Pub Date : 2024-07-30DOI: 10.1007/s00125-024-06231-3
Agnete T Lundgaard, David Westergaard, Timo Röder, Kristoffer S Burgdorf, Margit H Larsen, Michael Schwinn, Lise W Thørner, Erik Sørensen, Kaspar R Nielsen, Henrik Hjalgrim, Christian Erikstrup, Bertram D Kjerulff, Lotte Hindhede, Thomas F Hansen, Mette Nyegaard, Ewan Birney, Hreinn Stefansson, Kári Stefánsson, Ole B V Pedersen, Sisse R Ostrowski, Peter Rossing, Henrik Ullum, Laust H Mortensen, Dorte Vistisen, Karina Banasik, Søren Brunak
Aims/hypothesis: Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes.
Methods: We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose.
Results: We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone.
Conclusions/interpretation: Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models.
{"title":"Longitudinal metabolite and protein trajectories prior to diabetes mellitus diagnosis in Danish blood donors: a nested case-control study.","authors":"Agnete T Lundgaard, David Westergaard, Timo Röder, Kristoffer S Burgdorf, Margit H Larsen, Michael Schwinn, Lise W Thørner, Erik Sørensen, Kaspar R Nielsen, Henrik Hjalgrim, Christian Erikstrup, Bertram D Kjerulff, Lotte Hindhede, Thomas F Hansen, Mette Nyegaard, Ewan Birney, Hreinn Stefansson, Kári Stefánsson, Ole B V Pedersen, Sisse R Ostrowski, Peter Rossing, Henrik Ullum, Laust H Mortensen, Dorte Vistisen, Karina Banasik, Søren Brunak","doi":"10.1007/s00125-024-06231-3","DOIUrl":"https://doi.org/10.1007/s00125-024-06231-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes.</p><p><strong>Methods: </strong>We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose.</p><p><strong>Results: </strong>We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone.</p><p><strong>Conclusions/interpretation: </strong>Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792098","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}
Pub Date : 2024-07-30DOI: 10.1007/s00125-024-06228-y
Liv Vernstrøm, Søren Gullaksen, Steffen S Sørensen, Steffen Ringgaard, Christoffer Laustsen, Henrik Birn, Kristian L Funck, Esben Laugesen, Per L Poulsen
Aims/hypothesis: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV).
Methods: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI.
Results: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c.
Conclusions/interpretation: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin signifi
目的/假设:弥散加权磁共振成像(DWI-MRI)得出的表观弥散系数(ADC)被认为是衡量肾脏微观结构变化(包括肾脏纤维化)的指标。在晚期肾病中,肾脏通常会萎缩;然而,在 2 型糖尿病的初期阶段,肾脏体积会增大。胰高血糖素样肽-1 受体激动剂和钠-葡萄糖共转运体 2 抑制剂都能防止糖尿病肾病的恶化。然而,人们对其中的机制尚不完全清楚。为了探讨这一问题,我们研究了赛马鲁肽、恩格列净及其联合用药对肾脏ADC和肾脏总体积(TKV)的影响:本研究是一项随机临床试验的子研究,研究对象为塞马鲁肽和恩格列净单独使用或联合使用的效果。80名2型糖尿病和心血管疾病高风险患者被随机分为四组(每组20人),分别接受片剂安慰剂、恩格列净、塞马鲁肽和片剂安慰剂的组合(以下简称 "塞马鲁肽组")或塞马鲁肽和恩格列净的组合(以下简称 "组合疗法组")。半格鲁肽组和联合疗法组接受半格鲁肽治疗16周后,再分别接受片剂安慰剂或恩格列净治疗16周;安慰剂组和恩格列净组接受各自的单一疗法治疗32周。我们分析了治疗对ADC(皮质、髓质和皮质-髓质差值[ΔADC;髓质ADC减去皮质ADC])变化以及核磁共振成像测量的TKV的影响:与安慰剂相比,semaglutide和empagliflozin都能显著降低皮质ADC(semaglutide:-0.20×10-3 mm2/s [95% CI -0.30, -0.10],p-3 mm2/s [95% CI -0.26, -0.04],p=0.01)。联合治疗组未观察到明显变化(-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo)。皮质 ADC 的变化与 GFR、白蛋白尿、TKV 或炎症指标的变化无关。此外,与安慰剂相比,各组髓质 ADC 均无变化。与安慰剂相比,只有使用semaglutide治疗的ΔADC发生了显著变化,降幅为-0.13×10-3 mm2/s(95% CI -0.22,-0.04;P=0.01)。与安慰剂相比,TKV下降了-3%(95% CI -5%,-0.3%;p=0.04)、-3%(95% CI -5%,-0.4%;p=0.02)和-5%(95% CI -8%,-2%;p1c.结论/解释:在2型糖尿病和心血管疾病高风险人群中,与安慰剂相比,semaglutide和empagliflozin能显著降低皮质ADC,这表明肾脏的微观结构发生了变化。这些变化与肾小球滤过率、白蛋白尿或炎症的变化无关。此外,我们还发现所有积极治疗组的 TKV 均有所下降,这可能是由于高滤过的减少所致。我们的研究结果表明,DWI-MRI 可以作为一种有前途的工具,用于研究 2 型糖尿病患者医疗干预的潜在机制,但可能反映出与纤维化无关的效应:欧盟药物管理局临床试验数据库(EudraCT)2019-000781-38。
