Diabetologia最新文献

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Correction: Diabetes technology in people with diabetes and advanced chronic kidney disease. 更正:糖尿病和晚期慢性肾病患者的糖尿病技术。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 DOI: 10.1007/s00125-024-06278-2
Rodolfo J Galindo, Diana Soliman, Daniel Cherñavvsky, Connie M Rhee
{"title":"Correction: Diabetes technology in people with diabetes and advanced chronic kidney disease.","authors":"Rodolfo J Galindo, Diana Soliman, Daniel Cherñavvsky, Connie M Rhee","doi":"10.1007/s00125-024-06278-2","DOIUrl":"10.1007/s00125-024-06278-2","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281842","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
The SWI/SNF chromatin remodelling complex regulates pancreatic endocrine cell expansion and differentiation in mice in vivo. SWI/SNF 染色质重塑复合物调节小鼠体内胰腺内分泌细胞的扩增和分化。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-03 DOI: 10.1007/s00125-024-06211-7
Rebecca K Davidson, Wenting Wu, Sukrati Kanojia, Rajani M George, Kayla Huter, Kassandra Sandoval, Meredith Osmulski, Nolan Casey, Jason M Spaeth
{"title":"The SWI/SNF chromatin remodelling complex regulates pancreatic endocrine cell expansion and differentiation in mice in vivo.","authors":"Rebecca K Davidson, Wenting Wu, Sukrati Kanojia, Rajani M George, Kayla Huter, Kassandra Sandoval, Meredith Osmulski, Nolan Casey, Jason M Spaeth","doi":"10.1007/s00125-024-06211-7","DOIUrl":"10.1007/s00125-024-06211-7","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Strategies to augment functional beta cell mass include directed differentiation of stem cells towards a beta cell fate, which requires extensive knowledge of transcriptional programs governing endocrine progenitor cell differentiation in vivo. We aimed to study the contributions of the Brahma-related gene-1 (BRG1) and Brahma (BRM) ATPase subunits of the SWI/SNF chromatin remodelling complex to endocrine cell development.</p><p><strong>Methods: </strong>We generated mice with endocrine progenitor-specific Neurog3-Cre BRG1 removal in the presence of heterozygous (Brg1<sup>Δendo</sup>;Brm<sup>+/-</sup>) or homozygous (double knockout: DKO<sup>Δendo</sup>) BRM deficiency. Whole-body metabolic phenotyping, islet function characterisation, islet quantitative PCR and histological characterisation were performed on animals and tissues postnatally. To test the mechanistic actions of SWI/SNF in controlling gene expression during endocrine cell development, single-cell RNA-seq was performed on flow-sorted endocrine-committed cells from embryonic day 15.5 control and mutant embryos.</p><p><strong>Results: </strong>Brg1<sup>Δendo</sup>;Brm<sup>+/-</sup> mice exhibit severe glucose intolerance, hyperglycaemia and hypoinsulinaemia, resulting, in part, from reduced islet number; diminished alpha, beta and delta cell mass; compromised islet insulin secretion; and altered islet gene expression programs, including reductions in MAFA and urocortin 3 (UCN3). DKO<sup>Δendo</sup> mice were not recovered at weaning; however, postnatal day 6 DKO<sup>Δendo</sup> mice were severely hyperglycaemic with reduced serum insulin levels and beta cell area. Single-cell RNA-seq of embryonic day 15.5 lineage-labelled cells revealed endocrine progenitor, alpha and beta cell populations from SWI/SNF mutants have reduced expression of Mafa, Gcg, Ins1 and Ins2, suggesting limited differentiation capacity. Reduced Neurog3 transcripts were discovered in DKO<sup>Δendo</sup> endocrine progenitor clusters, and the proliferative capacity of neurogenin 3 (NEUROG3)<sup>+</sup> cells was reduced in Brg1<sup>Δendo</sup>;Brm<sup>+/-</sup> and DKO<sup>Δendo</sup> mutants.</p><p><strong>Conclusions/interpretation: </strong>Loss of BRG1 from developing endocrine progenitor cells has a severe postnatal impact on glucose homeostasis, and loss of both subunits impedes animal survival, with both groups exhibiting alterations in hormone transcripts embryonically. Taken together, these data highlight the critical role SWI/SNF plays in governing gene expression programs essential for endocrine cell development and expansion.</p><p><strong>Data availability: </strong>Raw and processed data for scRNA-seq have been deposited into the NCBI Gene Expression Omnibus (GEO) database under the accession number GSE248369.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491256","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
