Diabetologia最新文献

{"title":"Metformin therapy modifies corneal neuroimmune abnormalities in people with type 2 diabetes","authors":"Amy T. Tsoi, Janice Sng, Shyam S. Tummanapalli, Tushar Issar, Ann M. Poynten, Kerry-Lee Milner, Maria Markoulli, Roshan Dhanapalaratnam, Arun V. Krishnan","doi":"10.1007/s00125-025-06399-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06399-2","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Diabetic peripheral neuropathy is a debilitating microvascular complication of diabetes mellitus, with limited disease-modifying therapies to date. This study aimed to assess the effect of metformin on the corneal sub-basal nerve plexus as a peripheral neuropathy outcome measure in people with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A cohort of 36 participants with type 2 diabetes receiving metformin therapy were recruited and underwent clinical assessment, corneal confocal microscopy and nerve conduction studies. Concurrently, 36 participants with type 2 diabetes not receiving metformin therapy were selected as disease controls and matched to participants on metformin therapy for age, sex, diabetes duration, BMI, eGFR, HbA_1c, use of other oral glucose-lowering agents and therapies used for the treatment of the metabolic syndrome. Additionally, 25 healthy control participants were assessed and matched for age and sex. Medical record data over the previous 20 years were analysed for prior and current metformin use in all participants with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Participants receiving metformin therapy had higher corneal nerve fibre density (<i>p</i>=0.020), corneal nerve fibre length (<i>p</i>=0.020) and corneal fractal dimension (<i>p</i>=0.003) compared with those not receiving metformin therapy. The inferior whorl dendritic cell density was significantly lower in the metformin group compared with the non-metformin group (<i>p</i>=0.043).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Metformin treatment is associated with superior corneal nerve parameters and neuroimmune tone in the corneal sub-basal nerve plexus. This study provides further evidence that metformin may be neuroprotective in diabetic peripheral neuropathy.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"7 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570345","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}

{"title":"The relationship of changes in insulin demand and insulin adequacy over the life course.","authors":"Yingchai Zhang, Claudia H T Tam, Eric S H Lau, Noel Y H Ng, Aimin Yang, Baoqi Fan, Hongjiang Wu, Cadmon K P Lim, Elaine Y K Chow, Andrea O Y Luk, Alice P S Kong, Wing Hung Tam, Juliana C N Chan, Ronald C W Ma","doi":"10.1007/s00125-024-06328-9","DOIUrl":"10.1007/s00125-024-06328-9","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Insulin requirements in the human body undergo continuous changes in response to growth and development. We assessed the life course relationships between insulin demand and insulin adequacy.</p><p><strong>Methods: </strong>Three independent Chinese cohorts (204 children, aged [mean ± SD] 7.0 ± 0.5 years; 214 adolescents, aged 15.0 ± 1.8 years; 605 adults, aged 41.5 ± 9.3 years), recruited between 1998 and 2013, underwent OGTT tests. Indices of insulin sensitivity and insulin secretion were calculated based on paired glucose/insulin values during fasting, early phase and late phase of OGTT. Insulin demand and insulin adequacy were calculated by standardised major axis (SMA) regression from the paired insulin sensitivity and secretion indices. We derived the natural logarithm of ratio between the exponential functions of insulin adequacy and insulin demand (RAD) index for further evaluating the relationship between insulin demand and adequacy. The risk of abnormal glucose tolerance (AGT) was evaluated by logistic regression analyses. Area under the receiver-operating characteristic curve (AUC-ROC) analyses, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices were used to demonstrate the discriminative value of the RAD method model.</p><p><strong>Results: </strong>Adolescents had the lowest insulin sensitivity and the highest insulin secretion in all phases (fasting, early and late phase) of the OGTT, as compared with children and adults in each phase (all p<0.001). Adolescents had the highest insulin demand in all phases and lowest insulin adequacy in the fasting phase (p<0.001). In general, adults had the lowest insulin adequacy in both the early phase (p>0.05) and late phase (p<0.001) of the OGTT. Adolescents had negative RAD values irrespective of overweight and obesity, while, in general, children and adults had positive RAD values (p<0.001 between age groups in each of the fasting, early and late phases of the OGTT). Participants with RAD values below the 25th percentile had a higher risk of AGT compared with those above the 25th percentile (fasting-phase OR 1.86 [95% CI 1.18, 2.91]; early-phase OR 1.99 [95% CI 1.24, 3.19]; late-phase OR 2.49 [95% CI 1.57, 3.97]). The late-phase RAD index had the best performance in evaluating the risk of AGT compared with the fasting- and early-phase RAD indices (late-phase AUC-ROC = 0.635 [95% CI 0.583, 0.687]; late-phase NRI = 0.350 [95% CI 0.190, 0.510]; late-phase IDI = 0.033 [95% CI 0.015, 0.050]).</p><p><strong>Conclusions/interpretation: </strong>The relationship between insulin demand and insulin adequacy changed throughout the life course. Adolescents had an imbalanced relationship between insulin demand and insulin adequacy, while, in general, children and adults had a balanced relationship. RAD is a novel index that was used to efficiently describe this relationship and evaluate the risk of AGT.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"526-536"},"PeriodicalIF":8.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750077","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}

