between cell position and type. The effect size was measured via the OR <0.8, showing that non-beta cells are more likely to be found at the mantle (and vice versa). At the islet level, the EMD between the distributions of <i>r</i> values of the observed islets and the digital siblings was emd-1d=0.10951 (0<emd-1d<1). The transport plan showed a substantial group of islets with a small <i>r</i> value, thus supporting the M-C hypothesis. The bidimensional distri
{"title":"Beyond the loss of beta cells: a quantitative analysis of islet architecture in adults with and without type 1 diabetes","authors":"Nicolás Verschueren van Rees, Peter Ashwin, Conor McMullan, Lars Krogvold, Knut Dahl-Jørgensen, Noel G. Morgan, Pia Leete, Kyle C. A. Wedgwood","doi":"10.1007/s00125-025-06376-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06376-9","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;The organisation and cellular architecture of islets of Langerhans are critical to the physiological regulation of hormone secretion but it is debated whether human islets adhere to the characteristic mantle–core (M-C) structure seen in rodents. It is also unclear whether inherent architectural changes contribute to islet dysfunction in type 1 diabetes, aside from the loss of beta cells. Therefore, we have exploited advances in immunostaining, spatial biology and machine learning to undertake a detailed, systematic analysis of adult human islet architecture in health and type 1 diabetes, by a quantitative analysis of a dataset of &gt;250,000 endocrine cells in &gt;3500 islets from ten individuals.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;Formalin-fixed paraffin-embedded pancreatic sections (4 μm) from organ donors without diabetes and living donors with recent-onset type 1 diabetes were stained for all five islet hormones and imaged prior to analysis, which employed a novel automated pipeline using QuPath software, capable of running on a standard laptop. Whole-slide image analysis involved segmentation classifiers, cell detection and phenotyping algorithms to identify islets, specific cell types and their locations as (&lt;i&gt;x,y&lt;/i&gt;)-coordinates in regions of interest. Each endocrine cell was categorised into binary variables for cell type (i.e. beta or non-beta) and position (mantle or core). A χ&lt;sup&gt;2&lt;/sup&gt; test for independence of these properties was performed and the OR was considered to estimate the effect size of the potential association between position and cell type. A quantification of the M-C structure at islet level was performed by computing the probability, &lt;i&gt;r&lt;/i&gt;, that the observed number of non-beta cells in the mantle is due to a random arrangement. The distribution of the &lt;i&gt;r&lt;/i&gt; values for the islets in the study was contrasted against the &lt;i&gt;r&lt;/i&gt; values of a digital population of equivalent randomly arranged islets, termed digital siblings. Both distributions of &lt;i&gt;r&lt;/i&gt; values were compared using the earth mover’s distance (EMD), a mathematical tool employed to describe differences in distribution patterns. The EMD was also used to contrast the distribution of islet size and beta cell fraction between type 1 diabetes and control islets.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;The χ&lt;sup&gt;2&lt;/sup&gt; test supports the existence of a significant (&lt;i&gt;p&lt;/i&gt;&lt;0.001) relationship between cell position and type. The effect size was measured via the OR &lt;0.8, showing that non-beta cells are more likely to be found at the mantle (and vice versa). At the islet level, the EMD between the distributions of &lt;i&gt;r&lt;/i&gt; values of the observed islets and the digital siblings was emd-1d=0.10951 (0&lt;emd-1d&lt;1). The transport plan showed a substantial group of islets with a small &lt;i&gt;r&lt;/i&gt; value, thus supporting the M-C hypothesis. The bidimensional distri","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"1 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507123","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
Correction: Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes: a Phase I/II randomised double-blind placebo-controlled trial.
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-25 DOI: 10.1007/s00125-025-06371-0
Per-Ola Carlsson, Daniel Espes, Sofia Sisay, Lindsay C Davies, C I Edvard Smith, Mathias G Svahn
{"title":"Correction: Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes: a Phase I/II randomised double-blind placebo-controlled trial.","authors":"Per-Ola Carlsson, Daniel Espes, Sofia Sisay, Lindsay C Davies, C I Edvard Smith, Mathias G Svahn","doi":"10.1007/s00125-025-06371-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06371-0","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491243","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
Associations between the timing of 24 h physical activity and diabetes mellitus: results from a nationally representative sample of the US population
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-21 DOI: 10.1007/s00125-025-06368-9
Qian Xiao, Qiuyu Feng, Martin K. Rutter, Gali Albalak, Heming Wang, Raymond Noordam

Aims/hypothesis

Growing evidence suggests that timing may be an important aspect of physical activity that influences cardiometabolic health. However, the current literature is inconclusive regarding the time of day that physical activity offers the greatest metabolic advantages. We investigated associations between hourly physical activity levels and diabetes mellitus and glycaemic biomarkers in a cross-sectional and nationally representative sample of US adults.

Methods

We studied 7074 adults (mean age 48 years; 52% women) from the National Health and Nutrition Examination Survey (2011–2014). Physical activity was measured by actigraphy. A monitor-independent movement summary (MIMS) unit was used to derive the total activity level (divided into quintiles) for hourly windows that were defined relative to sleep timing and according to clock time. The primary outcome was prevalent diabetes, and secondary outcomes included fasting glucose, fasting insulin, HOMA-IR and 2 h OGTT results.

Results

Physical activity levels in late morning and late afternoon were associated with lower adjusted odds of diabetes. Specifically, in late morning (8:01–9:00 h after the sleep midpoint), the highest quintile of activity was associated with a 35% decrease (OR 0.65; 95% CI 0.44, 0.96) in the odds of diabetes when compared with the lowest quintile, while in late afternoon (11:01–17:00 h after the sleep midpoint), the highest quintiles were associated with 56% and 36% lower odds (OR 0.44; 95% CI 0.29, 0.69 and OR 0.64; 95% CI 0.43, 0.95). Higher night-time activity was associated with higher odds of diabetes. Similar patterns of results were observed with OGTT data and across subgroups of age, gender, race/ethnicity, chronotype and sleep duration.

Conclusions/interpretation

Our findings suggest that the timing of physical activity may modulate its metabolic effects.

Graphical Abstract

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引用次数: 0
Identification and interpretation of risk factors for Charcot foot.
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-20 DOI: 10.1007/s00125-025-06386-7
Victoria E L Milbourn, Sicco A Bus, Frances Game, Jaap J van Netten
{"title":"Identification and interpretation of risk factors for Charcot foot.","authors":"Victoria E L Milbourn, Sicco A Bus, Frances Game, Jaap J van Netten","doi":"10.1007/s00125-025-06386-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06386-7","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457153","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
Identification and interpretation of risk factors for Charcot foot. Reply to Milbourn VEL, Bus SA, Game F, van Netten JJ [letter].
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-20 DOI: 10.1007/s00125-025-06389-4
Georgios Tsatsaris, Neda Rajamand Ekberg, Tove Fall, Sergiu-Bogdan Catrina
{"title":"Identification and interpretation of risk factors for Charcot foot. Reply to Milbourn VEL, Bus SA, Game F, van Netten JJ [letter].","authors":"Georgios Tsatsaris, Neda Rajamand Ekberg, Tove Fall, Sergiu-Bogdan Catrina","doi":"10.1007/s00125-025-06389-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06389-4","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457156","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
期刊
Diabetologia
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