Diabetologia最新文献

{"title":"Up Front","authors":"","doi":"10.1007/s00125-024-06345-8","DOIUrl":"https://doi.org/10.1007/s00125-024-06345-8","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"31 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867318","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":"Correction: Addressing disparities in the long-term mortality risk in individuals with non-ST segment myocardial infarction (NSTEMI) by diabetes mellitus status: a nationwide cohort study.","authors":"Andrew Cole, Nicholas Weight, Shivani Misra, Julia Grapsa, Martin K Rutter, Zbigniew Siudak, Saadiq Moledina, Evangelos Kontopantelis, Kamlesh Khunti, Mamas A Mamas","doi":"10.1007/s00125-024-06337-8","DOIUrl":"https://doi.org/10.1007/s00125-024-06337-8","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863569","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":"Insulin clearance at randomisation and in response to treatment in youth with type 2 diabetes: a secondary analysis of the TODAY randomised clinical trial","authors":"Kristen J. Nadeau, Silva A. Arslanian, Fida Bacha, Sonia Caprio, Lily C. Chao, Ryan Farrell, Kara S. Hughan, Maria Rayas, Melinda Tung, Kaitlyn Cross, Laure El ghormli","doi":"10.1007/s00125-024-06327-w","DOIUrl":"https://doi.org/10.1007/s00125-024-06327-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Insulin resistance and compensatory hyperinsulinaemia are core features leading to beta cell failure in youth-onset type 2 diabetes. Insulin clearance (IC) is also a key regulator of insulin concentrations, but few data exist on IC in youth-onset type 2 diabetes. In a secondary analysis of our Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomised clinical trial, we investigated potential sex-, race-, ethnicity- and treatment-related differences in IC in youth-onset type 2 diabetes and aimed to identify metabolic phenotypes associated with IC at baseline and in response to metformin, metformin plus a lifestyle intervention, and metformin plus rosiglitazone.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A total of 640 youth aged 10–18 years with type 2 diabetes underwent fasting blood tests, anthropometric measurements, dual-energy x-ray absorptiometry to estimate subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) mass, and OGTTs longitudinally over 5 years. IC was calculated from the fasting C-peptide:insulin ratio (fasting IC) and 2 h OGTT C-peptide incremental AUC (iAUC):insulin iAUC ratio (2 h IC). Linear mixed models were used to assess covariate effects on the mean of IC over repeated time points.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Baseline fasting IC (×10<sup>−2</sup> nmol/pmol) was significantly lower in female participants than male participants (median [IQR] 0.72 [0.57–0.93] vs 0.79 [0.63–1.00], respectively; <i>p</i>=0.04) and in non-Hispanic Black participants than Hispanic and non-Hispanic White participants (median [IQR] 0.64 [0.51–0.81] vs 0.78 [0.64–1.00] vs 0.84 [0.68–1.01], respectively; <i>p</i><0.0001). Similar results were observed for 2 h IC. Lower IC most strongly correlated with higher weight over time (% change [95% CI] in IC per 5 kg increase: fasting IC –1.52 [–2.05, –0.99]; 2 h IC –3.46 [–4.05, –2.86]). Lower IC also correlated with other markers of adiposity (higher BMI and SAT mass), and markers of insulin sensitivity (higher waist:height ratio, VAT mass, VAT:SAT mass ratio, triacylglycerol concentrations, triacylglycerol:HDL-cholesterol ratio, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] concentrations, and systolic and diastolic BP, and lower HDL-cholesterol and total and high molecular weight adiponectin concentrations) over time. Beta cell function as determined from OGTTs, not insulin sensitivity or IC, was predictive of persistently elevated blood glucose levels. IC was higher with metformin+rosiglitazone than metformin alone (<i>p</i>=0.03 for fasting IC; <i>p</i>=0.02 for 2 h IC) and metformin+lifestyle (2 h IC, <i>p</i>=0.005), but not after adjusting for adiponectin (<i>p</i> value not significant for all).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>In youth with type 2 diabetes, low IC is correlated with female sex, non-","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"89 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867315","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":"Single-cell RNA sequencing identifies endothelial-derived HBEGF as promoting pancreatic beta cell proliferation in mice via the EGFR–Kmt5a–H4K20me pathway","authors":"Fengling Lai, Kaixin Zhou, Yingjie Ma, Hao Lv, Weilin Wang, Rundong Wang, Tao Xu, Rong Huang","doi":"10.1007/s00125-024-06341-y","DOIUrl":"https://doi.org/10.1007/s00125-024-06341-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Pancreatic beta cell mass is dynamically regulated in response to increased physiological and pathological demands. Understanding the mechanisms that control physiological beta cell proliferation could provide valuable insights into novel therapeutic approaches to diabetes. Here, we aimed to analyse the intracellular and extracellular signalling pathways involved in regulating the physiological proliferation of beta cells using single-cell RNA-seq (scRNA-seq) and in vitro functional assays.