{"title":"Genome-wide association study identifying novel risk variants associated with glycaemic traits in the continental African AWI-Gen cohort","authors":"Vivien J. Chebii, Alisha N. Wade, Nigel J. Crowther, Engelbert A. Nonterah, Godfred Agongo, Z. Simayi, Palwende R. Boua, Isaac Kisiangani, Michèle Ramsay, Ananyo Choudhury, Dhriti Sengupta","doi":"10.1007/s00125-025-06395-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06395-6","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Glycaemic traits such as high fasting glucose levels and insulin resistance are positively associated with the risk of type 2 diabetes and other cardiometabolic diseases. Genetic association studies have identified hundreds of associations for each glycaemic trait, yet very few studies have involved continental African populations. We report the results of genome-wide association studies (GWASs) in a pan-African cohort for four glycaemic traits, namely fasting glucose, fasting insulin, insulin resistance (HOMA-IR) and beta cell function (HOMA-B), which are quantitative variables that affect the risk of developing type 2 diabetes.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;GWASs for the four traits were conducted in approximately 10,000 individuals from the Africa Wits-INDEPTH Partnership for Genomics Studies (AWI-Gen) cohort, with participants from Burkina Faso, Ghana, Kenya and South Africa. Association testing was performed using linear mixed models implemented in BOLT-LMM, with age, sex, BMI and principal components as covariates. Replication, fine mapping and functional annotation were performed using standard approaches.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;We identified a novel signal (rs574173815) in the intron of the ankyrin repeat domain 33B (&lt;i&gt;ANKRD33B&lt;/i&gt;) gene associated with fasting glucose, and a novel signal (rs114029796) in the intronic region of the WD repeat domain 7 (&lt;i&gt;WDR7&lt;/i&gt;) gene associated with fasting insulin. SNPs in &lt;i&gt;WDR7&lt;/i&gt; have been shown to be associated with type 2 diabetes. A variant (rs74806991) in the intron of ADAM metallopeptidase with thrombospondin type 1 motif 16 (&lt;i&gt;ADAMTS16&lt;/i&gt;) and another variant (rs6506934) in the β-1,4-galactosyltransferase 6 gene (&lt;i&gt;B4GALT6&lt;/i&gt;) are associated with HOMA-IR. Both &lt;i&gt;ADAMTS16&lt;/i&gt; and &lt;i&gt;B4GALT6&lt;/i&gt; are implicated in the development of type 2 diabetes. In addition, our study replicated several well-established fasting glucose signals in the &lt;i&gt;GCK-YTK6&lt;/i&gt;, &lt;i&gt;SLC2A2&lt;/i&gt; and &lt;i&gt;THORLNC&lt;/i&gt; gene regions.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Our findings highlight the importance of performing GWASs for glycaemic traits in under-represented populations, especially continental African populations, to discover novel associated variants and broaden our knowledge of the genetic aetiology of glycaemic traits. The limited replication of well-known signals in this study hints at the possibility of a unique genetic architecture of these traits in African populations.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Data availability&lt;/h3&gt;&lt;p&gt;The dataset used in this study is available in the European Genome–Phenome Archive (EGA) database (https://ega-archive.org/) under study accession code EGAS00001002482. The phenotype dataset accession code is EGAD00001006425 and the genotype dataset accession code is EGAD00010001996. The availability of these datasets is sub","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"25 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526180","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}