{"title":"Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial.","authors":"Liv Vernstrøm, Søren Gullaksen, Steffen S Sørensen, Steffen Ringgaard, Christoffer Laustsen, Henrik Birn, Kristian L Funck, Esben Laugesen, Per L Poulsen","doi":"10.1007/s00125-024-06228-y","DOIUrl":"https://doi.org/10.1007/s00125-024-06228-y","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV).</p><p><strong>Methods: </strong>This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI.</p><p><strong>Results: </strong>Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10<sup>-3</sup> mm<sup>2</sup>/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10<sup>-3</sup> mm<sup>2</sup>/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10<sup>-3</sup> mm<sup>2</sup>/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10<sup>-3</sup> mm<sup>2</sup>/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA<sub>1c</sub>.</p><p><strong>Conclusions/interpretation: </strong>In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin signifi","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792151","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}
Pub Date : 2024-07-30DOI: 10.1007/s00125-024-06232-2
Noura Aldous, Ahmed K Elsayed, Bushra Memon, Sadaf Ijaz, Sikander Hayat, Essam M Abdelalim
Aims/hypothesis: Homozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6's known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6.
Methods: We examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs).
Results: RFX6 expression was detected in PDX1+ cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets.
Conclusions/interpretation: These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+/NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes.
Data availability: RNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891 ).
{"title":"Deletion of RFX6 impairs iPSC-derived islet organoid development and survival, with no impact on PDX1<sup>+</sup>/NKX6.1<sup>+</sup> progenitors.","authors":"Noura Aldous, Ahmed K Elsayed, Bushra Memon, Sadaf Ijaz, Sikander Hayat, Essam M Abdelalim","doi":"10.1007/s00125-024-06232-2","DOIUrl":"https://doi.org/10.1007/s00125-024-06232-2","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Homozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6's known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6.</p><p><strong>Methods: </strong>We examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs).</p><p><strong>Results: </strong>RFX6 expression was detected in PDX1<sup>+</sup> cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets.</p><p><strong>Conclusions/interpretation: </strong>These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1<sup>+</sup>/NKX6.1<sup>+</sup> PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes.</p><p><strong>Data availability: </strong>RNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891 ).</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855121","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}
Pub Date : 2024-07-30DOI: 10.1007/s00125-024-06239-9
Dominic Ehrmann, Norbert Hermanns, Andreas Schmitt, Laura Klinker, Thomas Haak, Bernhard Kulzer
Aims/hypothesis: Diabetes distress is one of the most frequent mental health issues identified in people with type 1 and type 2 diabetes. Little is known about the role of glucose control as a potential contributor to diabetes distress and whether the subjective perception of glucose control or the objective glycaemic parameters are more important for the experience. With the emergence of continuous glucose monitoring (CGM), this is a relevant question as glucose values are now visible in real-time. We employed a precision monitoring approach to analyse the independent associations of perceived and measured glucose control with diabetes distress on a daily basis. By using n-of-1 analyses, we aimed to identify individual contributors to diabetes distress per person and analyse the associations of these individual contributors with mental health at a 3 month follow-up.