Molecular circadian clock disruption in the leukocytes of individuals with type 2 diabetes and overweight, and its relationship with leukocyte-endothelial interactions. 2 型糖尿病和超重患者白细胞中的分子昼夜节律时钟紊乱及其与白细胞-内皮相互作用的关系。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-10 DOI: 10.1007/s00125-024-06219-z
Clara Luna-Marco, Deédeni Devos, Julia Cacace, Meylin Fernandez-Reyes, Pedro Díaz-Pozo, Juan D Salazar, Eva Solá, Carlos Morillas, Milagros Rocha, Víctor M Víctor, Susana Rovira-Llopis
{"title":"Molecular circadian clock disruption in the leukocytes of individuals with type 2 diabetes and overweight, and its relationship with leukocyte-endothelial interactions.","authors":"Clara Luna-Marco, Deédeni Devos, Julia Cacace, Meylin Fernandez-Reyes, Pedro Díaz-Pozo, Juan D Salazar, Eva Solá, Carlos Morillas, Milagros Rocha, Víctor M Víctor, Susana Rovira-Llopis","doi":"10.1007/s00125-024-06219-z","DOIUrl":"10.1007/s00125-024-06219-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims/hypothesis: &lt;/strong&gt;Alterations in circadian rhythms increase the likelihood of developing type 2 diabetes and CVD. Circadian rhythms are controlled by several core clock genes, which are expressed in nearly every cell, including immune cells. Immune cells are key players in the pathophysiology of type 2 diabetes, and participate in the atherosclerotic process that underlies cardiovascular risk in these patients. The role of the core clock in the leukocytes of people with type 2 diabetes and the inflammatory process associated with it are unknown. We aimed to evaluate whether the molecular clock system is impaired in the leukocytes of type 2 diabetes patients and to explore the mechanism by which this alteration leads to an increased cardiovascular risk in this population.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This is an observational cross-sectional study performed in 25 participants with type 2 diabetes and 28 healthy control participants. Clinical and biochemical parameters were obtained. Peripheral blood leukocytes were isolated using magnetic bead technology. RNA and protein lysates were obtained to assess clock-related gene transcript and protein levels using real-time PCR and western blot, respectively. Luminex XMAP technology was used to assess levels of inflammatory markers. Leukocyte-endothelial interaction assays were performed by perfusing participants' leukocytes or THP-1 cells (with/without CLK8) over a HUVEC monolayer in a parallel flow chamber using a dynamic adhesion system.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Participants with type 2 diabetes showed increased BMAL1 and NR1D1 mRNA levels and decreased protein levels of circadian locomotor output cycles kaput (CLOCK), cryptochrome 1 (CRY1), phosphorylated basic helix-loop-helix ARNT like 1 (p-BMAL1) and period circadian protein homologue 2 (PER2). Correlation studies revealed that these alterations in clock proteins were negatively associated with glucose, HbA&lt;sub&gt;1c&lt;/sub&gt;, insulin and HOMA-IR levels and leukocyte cell counts. The leukocyte rolling velocity was reduced and rolling flux and adhesion were enhanced in individuals with type 2 diabetes compared with healthy participants. Interestingly, inhibition of CLOCK/BMAL1 activity in leukocytes using the CLOCK inhibitor CLK8 mimicked the effects of type 2 diabetes on leukocyte-endothelial interactions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions/interpretation: &lt;/strong&gt;Our study demonstrates alterations in the molecular clock system in leukocytes of individuals with type 2 diabetes, manifested in increased mRNA levels and decreased protein levels of the core clock machinery. These alterations correlated with the impaired metabolic and proinflammatory profile of the participants with type 2 diabetes. Our findings support a causal role for decreased CLOCK/BMAL1 activity in the increased level of leukocyte-endothelial interactions. Overall, our data suggest that alterations in core clock proteins accelerate the inflammatory process, which may","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562930","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
Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1. 含锌指 BED 型 3 通过与多嘧啶束结合蛋白 1 相互作用促进肝脏脂肪变性。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-22 DOI: 10.1007/s00125-024-06224-2
Yao Wu, Min Yang, Shao-Bo Wu, Pei-Qi Luo, Cheng Zhang, Chang-Shun Ruan, Wei Cui, Qiu-Rong Zhao, Lin-Xin Chen, Juan-Juan Meng, Qiang Song, Wen-Jin Zhang, Qin-Qin Pei, Fang Li, Ting Zeng, Hong-Xin Du, Li-Xin Xu, Weizhen Zhang, Xian-Xiang Zhang, Xiao-He Luo
{"title":"Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.","authors":"Yao Wu, Min Yang, Shao-Bo Wu, Pei-Qi Luo, Cheng Zhang, Chang-Shun Ruan, Wei Cui, Qiu-Rong Zhao, Lin-Xin Chen, Juan-Juan Meng, Qiang Song, Wen-Jin Zhang, Qin-Qin Pei, Fang Li, Ting Zeng, Hong-Xin Du, Li-Xin Xu, Weizhen Zhang, Xian-Xiang Zhang, Xiao-He Luo","doi":"10.1007/s00125-024-06224-2","DOIUrl":"10.1007/s00125-024-06224-2","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD.</p><p><strong>Methods: </strong>Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c).</p><p><strong>Results: </strong>In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing.</p><p><strong>Conclusions/interpretation: </strong>This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD.</p><p><strong>Data availability: </strong>RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 ).</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733749","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
tRNA-derived fragments in T lymphocyte-beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice. tRNA 衍生片段在 T 淋巴细胞-β 细胞串联和 NOD 小鼠 1 型糖尿病发病机制中的作用。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-05 DOI: 10.1007/s00125-024-06207-3
Flora Brozzi, Cécile Jacovetti, Cristina Cosentino, Véronique Menoud, Kejing Wu, Mustafa Bilal Bayazit, Baroj Abdulkarim, Christian Iseli, Nicolas Guex, Claudiane Guay, Romano Regazzi
{"title":"tRNA-derived fragments in T lymphocyte-beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice.","authors":"Flora Brozzi, Cécile Jacovetti, Cristina Cosentino, Véronique Menoud, Kejing Wu, Mustafa Bilal Bayazit, Baroj Abdulkarim, Christian Iseli, Nicolas Guex, Claudiane Guay, Romano Regazzi","doi":"10.1007/s00125-024-06207-3","DOIUrl":"10.1007/s00125-024-06207-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>tRNAs play a central role in protein synthesis. Besides this canonical function, they were recently found to generate non-coding RNA fragments (tRFs) regulating different cellular activities. The aim of this study was to assess the involvement of tRFs in the crosstalk between immune cells and beta cells and to investigate their contribution to the development of type 1 diabetes.</p><p><strong>Methods: </strong>Global profiling of the tRFs present in pancreatic islets of 4- and 8-week-old NOD mice and in extracellular vesicles released by activated CD4<sup>+</sup> T lymphocytes was performed by small RNA-seq. Changes in the level of specific fragments were confirmed by quantitative PCR. The transfer of tRFs from immune cells to beta cells occurring during insulitis was assessed using an RNA-tagging approach. The functional role of tRFs increasing in beta cells during the initial phases of type 1 diabetes was determined by overexpressing them in dissociated islet cells and by determining the impact on gene expression and beta cell apoptosis.</p><p><strong>Results: </strong>We found that the tRF pool was altered in the islets of NOD mice during the initial phases of type 1 diabetes. Part of these changes were triggered by prolonged exposure of beta cells to proinflammatory cytokines (IL-1β, TNF-α and IFN-γ) while others resulted from the delivery of tRFs produced by CD4<sup>+</sup> T lymphocytes infiltrating the islets. Indeed, we identified several tRFs that were enriched in extracellular vesicles from CD4<sup>+</sup>/CD25<sup>-</sup> T cells and were transferred to beta cells upon adoptive transfer of these immune cells in NOD.SCID mice. The tRFs delivered to beta cells during the autoimmune reaction triggered gene expression changes that affected the immune regulatory capacity of insulin-secreting cells and rendered the cells more prone to apoptosis.