Diabetologia最新文献

{"title":"Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA1c levels but not with type 2 diabetes","authors":"Kimmie V. Sørensen, Johanne M. Justesen, Lars Ängquist, Jette Bork-Jensen, Bolette Hartmann, Niklas R. Jørgensen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens J. Holst, Oluf Pedersen, Allan Linneberg, Torben Hansen, Niels Grarup","doi":"10.1007/s00125-025-06381-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06381-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>An intronic variant (rs10830963) in <i>MTNR1B</i> (encoding the melatonin receptor type 2 [MT2]) has been shown to strongly associate with impaired glucose regulation and elevated type 2 diabetes prevalence. However, <i>MTNR1B</i> missense variants have shown conflicting results on type 2 diabetes. Thus, we aimed to gain further insights into the impact of <i>MTNR1B</i> coding variants on type 2 diabetes prevalence and related phenotypes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We conducted a cross-sectional study, performing <i>MTNR1B</i> variant burden testing of glycaemic phenotypes (<i>N</i>=248,454, without diabetes), other cardiometabolic phenotypes (<i>N</i>=330,453) and type 2 diabetes prevalence (case–control study; <i>N</i>=263,739) in the UK Biobank. Similar burden testing with glycaemic phenotypes was performed in Danish Inter99 participants without diabetes (<i>N</i>=5711), and type 2 diabetes prevalence (DD2 cohort serving as cases [<i>N</i>=2930] and Inter99 serving as controls [<i>N</i>=4243]). Finally, we evaluated the effects of <i>MTNR1B</i> variants on the melatonin-induced glucose regulation response in a recall-by-genotype study of individuals without diabetes.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In the UK Biobank, <i>MTNR1B</i> variants were not associated with cardiometabolic phenotypes, including type 2 diabetes prevalence, except that carriers of missense <i>MTNR1B</i> variants causing impaired MT2 signalling exhibited higher HbA_1c levels compared with non-carriers (effect size, β, 0.087 SD [95% CI 0.039, 0.135]). Similarly, no significant associations were observed with phenotypes associated with glycaemic phenotypes in the Inter99 population. However, carriers of variants impairing MT2 signalling demonstrated a nominally significant lower glucose-stimulated insulin response (β −0.47 SD [95% CI −0.82, −0.11]). A reduced insulin response was also observed in carriers of variants impairing MT2 signalling (β −476.0 [95% CI −928.6, −24.4]) or the rs10830963 variant (β −390.8 [95% CI −740.1, −41.6]) compared with non-carriers after melatonin treatment.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The higher type 2 diabetes prevalence previously observed in carriers of missense <i>MTNR1B</i> variants causing impairment in MT2 signalling was not replicated in the UK Biobank, yet carriers had elevated HbA_1c levels.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>Data (Inter99 cohort and recall-by-genotype study) are available on reasonable request from the corresponding author. Requests for DD2 data are through the application form at https://dd2.dk/forskning/ansoeg-om-data. Access to UK Biobank data can be requested through the UK Biobank website (https://www.ukbiobank.ac.uk/enable-your-research).</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589632","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":"Clonal haematopoiesis of indeterminate potential: an emerging risk factor for type 2 diabetes and related complications","authors":"María A. Zuriaga, José J. Fuster","doi":"10.1007/s00125-025-06393-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06393-8","url":null,"abstract":"<p>The accumulation of acquired somatic mutations is a natural consequence of ageing, but the pathophysiological implications of these mutations beyond cancer are only beginning to be understood. Most somatic mutations are functionally neutral, but a few may confer a competitive advantage to a stem cell, driving its clonal expansion. When such a mutation arises in haematopoietic stem cells, it leads to clonal haematopoiesis, in which a significant proportion of blood cells originate from the mutant stem cell and share the same mutation. Clonal haematopoiesis of indeterminate potential (CHIP), a specific subset of clonal haematopoiesis driven by myeloid leukaemia-related somatic mutations, has been linked to a higher risk of various age-related conditions, particularly CVD, by exacerbating inflammatory responses. Emerging evidence suggests that CHIP may also contribute to the pathogenesis of type 2 diabetes and some of its complications. This review synthesises current knowledge on CHIP and its potential as a novel risk factor for type 2 diabetes, highlighting the need for further research to clarify this relationship and to explore its potential value in developing personalised preventive care strategies for type 2 diabetes and related conditions.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"37 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143590278","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":"TBC1D30 regulates proinsulin and insulin secretion and is the target of a genomic association signal for proinsulin","authors":"Victoria A. Parsons, Swarooparani Vadlamudi, Kayleigh M. Voos, Abigail E. Rohy, Anne H. Moxley, Maren E. Cannon, Jonathan D. Rosen, Christine A. Mills, Laura E. Herring, K. Alaine Broadaway, Damaris N. Lorenzo, Karen L. Mohlke","doi":"10.1007/s00125-025-06391-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06391-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Components of the insulin processing and secretion pathways remain incompletely understood. Here, we examined a genome-wide association study (GWAS) signal for plasma proinsulin levels. Lead GWAS variant rs150781447-T encodes an Arg279Cys substitution in TBC1 domain family member 30 (TBC1D30), but no role for this protein in insulin processing or secretion has been established previously. This study aimed to evaluate whether TBC1D30 drives the GWAS association signal by determining whether TBC1D30 is involved in proinsulin secretion and, if so, to examine the effects of variant alleles and potential mechanisms.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Using CRISPR/Cas9 genome editing to create double-strand breaks and prime editing to install substitutions in INS1 832/13 insulinoma cells, we generated clonal cell lines with altered TBC1D30, as well as homozygous and heterozygous lines carrying the lead GWAS variant. We characterised lines by Sanger sequencing, quantitative PCR and ELISAs to measure glucose-stimulated proinsulin and insulin secretion. We also tested the effects of <i>TBC1D30</i> knockdown on proinsulin and insulin secretion in human islets. We further assessed TBC1D30’s contribution to secretory pathways by examining the effects of altered gene function on intracellular proinsulin and insulin content and insulin localisation, and by identifying potential proteins that interact with TBC1D30 using affinity purification mass spectrometry.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Compared with mock-edited cells, cell lines with reduced <i>TBC1D30</i> expression or altered Rab GTPase-activating protein (RabGAP) domain had significantly more secreted proinsulin, 1.8- and 2.6-fold more than controls, respectively. Similarly, cells expressing the variant substitution demonstrated increased proinsulin secretion. Cell lines with a partial deletion of a critical functional domain showed 1.8-fold higher expression of <i>Tbc1d30</i> and at least 2.0-fold less secreted proinsulin. Cells with altered RabGAP domain sequence also demonstrated, to a lesser extent, changes in secreted insulin levels. <i>TBC1D30</i> knockdown in human islets resulted in increased insulin secretion with no significant effect on proinsulin secretion. The effects of altered TBC1D30 on mislocalisation of insulin, intracellular proinsulin and insulin content and the identities of interacting proteins are consistent with a role for TBC1D30 in proinsulin and insulin secretion.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>These findings suggest that effects on <i>TBC1D30</i> are responsible for the GWAS signal and that TBC1D30 plays a critical role in the secretion of mature insulin.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"40 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589850","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":"Up Front","authors":"","doi":"10.1007/s00125-025-06390-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06390-x","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"27 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570351","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":"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":"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":"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":"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}