Methods: In this prospective, observational study, perceived (hypoglycaemia/hyperglycaemia/glucose variability burden) and measured glucose control (time in hypoglycaemia and hyperglycaemia, CV) were assessed daily for 17 days using an ecological momentary assessment (EMA) approach with a special EMA app and CGM, respectively. Mixed-effect regression analysis was performed, with daily diabetes distress as the dependent variable and daily perceived and CGM-measured metrics of glucose control as random factors. Individual regression coefficients of daily distress with perceived and CGM-measured metrics were correlated with levels of psychosocial well-being at a 3 month follow-up.
Results: Data from 379 participants were analysed (50.9% type 1 diabetes; 49.6% female). Perceived glucose variability (t=14.360; p<0.0001) and perceived hyperglycaemia (t=13.637; p<0.0001) were the strongest predictors of daily diabetes distress, while CGM-based glucose variability was not significantly associated (t=1.070; p=0.285). There was great heterogeneity between individuals in the associations of perceived and measured glucose parameters with diabetes distress. Individuals with a stronger association between perceived glucose control and daily distress had more depressive symptoms (β=0.32), diabetes distress (β=0.39) and hypoglycaemia fear (β=0.34) at follow-up (all p<0.001). Individuals with a stronger association between CGM-measured glucose control and daily distress had higher levels of psychosocial well-being at follow-up (depressive symptoms: β=-0.31; diabetes distress: β=-0.33; hypoglycaemia fear: β=-0.27; all p<0.001) but also higher HbA1c (β=0.12; p<0.05).
Conclusions/interpretation: Overall, subjective perceptions of glucose seem to be more influential on diabetes distress than objective CGM parameters of glycaemic control. N-of-1 analyses showed that CGM-measured and perceived glucose control had differential associations with diabetes distress and psychosocial well-being 3 months later. The
{"title":"Perceived glucose levels matter more than CGM-based data in predicting diabetes distress in type 1 or type 2 diabetes: a precision mental health approach using n-of-1 analyses.","authors":"Dominic Ehrmann, Norbert Hermanns, Andreas Schmitt, Laura Klinker, Thomas Haak, Bernhard Kulzer","doi":"10.1007/s00125-024-06239-9","DOIUrl":"https://doi.org/10.1007/s00125-024-06239-9","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Diabetes distress is one of the most frequent mental health issues identified in people with type 1 and type 2 diabetes. Little is known about the role of glucose control as a potential contributor to diabetes distress and whether the subjective perception of glucose control or the objective glycaemic parameters are more important for the experience. With the emergence of continuous glucose monitoring (CGM), this is a relevant question as glucose values are now visible in real-time. We employed a precision monitoring approach to analyse the independent associations of perceived and measured glucose control with diabetes distress on a daily basis. By using n-of-1 analyses, we aimed to identify individual contributors to diabetes distress per person and analyse the associations of these individual contributors with mental health at a 3 month follow-up.</p><p><strong>Methods: </strong>In this prospective, observational study, perceived (hypoglycaemia/hyperglycaemia/glucose variability burden) and measured glucose control (time in hypoglycaemia and hyperglycaemia, CV) were assessed daily for 17 days using an ecological momentary assessment (EMA) approach with a special EMA app and CGM, respectively. Mixed-effect regression analysis was performed, with daily diabetes distress as the dependent variable and daily perceived and CGM-measured metrics of glucose control as random factors. Individual regression coefficients of daily distress with perceived and CGM-measured metrics were correlated with levels of psychosocial well-being at a 3 month follow-up.</p><p><strong>Results: </strong>Data from 379 participants were analysed (50.9% type 1 diabetes; 49.6% female). Perceived glucose variability (t=14.360; p<0.0001) and perceived hyperglycaemia (t=13.637; p<0.0001) were the strongest predictors of daily diabetes distress, while CGM-based glucose variability was not significantly associated (t=1.070; p=0.285). There was great heterogeneity between individuals in the associations of perceived and measured glucose parameters with diabetes distress. Individuals with a stronger association between perceived glucose control and daily distress had more depressive symptoms (β=0.32), diabetes distress (β=0.39) and hypoglycaemia fear (β=0.34) at follow-up (all p<0.001). Individuals with a stronger association between CGM-measured glucose control and daily distress had higher levels of psychosocial well-being at follow-up (depressive symptoms: β=-0.31; diabetes distress: β=-0.33; hypoglycaemia fear: β=-0.27; all p<0.001) but also higher HbA<sub>1c</sub> (β=0.12; p<0.05).</p><p><strong>Conclusions/interpretation: </strong>Overall, subjective perceptions of glucose seem to be more influential on diabetes distress than objective CGM parameters of glycaemic control. N-of-1 analyses showed that CGM-measured and perceived glucose control had differential associations with diabetes distress and psychosocial well-being 3 months later. The","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792099","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}
Pub Date : 2024-07-30DOI: 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
Aims/hypothesis: 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.