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Islets isolated from nulliparous mice, mice at different time points of gestation and mice at day 4 after delivery were analysed using scRNA-seq. Bioinformatics analyses of scRNA-seq data were performed to determine the heterogeneous transcriptomic characteristics of beta cells and to identify the proliferating subpopulation. CellChat was used to analyse cell–cell communication and identify the ligand–receptor pairs between beta cell subclusters as well as between non-beta cells and proliferating beta cells. In vitro functional assays were conducted in mouse and rat beta cell lines and isolated mouse primary islets to validate the role of <i>Kmt5a</i>– mono-methylation of histone H4 at lysine 20 (H4K20me) signalling and endothelial-derived heparin-binding EGF-like growth factor (HBEGF) in beta cell proliferation.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of 43,724 endocrine and non-endocrine cells within islets analysed by scRNA-seq, 15,569 beta cells were clustered into eight distinct populations, each exhibiting unique heterogeneity. A proliferating beta cell subcluster was identified that highly expressed the histone methyltransferase <i>Kmt5a</i>. Activation of <i>Kmt5a</i>–H4K20me signalling upregulated the expression of <i>Cdk1</i> and promoted beta cell proliferation. The crosstalk between endothelial cells and the proliferating beta cell subcluster, mediated by the HBEGF–EGF receptor (EGFR) ligand–receptor interaction, increased as beta cell mass expanded. HBEGF increased the expression levels of genes involved in the cell cycle and promoted beta cell proliferation by regulating the <i>Kmt5a</i>–H4K20me signalling pathway.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Our study demonstrates that, under physiological conditions, endothelial-derived HBEGF regulates beta cell proliferation through the <i>Kmt5a</i>–H4K20me signalling pathway, which may serve as a potential target to promote beta cell expansion and treat diabetes.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>The scRNA-seq and RNA-seq datasets are available from the Gene Expression Omnibus (GEO) using the accession numbers GSE278860 and GSE278861, respectively.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849179","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":"Leveraging artificial intelligence and machine learning to accelerate discovery of disease-modifying therapies in type 1 diabetes","authors":"Melanie R. Shapiro, Erin M. Tallon, Matthew E. Brown, Amanda L. Posgai, Mark A. Clements, Todd M. Brusko","doi":"10.1007/s00125-024-06339-6","DOIUrl":"https://doi.org/10.1007/s00125-024-06339-6","url":null,"abstract":"<p>Progress in developing therapies for the maintenance of endogenous insulin secretion in, or the prevention of, type 1 diabetes has been hindered by limited animal models, the length and cost of clinical trials, difficulties in identifying individuals who will progress faster to a clinical diagnosis of type 1 diabetes, and heterogeneous clinical responses in intervention trials. Classic placebo-controlled intervention trials often include monotherapies, broad participant populations and extended follow-up periods focused on clinical endpoints. While this approach remains the ‘gold standard’ of clinical research, efforts are underway to implement new approaches harnessing the power of artificial intelligence and machine learning to accelerate drug discovery and efficacy testing. Here, we review emerging approaches for repurposing agents used to treat diseases that share pathogenic pathways with type 1 diabetes and selecting synergistic combinations of drugs to maximise therapeutic efficacy. We discuss how emerging multi-omics technologies, including analysis of antigen processing and presentation to adaptive immune cells, may lead to the discovery of novel biomarkers and subsequent translation into antigen-specific immunotherapies. We also discuss the potential for using artificial intelligence to create ‘digital twin’ models that enable rapid in silico testing of personalised agents as well as dose determination. To conclude, we discuss some limitations of artificial intelligence and machine learning, including issues pertaining to model interpretability and bias, as well as the continued need for validation studies via confirmatory intervention trials.