</p><p><strong>Conclusions/interpretation: </strong>Our data point to tRFs as novel players in the crosstalk between the immune system and insulin-secreting cells and suggest a potential involvement of this novel class of non-coding RNAs in type 1 diabetes pathogenesis.</p><p><strong>Data availability: </strong>Sequences are available from the Gene Expression Omnibus (GEO) with accession numbers GSE242568 and GSE256343.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533955","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
Applying technologies to simplify strategies for exercise in type 1 diabetes. 应用技术简化 1 型糖尿病患者的运动策略。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-08-15 DOI: 10.1007/s00125-024-06229-x
Bruce A Perkins, Lauren V Turner, Michael C Riddell
{"title":"Applying technologies to simplify strategies for exercise in type 1 diabetes.","authors":"Bruce A Perkins, Lauren V Turner, Michael C Riddell","doi":"10.1007/s00125-024-06229-x","DOIUrl":"10.1007/s00125-024-06229-x","url":null,"abstract":"<p><p>Challenges and fears related to managing glucose levels around planned and spontaneous exercise affect outcomes and quality of life in people living with type 1 diabetes. Advances in technology, including continuous glucose monitoring, open-loop insulin pump therapy and hybrid closed-loop (HCL) systems for exercise management in type 1 diabetes, address some of these challenges. In this review, three research or clinical experts, each living with type 1 diabetes, leverage published literature and clinical and personal experiences to translate research findings into simplified, patient-centred strategies. With an understanding of limitations in insulin pharmacokinetics, variable intra-individual responses to aerobic and anaerobic exercise, and the features of the technologies, six steps are proposed to guide clinicians in efficiently communicating simplified actions more effectively to individuals with type 1 diabetes. Fundamentally, the six steps centre on two aspects. First, regardless of insulin therapy type, and especially needed for spontaneous exercise, we provide an estimate of glucose disposal into active muscle meant to be consumed as extra carbohydrates for exercise ('ExCarbs'; a common example is 0.5 g/kg body mass per hour for adults and 1.0 g/kg body mass per hour for youth). Second, for planned exercise using open-loop pump therapy or HCL systems, we additionally recommend pre-emptive basal insulin reduction or using HCL exercise modes initiated 90 min (1-2 h) before the start of exercise until the end of exercise. Modifications for aerobic- and anaerobic-type exercise are discussed. The burden of pre-emptive basal insulin reductions and consumption of ExCarbs are the limitations of HCL systems, which may be overcome by future innovations but are unquestionably required for currently available systems.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981972","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
Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h. 人类胰岛的单细胞转录组分析揭示了基因对葡萄糖暴露 24 小时的反应。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-05 DOI: 10.1007/s00125-024-06214-4
Caleb M Grenko, Henry J Taylor, Lori L Bonnycastle, Dongxiang Xue, Brian N Lee, Zoe Weiss, Tingfen Yan, Amy J Swift, Erin C Mansell, Angela Lee, Catherine C Robertson, Narisu Narisu, Michael R Erdos, Shuibing Chen, Francis S Collins, D Leland Taylor