Methods: 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.
Results: 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).
Conclusions/interpretation: 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.
{"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":"https://doi.org/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":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aims/hypothesis: The relationship between pre-meal insulin type, exercise timing and the risk of postprandial exercise-induced hypoglycaemia in people living with type 1 diabetes is unknown. We aimed to evaluate the effects of exercise timing (60 vs 120 min post meal) and different insulin types (aspart vs ultra-rapid aspart) on hypoglycaemic risk.
Methods: This was a four-way crossover randomised trial including 40 individuals with type 1 diabetes using multiple daily injections (mean HbA1c 56 mmol/mol [7.4%]). Participants, who were recruited from the Montreal Clinical Research Institute, undertook 60 min cycling sessions (60% of ) after breakfast (60 min [EX60min] or 120 min [EX120min] post meal) with 50% of their usual insulin dose (aspart or ultra-rapid aspart). Eligibility criteria included age ≥18 years old, clinical diagnosis of type 1 diabetes for at least 1 year and HbA1c ≤80 mmol/mol (9.5%). Participants were allocated using sequentially numbered, opaque sealed envelopes. Participants were masked to their group assignment, and each participant was allocated a unique identification number to ensure anonymisation. The primary outcome was change in blood glucose levels between exercise onset and nadir.
Results: Prior to exercise onset, time spent in hyperglycaemia was lower for EX60min vs EX120min (time >10.0 mmol/l: 56.6% [1.2-100%] vs 78.0% [52.7-97.9%]; p<0.001). The glucose reduction between exercise onset and nadir was less pronounced with EX60min vs EX120min (-3.8±2.7 vs -4.7±2.5 mmol/l; p<0.001). A similar number of hypoglycaemic events occurred during both exercise timings. Blood glucose between exercise onset and nadir decreased less with ultra-rapid aspart compared with aspart (-4.1±2.3 vs -4.4±2.8 mmol/l; p=0.037). While a similar number of hypoglycaemic events during exercise were observed, less post-exercise hypoglycaemia occurred with ultra-rapid aspart (n=0, 0%, vs n=15, 38%; p=0.003). No interactions between insulin types and exercise timings were found.
Conclusions/interpretation: EX60min blunted the pre-exercise glucose increase following breakfast and was associated with a smaller glucose reduction during exercise. Ultra-rapid aspart led to a smaller blood glucose reduction during exercise and might be associated with diminished post-exercise hypoglycaemia.
Trial registration: ClinicalTrials.gov NCT03659799 FUNDING: This study was funded by Novo Nordisk Canada.
{"title":"Assessing the influence of insulin type (ultra-rapid vs rapid insulin) and exercise timing on postprandial exercise-induced hypoglycaemia risk in individuals with type 1 diabetes: a randomised controlled trial.","authors":"Joséphine Molveau, Étienne Myette-Côté, Sémah Tagougui, Nadine Taleb, Roxane St-Amand, Corinne Suppère, Valérie Bourdeau, Elsa Heyman, Rémi Rabasa-Lhoret","doi":"10.1007/s00125-024-06234-0","DOIUrl":"https://doi.org/10.1007/s00125-024-06234-0","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The relationship between pre-meal insulin type, exercise timing and the risk of postprandial exercise-induced hypoglycaemia in people living with type 1 diabetes is unknown. We aimed to evaluate the effects of exercise timing (60 vs 120 min post meal) and different insulin types (aspart vs ultra-rapid aspart) on hypoglycaemic risk.