{"title":"Research and data sovereignty in genetically admixed populations. Reply to Zoller L, Kumar R and Lorenzo Bermejo J [letter].","authors":"Joseph Yracheta, Taylor Morriseau, Kali Dale, Ashlynn Gerth, Jonathan McGavock","doi":"10.1007/s00125-025-06400-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06400-y","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531261","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}

{"title":"Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab.","authors":"Alfonso Galderisi, Emily K Sims, Carmella Evans-Molina, Alessandra Petrelli, David Cuthbertson, Brandon M Nathan, Heba M Ismail, Kevan C Herold, Antoinette Moran","doi":"10.1007/s00125-024-06323-0","DOIUrl":"10.1007/s00125-024-06323-0","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate.</p><p><strong>Methods: </strong>OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or <math><mo>≤</mo></math> 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8⁺ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group.</p><p><strong>Results: </strong>Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance significantly decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1⁺ CD8⁺ T effector memory cells.</p><p><strong>Conclusions/interpretation: </strong>OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"646-661"},"PeriodicalIF":8.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667393","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}

{"title":"Microvascular insulin resistance with enhanced muscle glucose disposal in CD36 deficiency.","authors":"Cyndya A Shibao, Vivek S Peche, Terri A Pietka, Dmitri Samovski, Ian M Williams, Naji N Abumrad, Eric R Gamazon, Ira J Goldberg, David H Wasserman, Nada A Abumrad","doi":"10.1007/s00125-024-06292-4","DOIUrl":"10.1007/s00125-024-06292-4","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal.</p><p><strong>Methods: </strong>Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36^-/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion.</p><p><strong>Results: </strong>Insulin clamps showed that Cd36^-/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal.</p><p><strong>Conclusions/interpretation: </strong>CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism.</p><p><strong>Trial registration: </strong>Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ).</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"662-675"},"PeriodicalIF":8.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581473","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}

