Diabetologia最新文献

{"title":"Improved wound healing by dual inhibition of miR-146a-5p and miR-29a-3p supports a network action of dysregulated miRNAs in diabetic skin.","authors":"Marija Petkovic, Ermelindo C Leal, Anja E Sørensen, Per T Jørgensen, Jesper T Wengel, Rosa R Jersie-Christensen, Jesper T Troelsen, Eugenia Carvalho, Louise T Dalgaard","doi":"10.1007/s00125-025-06522-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06522-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Upregulation of miR-146a-5p and miR-29-3p is observed in chronic non-healing wounds in diabetes. Their single or combined inhibition's molecular and cellular effects were assessed in human keratinocytes (HaCaT cells) and in vivo using a mouse model of type 1 diabetes.</p><p><strong>Methods: </strong>As primary outcomes, we screened for proteome changes in HaCaT cells by LC-MS/MS after transfection with miR-146a-5p or miR-29a-3p inhibitors individually or in combination and following stimulation with TNF-α. Moreover, as a secondary outcome, we collected the data and cryopreserved and paraffin-embedded skin biopsies to estimate the tissue response to miRNA inhibition using immunofluorescence and histological analysis. Cryopreserved biopsies were also used for the LC-MS/MS proteome profiling to identify targets and cellular pathways involved in observed tissue changes.</p><p><strong>Results: </strong>We identified a panel of extracellular matrix proteins, mainly laminins, whose levels changed after transfection with miR-146a-5p or miR-29a-3p inhibitors in HaCaT cells, counteracting TNF-α effects. There was a difference in wound closure rate in vivo between the dual inhibition of miR-146a-5p and miR-29a-3p and scramble controls on day 8 (p<0.01) and day 9 (p<0.05), although not at day 10. Histological analysis at day 10 shows a loose papillary layer in the scramble inhibition group, indicating incomplete wound closure compared with dual miRNA inhibition. Moreover, the dual action of the inhibitors decreased inflammation at day 3 and day 10 (both p<0.001) and reactive oxygen species formation (p<0.01) 3 days post wounding, while increasing the angiogenesis on day 3 (p<0.01) and day 10 (p<0.001). This was consistent with cytoskeletal rearrangements and collagen alterations observed in proteome profiling.</p><p><strong>Conclusions/interpretation: </strong>These findings demonstrate that dual inhibition of miR-146a-5p and miR-29a-3p in vitro synergises in a bidirectional manner, resulting either in intermediate effects or in cancelling each other's activity for the levels of specific proteins of basal lamina that impair proliferation and cell motility, compared with the individual inhibitors. Topical supplementation of miR-146a-5p and miR-29a-3p inhibitors to diabetic mouse wounds resulted in a reduction in wound size on days 8 and 9, which correspond to the later stages of healing, but did not lead to complete healing by day 10. However, dual inhibition demonstrates favourable effects on high oxidative stress, elevated inflammation and poor angiogenesis. These effects are superior to single miRNA inhibition, suggesting that combined miRNA inhibition could be a promising therapeutic strategy for diabetic wound healing. Nevertheless, further studies in humans are warranted.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946329","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":"BMP5 signalling in beta cells and the impact on insulin secretion in the context of type 2 diabetes.","authors":"Esmée Dekker, Twan J J de Winter, Amadeo Muñoz Garcia, Natascha de Graaf, Maaike J Roodzant, Eelco J P de Koning, Françoise Carlotti","doi":"10.1007/s00125-025-06457-9","DOIUrl":"10.1007/s00125-025-06457-9","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Identifying signalling pathways that are important in pancreatic beta cell stress and failure can give insight into possible treatment options to prevent the loss of functional beta cell mass in diabetes. The bone morphogenetic protein (BMP)/SMAD family member BMP5 has been reported to be specifically expressed in human beta cells, but its function is unknown. Here we hypothesised that BMP5 plays a role in the maintenance of beta cell function.</p><p><strong>Methods: </strong>We assessed the expression of BMP5 in publicly available single-cell RNA sequencing (scRNA-seq) datasets of primary human pancreatic islet cells from donors with or without type 2 diabetes, or islets exposed to stress conditions. Human islets and EndoC-βH1 cells were exposed to recombinant BMP5 and used for gene analysis, mitochondrial respiration and glucose-stimulated insulin secretion tests. In addition, we performed lentivirus-mediated knockdown using short hairpin RNAs targeting BMP5 in human islets and EndoC-βH1 cells for gene expression and glucose-stimulated insulin secretion analyses.</p><p><strong>Results: </strong>scRNA-seq data revealed that BMP5 is the most predominantly expressed BMP ligand in beta cells. BMP5 and its target genes are upregulated in beta cells from donors with type 2 diabetes. Enhanced BMP5 signalling triggered an upregulation of stress-related genes, and a reduction in glucose-stimulated mitochondrial oxygen consumption and insulin secretion. In contrast, downregulation of BMP5 in primary human islets enhanced beta cell function, which was associated with increased expression of key beta cell genes.</p><p><strong>Conclusions/interpretation: </strong>Altogether, these findings point toward a role for BMP5 in the regulation of beta cell function.