</p><p><strong>Methods: </strong>This was a four-way crossover randomised trial including 40 individuals with type 1 diabetes using multiple daily injections (mean HbA<sub>1c</sub> 56 mmol/mol [7.4%]). Participants, who were recruited from the Montreal Clinical Research Institute, undertook 60 min cycling sessions (60% of <math> <msub> <mrow><mover><mi>V</mi> <mo>˙</mo></mover> <mtext>O</mtext></mrow> <mrow><mn>2</mn> <mtext>peak</mtext></mrow> </msub> </math> ) after breakfast (60 min [EX60min] or 120 min [EX120min] post meal) with 50% of their usual insulin dose (aspart or ultra-rapid aspart). Eligibility criteria included age ≥18 years old, clinical diagnosis of type 1 diabetes for at least 1 year and HbA<sub>1c</sub> ≤80 mmol/mol (9.5%). Participants were allocated using sequentially numbered, opaque sealed envelopes. Participants were masked to their group assignment, and each participant was allocated a unique identification number to ensure anonymisation. The primary outcome was change in blood glucose levels between exercise onset and nadir.</p><p><strong>Results: </strong>Prior to exercise onset, time spent in hyperglycaemia was lower for EX60min vs EX120min (time >10.0 mmol/l: 56.6% [1.2-100%] vs 78.0% [52.7-97.9%]; p<0.001). The glucose reduction between exercise onset and nadir was less pronounced with EX60min vs EX120min (-3.8±2.7 vs -4.7±2.5 mmol/l; p<0.001). A similar number of hypoglycaemic events occurred during both exercise timings. Blood glucose between exercise onset and nadir decreased less with ultra-rapid aspart compared with aspart (-4.1±2.3 vs -4.4±2.8 mmol/l; p=0.037). While a similar number of hypoglycaemic events during exercise were observed, less post-exercise hypoglycaemia occurred with ultra-rapid aspart (n=0, 0%, vs n=15, 38%; p=0.003). No interactions between insulin types and exercise timings were found.</p><p><strong>Conclusions/interpretation: </strong>EX60min blunted the pre-exercise glucose increase following breakfast and was associated with a smaller glucose reduction during exercise. Ultra-rapid aspart led to a smaller blood glucose reduction during exercise and might be associated with diminished post-exercise hypoglycaemia.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov NCT03659799 FUNDING: This study was funded by Novo Nordisk Canada.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787539","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}
Aims/hypothesis: Fatty acid-binding protein 4 (FABP4) has been reported to act as a hepatic insulin resistance factor. We previously reported that fasting FABP4 was correlated with insulin resistance measurements derived from the glucose clamp, and another study reported that postprandial FABP4 levels were decreased in healthy volunteers but were not reported (or known) in participants with type 2 diabetes. We have limited knowledge about the direct effect of FABP4 on muscle cells. We investigated the postprandial FABP4 levels in participants with type 2 diabetes, and the basic mechanism of muscle insulin resistance and FABP4.
Methods: We performed a meal tolerance test and hyperinsulinaemic-euglycaemic clamp in 22 participants with type 2 diabetes and 26 participants without diabetes. We measured fasting and postprandial serum FABP4. We cultured mouse C2C12 muscle cells, and investigated the effect of FABP4 on glucose uptake. We analysed insulin signalling by western blot and insulin binding assay.
Results: The postprandial FABP4 level in participants with type 2 diabetes was higher than that in participants without diabetes. Participants without diabetes had lower postprandial FABP4 than fasting except for one participant, whereas one-third of participants with type 2 diabetes had higher postprandial FABP4 than fasting. Postprandial FABP4 was correlated with the muscle insulin resistance M/I value from a glucose clamp in participants without diabetes (r=-0.42, p<0.05). The increase in FABP4 after a meal correlated with the muscle insulin resistance M/I value (r=-0.44, p<0.05) and the difference between fasting and postprandial glucagon in participants with type 2 diabetes (r=0.36, p<0.05). FABP4 alone appears to increase glucose uptake, and the combination of FABP4 and insulin decreases glucose uptake when compared with insulin alone. FABP4 inhibits insulin signalling of muscle cells through decreases in phosphorylation of insulin receptor substrate 1 and Akt. The physiological concentration of FABP4 did not inhibit insulin binding to muscle cells.
Conclusions/interpretation: These results suggested that the postprandial FABP4 level is associated with insulin resistance, and FABP4 may suppress insulin signals.