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"47 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849134","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":"Bereavement and type 1 diabetes in childhood: a register-based cohort study in Sweden","authors":"Mona-Lisa Wernroth, Beatrice Kennedy, Katja Fall, Diem Nguyen, Awad I. Smew, Per-Ola Carlsson, Bodil Svennblad, Catarina Almqvist, Tove Fall","doi":"10.1007/s00125-024-06340-z","DOIUrl":"https://doi.org/10.1007/s00125-024-06340-z","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>The potential impact of childhood bereavement—a severe psychological stressor—on childhood type 1 diabetes development remains unclear. Here, we aimed to bridge this knowledge gap and assess whether bereavement characteristics influenced any impact.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We conducted a register-based cohort study encompassing 3,598,159 children born in Sweden between 1987 and 2020. Childhood bereavement was defined as the death of a biological mother, father or sibling. Diagnosis of type 1 diabetes in childhood (&lt;18 years) was ascertained through the National Patient Register. We applied a Cox proportional hazards regression model to investigate the impact of childhood bereavement on type 1 diabetes, while adjusting for potential confounders (including parental type 1 diabetes status, country of birth and demographic characteristics).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>During follow-up, 86,226 children (2.4%) lost a family member, and 18,817 children (0.52%) were diagnosed with type 1 diabetes (median age at onset 9.1 years). We did not detect any overall association between childhood bereavement and type 1 diabetes (adjusted HR 1.04; 95% CI 0.93, 1.17). We found no influence of age at loss, cause of death, familial relationship to the deceased, and time since loss.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>In this large population-based Swedish study, we observed no evidence supporting a link between childhood bereavement and type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"112 8 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849127","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":"Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress","authors":"Wenyue Yin, Suyun Zou, Min Sha, Liangjun Sun, Haoqiang Gong, Can Xiong, Xinyue Huang, Jianan Wang, Yuhan Zhang, Xirui Li, Jin Liang, Xiaoai Chang, Shusen Wang, Dongming Su, Wanhua Guo, Yaqin Zhang, Tijun Wu, Fang Chen","doi":"10.1007/s00125-024-06343-w","DOIUrl":"https://doi.org/10.1007/s00125-024-06343-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic <i>db/db</i> mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific <i>Scd1</i> knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and <i>db/db</i> mice compared with healthy controls, which was attributed to glucotoxicity-induced <i>Scd1</i> promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA–HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"14 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841559","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":"Dose-related effects of intraduodenal quinine on plasma glucose, glucoregulatory hormones and gastric emptying of a nutrient drink, and energy intake, in men with type 2 diabetes: a double-blind, randomised, crossover study","authors":"Vida Bitarafan, Javad Anjom-Shoae, Peyman Rezaie, Penelope C. E. Fitzgerald, Kylie Lange, Michael Horowitz, Christine Feinle-Bisset","doi":"10.1007/s00125-024-06344-9","DOIUrl":"https://doi.org/10.1007/s00125-024-06344-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Quinine, when administered intraduodenally to activate bitter-taste receptors, in a dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1) and insulin, slows gastric emptying and lowers postprandial glucose in healthy people, with consequent implications for the management of type 2 diabetes; the effect of quinine on energy intake is uncertain. We have investigated the dose-related effects of quinine on postprandial blood glucose levels and energy intake in people with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Male participants with type 2 diabetes (age: 68±5 years; HbA_1c: 49.0±5.0 mmol/mol [6.7±0.4%], BMI: 30±1 kg/m²) received in two study parts (A and B, <i>n</i>=12 each), on three separate occasions each, in randomised, crossover fashion, control, or 300 mg (QHCl-300) or 600 mg (QHCl-600) quinine hydrochloride, intraduodenally 30 min before a nutrient drink (2092 kJ, 74 g carbohydrate) (part A) or a standardised buffet-lunch (part B). Both the participants and investigators performing the study procedures were blinded to the treatments. In part A, plasma glucose, GLP-1, C-peptide and glucagon were measured at baseline, for 30 min after quinine alone and for 3 h post drink. Gastric emptying of the drink was measured with a ¹³C-acetate breath test. In part B, energy intake from the buffet-lunch was quantified.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Quinine alone had no effect. Post drink, both quinine doses reduced peak plasma glucose markedly (QHCl-600 by 2.8±0.6 mmol/l) and slowed gastric emptying (all <i>p</i>&lt;0.05; <i>n</i>=12, except for gastric emptying, <i>n</i>=11). QHCl-600, but not QHCl-300, stimulated plasma GLP-1 and C-peptide modestly (both <i>p</i>&lt;0.05). Quinine did not affect energy intake.