{"title":"Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h.","authors":"Caleb M Grenko, Henry J Taylor, Lori L Bonnycastle, Dongxiang Xue, Brian N Lee, Zoe Weiss, Tingfen Yan, Amy J Swift, Erin C Mansell, Angela Lee, Catherine C Robertson, Narisu Narisu, Michael R Erdos, Shuibing Chen, Francis S Collins, D Leland Taylor","doi":"10.1007/s00125-024-06214-4","DOIUrl":"10.1007/s00125-024-06214-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims/hypothesis: &lt;/strong&gt;Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycaemia, beta cell glucotoxicity and subsequently type 2 diabetes. In this study, we explored the effects of in vitro hyperglycaemic conditions on human pancreatic islet gene expression across 24 h in six pancreatic cell types: alpha; beta; gamma; delta; ductal; and acinar. We hypothesised that genes associated with hyperglycaemic conditions may be relevant to the onset and progression of diabetes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We exposed human pancreatic islets from two donors to low (2.8 mmol/l) and high (15.0 mmol/l) glucose concentrations over 24 h in vitro. To assess the transcriptome, we performed single-cell RNA-seq (scRNA-seq) at seven time points. We modelled time as both a discrete and continuous variable to determine momentary and longitudinal changes in transcription associated with islet time in culture or glucose exposure. Additionally, we integrated genomic features and genetic summary statistics to nominate candidate effector genes. For three of these genes, we functionally characterised the effect on insulin production and secretion using CRISPR interference to knock down gene expression in EndoC-βH1 cells, followed by a glucose-stimulated insulin secretion assay.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In the discrete time models, we identified 1344 genes associated with time and 668 genes associated with glucose exposure across all cell types and time points. In the continuous time models, we identified 1311 genes associated with time, 345 genes associated with glucose exposure and 418 genes associated with interaction effects between time and glucose across all cell types. By integrating these expression profiles with summary statistics from genetic association studies, we identified 2449 candidate effector genes for type 2 diabetes, HbA&lt;sub&gt;1c&lt;/sub&gt;, random blood glucose and fasting blood glucose. Of these candidate effector genes, we showed that three (ERO1B, HNRNPA2B1 and RHOBTB3) exhibited an effect on glucose-stimulated insulin production and secretion in EndoC-βH1 cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions/interpretation: &lt;/strong&gt;The findings of our study provide an in-depth characterisation of the 24 h transcriptomic response of human pancreatic islets to glucose exposure at a single-cell resolution. By integrating differentially expressed genes with genetic signals for type 2 diabetes and glucose-related traits, we provide insights into the molecular mechanisms underlying glucose homeostasis. Finally, we provide functional evidence to support the role of three candidate effector genes in insulin secretion and production.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Data availability: &lt;/strong&gt;The scRNA-seq data from the 24 h glucose exposure experiment performed in this study are available in the database of Genotypes and Phenotypes (dbGap; https://www.ncbi.nlm.nih.gov/gap/ ) with accession no. phs001188.v3.p1. Study ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533952","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
Trajectories of BMI before and after diagnosis of type 2 diabetes in a real-world population. 真实世界人群中确诊 2 型糖尿病前后的体重指数轨迹。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-05 DOI: 10.1007/s00125-024-06217-1
Louise A Donnelly, Rory J McCrimmon, Ewan R Pearson
{"title":"Trajectories of BMI before and after diagnosis of type 2 diabetes in a real-world population.","authors":"Louise A Donnelly, Rory J McCrimmon, Ewan R Pearson","doi":"10.1007/s00125-024-06217-1","DOIUrl":"10.1007/s00125-024-06217-1","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Few studies have examined the clinical characteristics associated with changes in weight before and after diagnosis of type 2 diabetes. Using a large real-world cohort, we derived trajectories of BMI before and after diabetes diagnosis, and examined the clinical characteristics associated with these trajectories, including assessing the impact of pre-diagnosis weight change on post-diagnosis weight change.