{"title":"Cardiac arrhythmia and hypoglycaemia among individuals with and without diabetes receiving haemodialysis (the CADDY study): a Danish multicentre cohort study","authors":"Dea H. Kofod, Søren Z. Diederichsen, Tobias Bomholt, Mads Ø. Andersen, Andreas Andersen, Ebba Mannheimer, Marianne Rix, Ylian S. Liem, Kristine Lindhard, Henrik P. Hansen, Casper Rydahl, Morten Lindhardt, Julie Brøsen, Kristine Schandorff, Theis Lange, Kirsten Nørgaard, Thomas P. Almdal, Jesper H. Svendsen, Bo Feldt-Rasmussen, Mads Hornum","doi":"10.1007/s00125-025-06388-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06388-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>We aimed to examine arrhythmias and hypoglycaemia among individuals with and without diabetes who are receiving haemodialysis and to investigate the association between arrhythmias and hypoglycaemia, hyperglycaemia and glycaemic variability.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>This prospective multicentre cohort study included 70 participants on maintenance haemodialysis (35 with diabetes and 35 without diabetes). We employed implantable cardiac monitors for continuous heart rhythm monitoring in combination with periodic use of continuous glucose monitoring. Logistic-regression-type linear mixed models were used to examine associations between arrhythmias and glycaemic measures.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>During 18 months of follow-up, clinically significant arrhythmias (bradyarrhythmia and ventricular tachycardia) were identified in 12 (34%) participants with diabetes and 11 (31%) without diabetes. Atrial fibrillation was detected in 13 (37%) participants with diabetes and 14 (40%) without, while other supraventricular tachycardia was detected in seven (20%) and 11 (31%) participants with and without diabetes, respectively. Hypoglycaemia (sensor glucose &lt;3.9 mmol/l) was observed in 27 (77%) participants with diabetes and 32 (91%) without diabetes. Compared with euglycaemia, hypoglycaemia was associated with an increased rate of arrhythmias among participants without diabetes (incidence rate ratio [IRR] 3.13 [95% CI 1.49, 6.55]), while hyperglycaemia (sensor glucose &gt;10.0 mmol/l) was associated with a decreased rate of arrhythmias among participants with diabetes (IRR 0.58 [95% CI 0.37, 0.92]). Glycaemic variability showed no association with arrhythmias regardless of the presence of diabetes.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Arrhythmias and hypoglycaemia were common in those undergoing haemodialysis regardless of diabetes status. Our data suggest a temporal relationship between arrhythmias and glucose level in both individuals with and without diabetes.</p><h3 data-test=\"abstract-sub-heading\">Trial registration</h3><p>Clinicaltrials.gov: NCT04841304.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"85 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517974","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}

{"title":"Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes affirms markers of disease","authors":"Robert Moulder, M. Karoliina Hirvonen, Tommi Välikangas, Tomi Suomi, Lut Overbergh, Mark Peakman, Søren Brunak, Chantal Mathieu, Mikael Knip, Laura L. Elo, Riitta Lahesmaa","doi":"10.1007/s00125-025-06394-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06394-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>While investigating markers for declining beta cell function in type 1 diabetes, we previously demonstrated 11 statistically significant protein associations with fasting C-peptide/glucose ratios in longitudinal serum samples from newly diagnosed (ND) individuals (<i>n</i>=86; 228 samples in total) participating in the INNODIA (Innovative approaches to understanding and arresting type 1 diabetes) study. Furthermore, comparison with protein measurements from age- and sex-matched autoantibody-negative unaffected family members (UFMs, <i>n</i>=194) revealed differences in the serum levels of 13 target proteins. To further evaluate these findings, we analysed longitudinal serum drawn during the first year after diagnosis from a new group of ND individuals subsequently enrolled in the study, together with samples from additional UFMs.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>To validate the previously reported statistically significant protein associations with type 1 diabetes progression, selected reaction monitoring (SRM) MS analyses were carried out. Sera from individuals diagnosed with type 1 diabetes under the age of 18 years (<i>n</i>=146) were collected within 6 weeks of diagnosis and at 3, 6 and 12 months after diagnosis (560 samples in total). The resulting SRM data were compared with fasting C-peptide/glucose measurements, which were used as a proxy for beta cell function. The protein data were further compared with cross-sectional SRM measurements from age- and sex-matched UFMs (<i>n</i>=272).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Our results confirmed the presence of significant (<i>p</i>&lt;0.05) inverse associations between fasting C-peptide/glucose ratios and peptides from apolipoprotein B-100, apolipoprotein M and glutathione peroxidase 3 (GPX3) in ND individuals. Additionally, we observed consistent differences in the levels of ten of the 13 targeted proteins between individuals with type 1 diabetes and UFMs. These proteins included GPX3, transthyretin, prothrombin, apolipoprotein C1 and afamin.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The validated results reflect the landscape of biological changes accompanying type 1 diabetes. For example, the association of the targeted apolipoproteins with fasting C-peptide/glucose ratios in the first year after diagnosis is likely to relate to lipid abnormalities observed in individuals with type 1 diabetes, and reiterates the connection of apolipoproteins with the underlying changes accompanying the disease. Further research is needed to explore the clinical value and relevance of these targets.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"32 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518497","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}