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>In type 2 diabetes, acute intraduodenal administration of quinine markedly reduces the plasma glucose response to oral carbohydrate, but does not affect energy intake. These findings support the potential use of quinine to reduce postprandial blood glucose levels in type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Trial registration</h3><p>anzctr.org.au ACTRN12620000972921/ACTRN12621000218897</p><h3 data-test=\"abstract-sub-heading\">Funding</h3><p>The study was funded by a Diabetes Australia Research Project Grant.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"47 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841616","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":"Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes","authors":"Maria J. Redondo, David Cuthbertson, Andrea K. Steck, Kevan C. Herold, Richard Oram, Mark Atkinson, Todd M. Brusko, Hemang M. Parikh, Jeffrey P. Krischer, Suna Onengut-Gumuscu, Stephen S. Rich, Jay M. Sosenko","doi":"10.1007/s00125-024-06338-7","DOIUrl":"https://doi.org/10.1007/s00125-024-06338-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking <i>HLA-DRB1*04-DQA1*03-DQB1*0302</i> (HLA-DR4-DQ8) and/or <i>HLA-DRB1*0301-DQA1*0501-DQB1*0201</i> (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; <i>n</i>=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; <i>n</i>=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; <i>n</i>=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; <i>n</i>=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A <i>p</i> value &lt;0.01 was considered statistically significant.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, <i>p</i>&lt;0.001) and DR3/DR4 (44.8%, <i>p</i>&lt;0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, <i>p</i>&lt;0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, <i>p</i>&lt;0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, <i>p</i>&lt;0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, <i>p</i>&lt;0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, <i>p</i>&lt;0.001).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"5 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816257","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":"Genetic variation in the RETN promoter, accompanied by latent sarcopenic obesity, led to insulin resistance in a Japanese cohort: the Toon Genome Study","authors":"Yosuke Ikeda, Ryoichi Kawamura, Yasuharu Tabara, Koutatsu Maruyama, Daisuke Shiokawa, Misaki Takakado, Toshimi Hadate, Yasunori Takata, Jun Ohashi, Isao Saito, Yoshihiro Ogawa, Haruhiko Osawa","doi":"10.1007/s00125-024-06322-1","DOIUrl":"https://doi.org/10.1007/s00125-024-06322-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Resistin, inducing insulin resistance, is elevated in the sera of individuals with the G-A haplotype at c.-420 C&gt;G (rs1862513) and c.-358 G&gt;A (rs3219175). This haplotype is associated with visceral obesity and low grip strength. To elucidate the hidden relationship between the G-A haplotype and insulin resistance, integration of specific phenotypes defined by body composition and 75 g OGTT would be a promising strategy.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The 803 Japanese participants (average age: 62 years), attending annual medical checkups, were evaluated every 5 years. Participants were categorised by skeletal muscle mass, visceral fat score and OGTT results. Hierarchical clustering was performed using body composition and glucose metabolism parameters. Whole blood cells from participants homozygous for the G-A or C-G haplotype (<i>n</i>=25 and 33, respectively), matched for age, sex and BMI, using propensity score matching, were used for RNA-seq, pathway analysis and RT-PCR.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Multivariate analysis showed that individuals with the G-A haplotype, when accompanied by latent skeletal muscle loss and visceral obesity (latent sarcopenic obesity), presented a pronounced deterioration in insulin resistance over a 5 year period. Cluster 2, identified using hierarchical clustering, was characterised by low skeletal muscle mass, visceral obesity and insulin resistance. This cluster, with the G-A haplotype, demonstrated deterioration in insulin resistance. RNA-seq and RT-PCR revealed altered expression of mitophagy-related genes in whole blood cells of the G-A homozygotes.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The G-A haplotype, accompanied by latent low skeletal muscle mass and visceral obesity, led to the deterioration of insulin resistance over a 5 year period in this cohort, possibly through the altered expression of mitophagy-related genes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"93 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816256","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}