{"title":"Postprandial fatty acid-binding protein 4 is associated with muscle insulin resistance.","authors":"Tsuyoshi Okura, Yuichi Ito, Mari Anno, Satomi Endo, Sonoko Kitao, Risa Nakamura, Kazuhisa Matsumoto, Kyoko Shoji, Hiroko Okura, Kazuhiko Matsuzawa, Shoichiro Izawa, Yoshinori Ichihara, Etsuko Ueta, Masahiko Kato, Takeshi Imamura, Shin-Ichi Taniguchi, Kazuhiro Yamamoto","doi":"10.1007/s00125-024-06222-4","DOIUrl":"10.1007/s00125-024-06222-4","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Fatty acid-binding protein 4 (FABP4) has been reported to act as a hepatic insulin resistance factor. We previously reported that fasting FABP4 was correlated with insulin resistance measurements derived from the glucose clamp, and another study reported that postprandial FABP4 levels were decreased in healthy volunteers but were not reported (or known) in participants with type 2 diabetes. We have limited knowledge about the direct effect of FABP4 on muscle cells. We investigated the postprandial FABP4 levels in participants with type 2 diabetes, and the basic mechanism of muscle insulin resistance and FABP4.</p><p><strong>Methods: </strong>We performed a meal tolerance test and hyperinsulinaemic-euglycaemic clamp in 22 participants with type 2 diabetes and 26 participants without diabetes. We measured fasting and postprandial serum FABP4. We cultured mouse C2C12 muscle cells, and investigated the effect of FABP4 on glucose uptake. We analysed insulin signalling by western blot and insulin binding assay.</p><p><strong>Results: </strong>The postprandial FABP4 level in participants with type 2 diabetes was higher than that in participants without diabetes. Participants without diabetes had lower postprandial FABP4 than fasting except for one participant, whereas one-third of participants with type 2 diabetes had higher postprandial FABP4 than fasting. Postprandial FABP4 was correlated with the muscle insulin resistance M/I value from a glucose clamp in participants without diabetes (r=-0.42, p<0.05). The increase in FABP4 after a meal correlated with the muscle insulin resistance M/I value (r=-0.44, p<0.05) and the difference between fasting and postprandial glucagon in participants with type 2 diabetes (r=0.36, p<0.05). FABP4 alone appears to increase glucose uptake, and the combination of FABP4 and insulin decreases glucose uptake when compared with insulin alone. FABP4 inhibits insulin signalling of muscle cells through decreases in phosphorylation of insulin receptor substrate 1 and Akt. The physiological concentration of FABP4 did not inhibit insulin binding to muscle cells.</p><p><strong>Conclusions/interpretation: </strong>These results suggested that the postprandial FABP4 level is associated with insulin resistance, and FABP4 may suppress insulin signals.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765763","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}
Pub Date : 2024-07-22DOI: 10.1007/s00125-024-06210-8
Ayano Kondo, Monee McGrady, Dhiraj Nallapothula, Hira Ali, Alexandro E Trevino, Amy Lam, Ryan Preska, H Blaize D'Angio, Zhenqin Wu, Lauren N Lopez, Harshanna K Badhesha, Chenoa R Vargas, Achyuta Ramesh, Nasim Wiegley, Seung Seok Han, Marc Dall'Era, Kuang-Yu Jen, Aaron T Mayer, Maryam Afkarian
Aims/hypothesis: Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage kidney disease in the USA and worldwide. Animal models have taught us much about DKD mechanisms, but translation of this knowledge into treatments for human disease has been slowed by the lag in our molecular understanding of human DKD.
Methods: Using our Spatial TissuE Proteomics (STEP) pipeline (comprising curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools), we imaged and analysed the expression of 21 proteins in 23 tissue sections from individuals with diabetes and healthy kidneys (n=5), compared to those with DKDIIA, IIA-B and IIB (n=2 each) and DKDIII (n=1).
Results: These analyses revealed the existence of 11 cellular clusters (kidney compartments/cell types): podocytes, glomerular endothelial cells, proximal tubules, distal nephron, peritubular capillaries, blood vessels (endothelial cells and vascular smooth muscle cells), macrophages, myeloid cells, other CD45+ inflammatory cells, basement membrane and the interstitium. DKD progression was associated with co-localised increases in inflammatory cells and collagen IV deposition, with concomitant loss of native proteins of each nephron segment. Cell-type frequency and neighbourhood analyses highlighted a significant increase in inflammatory cells and their adjacency to tubular and αSMA+ (α-smooth muscle actin-positive) cells in DKD. Finally, DKD progression showed marked regional variability within single tissue sections, as well as inter-individual variability within each DKD class.