</p><p><strong>Methods: </strong>We performed an observational cohort study using electronic medical records from individuals in the Scottish Care Information Diabetes Collaboration database. Two trajectories were calculated, based on observed BMI measurements between 3 years and 6 months before diagnosis and between 1 and 5 years after diagnosis. In the post-diagnosis trajectory, each BMI measurement was time-dependently adjusted for the effects of diabetes medications and HbA<sub>1c</sub> change.</p><p><strong>Results: </strong>A total of 2736 individuals were included in the study. There was a pattern of pre-diagnosis weight gain, with 1944 individuals (71%) gaining weight overall, and 875 (32%) gaining more than 0.5 kg/m<sup>2</sup> per year. This was followed by a pattern of weight loss after diagnosis, with 1722 individuals (63%) losing weight. Younger age and greater social deprivation were associated with increased weight gain before diagnosis. Pre-diagnosis weight change was unrelated to post-diagnosis weight change, but post-diagnosis weight loss was associated with older age, female sex, higher BMI, higher HbA<sub>1c</sub> and weight gain during the peri-diagnosis period. When considering the peri-diagnostic period (defined as from 6 months before to 12 months after diagnosis), we identified 986 (36%) individuals who had a high HbA<sub>1c</sub> at diagnosis but who lost weight rapidly and were most aggressively treated at 1 year; this subgroup had the best glycaemic control at 5 years.</p><p><strong>Conclusions/interpretation: </strong>Average weight increases before diagnosis and decreases after diagnosis; however, there were significant differences across the population in terms of weight changes. Younger individuals gained weight pre-diagnosis, but, in older individuals, type 2 diabetes is less associated with weight gain, consistent with other drivers for diabetes aetiology in older adults. We have identified a substantial group of individuals who have a rapid deterioration in glycaemic control, together with weight loss, around the time of diagnosis, and who subsequently stabilise, suggesting that a high HbA<sub>1c</sub> at diagnosis is not inevitably associated with a poor outcome and may be driven by reversible glucose toxicity.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533954","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
The impact of hypoglycaemia on daily functioning among adults with diabetes: a prospective observational study using the Hypo-METRICS app. 低血糖对成年糖尿病患者日常功能的影响:使用 Hypo-METRICS 应用程序进行的前瞻性观察研究。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-30 DOI: 10.1007/s00125-024-06233-1
Uffe Søholm, Melanie Broadley, Natalie Zaremba, Patrick Divilly, Petra Martina Baumann, Zeinab Mahmoudi, Gilberte Martine-Edith, Julia K Mader, Monika Cigler, Julie Maria Bøggild Brøsen, Allan Vaag, Simon Heller, Ulrik Pedersen-Bjergaard, Rory J McCrimmon, Eric Renard, Mark Evans, Bastiaan de Galan, Evertine Abbink, Stephanie A Amiel, Christel Hendrieckx, Jane Speight, Pratik Choudhary, Frans Pouwer
{"title":"The impact of hypoglycaemia on daily functioning among adults with diabetes: a prospective observational study using the Hypo-METRICS app.","authors":"Uffe Søholm, Melanie Broadley, Natalie Zaremba, Patrick Divilly, Petra Martina Baumann, Zeinab Mahmoudi, Gilberte Martine-Edith, Julia K Mader, Monika Cigler, Julie Maria Bøggild Brøsen, Allan Vaag, Simon Heller, Ulrik Pedersen-Bjergaard, Rory J McCrimmon, Eric Renard, Mark Evans, Bastiaan de Galan, Evertine Abbink, Stephanie A Amiel, Christel Hendrieckx, Jane Speight, Pratik Choudhary, Frans Pouwer","doi":"10.1007/s00125-024-06233-1","DOIUrl":"10.1007/s00125-024-06233-1","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The aim of this work was to examine the impact of hypoglycaemia on daily functioning among adults with type 1 diabetes or insulin-treated type 2 diabetes, using the novel Hypo-METRICS app.