{"title":"IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes","authors":"Emily K. Sims, David Cuthbertson, Lauric A. Ferrat, Emanuele Bosi, Carmella Evans-Molina, Linda A. DiMeglio, Brandon M. Nathan, Heba M. Ismail, Laura M. Jacobsen, Maria J. Redondo, Richard A. Oram, Jay M. Sosenko","doi":"10.1007/s00125-025-06382-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06382-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (<i>n</i>=192) and autoantibody-positive (<i>n</i>=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Compared with IA-2A⁻ individuals, IA-2A⁺ individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A⁻ stage 1 individuals. Individuals at highest risk within the single-IA-2A⁺ category included children (HR 14.2 [95% CI 1.9, 103.1], <i>p</i>=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], <i>p</i>&lt;0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], <i>p</i>&lt;0.001) and individuals with <i>HLA DR4</i>-positive status (HR 3.7 [95% CI 1.6, 8.3], <i>p</i>=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A⁺ individuals and dysglycaemic IA-2A⁻ individuals.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A⁻. Approaches to incorporate IA-2A⁺ status into monitoring strategies for autoantibody-positive individuals should be considered.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"10 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517975","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}

{"title":"Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease.","authors":"Sheng Ding, Jin-Ling Xu, Jia-Yue Tong, Yang-Yang Cheng, Ling-Feng Shi, Wei Wei, Li-Ming Zhang, Jia-Jia Zhang, Bi-Ying Meng, Xiang-Yan Peng, Lin Xiang, Shu-Guang Li, Ling Yue, Zhong-Jing Wang, Guang-da Xiang","doi":"10.1007/s00125-025-06385-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06385-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Brown adipose tissue (BAT) consumes excess energy through heat production by uncoupling protein 1 (UCP1) to regulate the metabolic profile, but the UCP1-independent mechanisms of BAT, such as in endocrine function, are largely unknown. Our previous study showed that BAT-derived neuregulin 4 (NRG4) displays anti-atherosclerotic properties. Thus, we hypothesised that BAT could regulate diabetic nephropathy, a diabetic microvascular complication, via NRG4.</p><p><strong>Methods: </strong>To investigate the influence of NRG4 from BAT on podocyte apoptosis, both loss- and gain-of-function approaches were used in in vivo experiments. Diabetic nephropathy models were created using BAT-specific Nrg4-knockout (BKO) mice, global Nrg4-knockout (KO) mice and wild-type (WT) mice. In in vitro studies, podocytes (MPC5) were exposed to glucose and recombinant NRG4 (rNrg4). Additionally, brown adipocytes were co-cultured with MPC5 podocytes using a transwell system. The expression levels of proteins associated with podocyte apoptosis and signalling pathways were measured.</p><p><strong>Results: </strong>BAT-specific NRG4 deficiency aggravated podocyte apoptosis (increased by 47.46%) and increased the urinary albumin/creatinine ratio (increased by 41.71%), decreased nephrin expression and increased desmin expression. As expected, these changes were reversed by NRG4 replenishment using adeno-associated virus-NRG4 interscapular BAT injection and BAT transplantation assays in KO mice. Additionally, co-culture experiments demonstrated that brown adipocytes from WT mice could alleviate high-glucose-induced podocyte apoptosis. In in vitro experiments, recombinant NRG4 inhibited high-glucose-induced podocyte apoptosis. Mechanistically, the Akt-glycogen synthase kinase 3 β (GSK-3β) pathway is crucial for the protection that BAT-derived NRG4 provides to podocytes in diabetic nephropathy.</p><p><strong>Conclusions/interpretation: </strong>Our data show that BAT had a protective effect on podocyte apoptosis in diabetic nephropathy through BAT-derived NRG4, and the Akt-GSK‑3β signalling pathway may mediate the inhibition of BAT-derived NRG4 on podocyte apoptosis in diabetic nephropathy.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}