Conclusions/interpretation: Using the STEP pipeline, we found alterations in protein expression, cellular phenotypic composition and microenvironment structure with DKD progression, demonstrating the power of this pipeline to reveal the pathophysiology of human DKD.
{"title":"Spatial proteomics of human diabetic kidney disease, from health to class III.","authors":"Ayano Kondo, Monee McGrady, Dhiraj Nallapothula, Hira Ali, Alexandro E Trevino, Amy Lam, Ryan Preska, H Blaize D'Angio, Zhenqin Wu, Lauren N Lopez, Harshanna K Badhesha, Chenoa R Vargas, Achyuta Ramesh, Nasim Wiegley, Seung Seok Han, Marc Dall'Era, Kuang-Yu Jen, Aaron T Mayer, Maryam Afkarian","doi":"10.1007/s00125-024-06210-8","DOIUrl":"https://doi.org/10.1007/s00125-024-06210-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage kidney disease in the USA and worldwide. Animal models have taught us much about DKD mechanisms, but translation of this knowledge into treatments for human disease has been slowed by the lag in our molecular understanding of human DKD.</p><p><strong>Methods: </strong>Using our Spatial TissuE Proteomics (STEP) pipeline (comprising curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools), we imaged and analysed the expression of 21 proteins in 23 tissue sections from individuals with diabetes and healthy kidneys (n=5), compared to those with DKDIIA, IIA-B and IIB (n=2 each) and DKDIII (n=1).</p><p><strong>Results: </strong>These analyses revealed the existence of 11 cellular clusters (kidney compartments/cell types): podocytes, glomerular endothelial cells, proximal tubules, distal nephron, peritubular capillaries, blood vessels (endothelial cells and vascular smooth muscle cells), macrophages, myeloid cells, other CD45<sup>+</sup> inflammatory cells, basement membrane and the interstitium. DKD progression was associated with co-localised increases in inflammatory cells and collagen IV deposition, with concomitant loss of native proteins of each nephron segment. Cell-type frequency and neighbourhood analyses highlighted a significant increase in inflammatory cells and their adjacency to tubular and αSMA<sup>+</sup> (α-smooth muscle actin-positive) cells in DKD. Finally, DKD progression showed marked regional variability within single tissue sections, as well as inter-individual variability within each DKD class.</p><p><strong>Conclusions/interpretation: </strong>Using the STEP pipeline, we found alterations in protein expression, cellular phenotypic composition and microenvironment structure with DKD progression, demonstrating the power of this pipeline to reveal the pathophysiology of human DKD.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733748","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}
Pub Date : 2024-07-22DOI: 10.1007/s00125-024-06225-1
Joseph Mellor, Dmitry Kuznetsov, Simon Heller, Mari-Anne Gall, Myriam Rosilio, Stephanie A Amiel, Mark Ibberson, Stuart McGurnaghan, Luke Blackbourn, William Berthon, Adel Salem, Yongming Qu, Rory J McCrimmon, Bastiaan E de Galan, Ulrik Pedersen-Bjergaard, Joanna Leaviss, Paul M McKeigue, Helen M Colhoun
Aims/hypothesis: Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA1c, blood glucose, blood glucose variability and weight.
Methods: Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes.
Results: The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced.
{"title":"Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.","authors":"Joseph Mellor, Dmitry Kuznetsov, Simon Heller, Mari-Anne Gall, Myriam Rosilio, Stephanie A Amiel, Mark Ibberson, Stuart McGurnaghan, Luke Blackbourn, William Berthon, Adel Salem, Yongming Qu, Rory J McCrimmon, Bastiaan E de Galan, Ulrik Pedersen-Bjergaard, Joanna Leaviss, Paul M McKeigue, Helen M Colhoun","doi":"10.1007/s00125-024-06225-1","DOIUrl":"https://doi.org/10.1007/s00125-024-06225-1","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA<sub>1c</sub>, blood glucose, blood glucose variability and weight.</p><p><strong>Methods: </strong>Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA<sub>1c</sub> were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes.</p><p><strong>Results: </strong>The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced.</p><p><strong","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733747","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}
Pub Date : 2024-07-22DOI: 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
Aims/hypothesis: 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.
Methods: 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).
Results: 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.
Conclusions/interpretation: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD.
Data availability: 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 ).
{"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":"https://doi.org/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":"2024-07-22","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}