</p><p><strong>Methods: </strong>For 70 consecutive days, 594 adults (type 1 diabetes, n=274; type 2 diabetes, n=320) completed brief morning and evening Hypo-METRICS 'check-ins' about their experienced hypoglycaemia and daily functioning. Participants wore a blinded glucose sensor (i.e. data unavailable to the participants) for the study duration. Days and nights with or without person-reported hypoglycaemia (PRH) and/or sensor-detected hypoglycaemia (SDH) were compared using multilevel regression models.</p><p><strong>Results: </strong>Participants submitted a mean ± SD of 86.3±12.5% morning and 90.8±10.7% evening check-ins. For both types of diabetes, SDH alone had no significant associations with the changes in daily functioning scores. However, daytime and night-time PRH (with or without SDH) were significantly associated with worsening of energy levels, mood, cognitive functioning, negative affect and fear of hypoglycaemia later that day or while asleep. In addition, night-time PRH (with or without SDH) was significantly associated with worsening of sleep quality (type 1 and type 2 diabetes) and memory (type 2 diabetes). Further, daytime PRH (with or without SDH), was associated with worsening of fear of hyperglycaemia while asleep (type 1 diabetes), memory (type 1 and type 2 diabetes) and social functioning (type 2 diabetes).</p><p><strong>Conclusions/interpretation: </strong>This prospective, real-world study reveals impact on several domains of daily functioning following PRH but not following SDH alone. These data suggest that the observed negative impact is mainly driven by subjective awareness of hypoglycaemia (i.e. PRH), through either symptoms or sensor alerts/readings and/or the need to take action to prevent or treat episodes.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855122","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
The use of technology in type 2 diabetes and prediabetes: a narrative review. 技术在 2 型糖尿病和糖尿病前期中的应用:叙述性综述。
IF 8.4 1区 医学
Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-06-29 DOI: 10.1007/s00125-024-06203-7
Alexandros L Liarakos, Jonathan Z M Lim, Lalantha Leelarathna, Emma G Wilmot
{"title":"The use of technology in type 2 diabetes and prediabetes: a narrative review.","authors":"Alexandros L Liarakos, Jonathan Z M Lim, Lalantha Leelarathna, Emma G Wilmot","doi":"10.1007/s00125-024-06203-7","DOIUrl":"10.1007/s00125-024-06203-7","url":null,"abstract":"<p><p>The increasing incidence of type 2 diabetes, which represents 90% of diabetes cases globally, is a major public health concern. Improved glucose management reduces the risk of vascular complications and mortality; however, only a small proportion of the type 2 diabetes population have blood glucose levels within the recommended treatment targets. In recent years, diabetes technologies have revolutionised the care of people with type 1 diabetes, and it is becoming increasingly evident that people with type 2 diabetes can also benefit from these advances. In this review, we describe the current knowledge regarding the role of technologies for people living with type 2 diabetes and the evidence supporting their use in clinical practice. We conclude that continuous glucose monitoring systems deliver glycaemic benefits for individuals with type 2 diabetes, whether treated with insulin or non-insulin therapy; further data are required to evaluate the role of these systems in those with prediabetes (defined as impaired glucose tolerance and/or impaired fasting glucose and/or HbA<sub>1c</sub> levels between 39 mmol/mol [5.7%] and 47 mmol/mol [6.4%]). The use of insulin pumps seems to be safe and effective in people with type 2 diabetes, especially in those with an HbA<sub>1c</sub> significantly above target. Initial results from studies exploring the impact of closed-loop systems in type 2 diabetes are promising. We discuss directions for future research to fully understand the potential benefits of integrating evidence-based technology into care for people living with type 2 diabetes and prediabetes.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476166","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
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