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1983-1996"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224605","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":"Glucagon-like peptide-1 receptor agonists and gastrointestinal cancer risk in individuals with type 2 diabetes.","authors":"Chia-Chih Kuo, Min-Hsiang Chuang, Chun-Hsien Li, Ya-Wen Tsai, Po-Yu Huang, Hsing-Tao Kuo, Chih-Cheng Lai","doi":"10.1007/s00125-025-06453-z","DOIUrl":"10.1007/s00125-025-06453-z","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Although benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been demonstrated in treatment of type 2 diabetes and weight management, their potential role in cancer prevention remains inadequately explored.</p><p><strong>Methods: </strong>Using the TriNetX Research Network, we conducted a retrospective cohort study comparing new users of GLP-1RAs with users of other glucose-lowering medications. Propensity score matching was performed for demographic factors, socioeconomic factors, family history, lifestyle factors and cancer risk factors. The primary outcome was the incidence of obesity-related gastrointestinal cancers, and secondary outcomes were the incidence of individual cancer types.</p><p><strong>Results: </strong>Using adjusted HRs (aHRs), GLP-1RA use was found to be associated with a significantly lower risk of overall gastrointestinal cancer compared with all other glucose-lowering medications (insulin: aHR 0.29; 95% CI 0.23, 0.37; metformin: aHR 0.84; 95% CI 0.71, 0.99; sulfonylureas: aHR 0.71; 95% CI 0.62, 0.80; thiazolidinediones: aHR 0.86; 95% CI 0.74, 0.99; dipeptidyl peptidase-4 inhibitors: aHR 0.80; 95% CI 0.70, 0.91; sodium-glucose cotransporter-2 inhibitors: aHR 0.80; 95% CI 0.68, 0.96). The protective effect was most pronounced compared with insulin therapy, with significant risk reductions across all individual cancers.</p><p><strong>Conclusions/interpretation: </strong>GLP-1RA use is associated with a reduced risk of gastrointestinal cancers in individuals with type 2 diabetes. These findings suggest potential cancer-protective benefits of GLP-1RAs beyond their established roles in glycaemic management and weight reduction.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1924-1936"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224606","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":"Glucose 6-phosphate dehydrogenase deficiency and Southeast Asian-specific mutations lower HbA_1c levels in a Thai population: implications for diabetes diagnosis.","authors":"Punchalee Mungkalasut, Makamas Chanda, Watcharapong Jugnam-Ang, Poonlarp Cheepsunthorn, Poranee Ganokroj, Chalisa L Cheepsunthorn","doi":"10.1007/s00125-025-06523-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06523-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims/hypothesis: &lt;/strong&gt;Glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common inherited enzymopathy, can affect HbA&lt;sub&gt;1c&lt;/sub&gt; levels and the diagnosis of type 2 diabetes. This cross-sectional study aimed to investigate the association between G6PD deficiency, its common mutations (G6PD Viangchan&lt;sup&gt;G871A&lt;/sup&gt;, G6PD Mahidol&lt;sup&gt;G487A&lt;/sup&gt;) and HbA&lt;sub&gt;1c&lt;/sub&gt; levels in a Thai cohort.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Blood samples from 1007 healthy hospital staff were collected during annual health checkups. Individuals with diabetes, diabetes medication use and conditions affecting erythrocyte turnover were excluded. HbA&lt;sub&gt;1c&lt;/sub&gt; levels were measured by enzymatic assay and HPLC, while fasting plasma glucose (FPG) and haematological variables were obtained from checkup records. Fructosamine levels and G6PD activity (classified as deficiency, intermediate, normal) were measured by spectrophotometric assay. Genotyping was performed using TaqMan SNP, PCR-Restriction Fragment Length Polymorphism (RFLP) and Sanger sequencing. Prediabetes and diabetes were diagnosed based on two abnormal results from FPG and HbA&lt;sub&gt;1c&lt;/sub&gt; at the same time, following the modified ADA criteria. Optimal HbA&lt;sub&gt;1c&lt;/sub&gt; cutoffs were determined using receiver operating characteristic curve analysis with bootstrapping in RStudio, optimising Youden's index and the harmonic mean of sensitivity and specificity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;HbA&lt;sub&gt;1c&lt;/sub&gt; levels were significantly lower in individuals with G6PD deficiency (25.68 mmol/mol [4.50%] by enzymatic assay; 27.33 mmol/mol [4.65%] by HPLC; n=28; p&lt;0.001) compared with those with normal G6PD levels (34.05 mmol/mol [5.27%] by enzymatic assay; 36.61 mmol/mol [5.50%] by HPLC; n=492). Similarly, individuals with G6PD Viangchan&lt;sup&gt;G871A&lt;/sup&gt; (29.46 mmol/mol [4.85%] by enzymatic assay; 31.15 mmol/mol [5.00%] by HPLC; n=52; p&lt;0.001) and G6PD Mahidol&lt;sup&gt;G487A&lt;/sup&gt; (28.63 mmol/mol [4.77%] by enzymatic assay; 31.15 mmol/mol [5.00%] by HPLC; n=15; p&lt;0.001) had significantly lower HbA&lt;sub&gt;1c&lt;/sub&gt; levels. HbA&lt;sub&gt;1c&lt;/sub&gt; levels positively correlated with G6PD activity (r=0.208, p&lt;0.001 by enzymatic assay; r=0.211, p&lt;0.001 by HPLC). The optimal HbA&lt;sub&gt;1c&lt;/sub&gt; cutoffs for predicting prediabetes in participants with G6PD mutation were 33 to &lt;42 mmol/mol (5.2% to &lt;6.0%) by enzymatic assay (sensitivity 70%; specificity 88.64%; accuracy 86.74%) and 34 to &lt;43 mmol/mol (5.3% to &lt;6.1%) measured by HPLC (sensitivity 72.73%; specificity 86.21%; accuracy 84.70%). For diabetes, the optimal cutoffs were ≥42 mmol/mol (≥6.0%) by enzymatic assay (sensitivity 100%; specificity 97.92%; accuracy 97.96%) and ≥43 mmol/mol (≥6.1%) by HPLC (sensitivity 100%; specificity 96.88%; accuracy 96.94%). Using the mutation-specific HbA&lt;sub&gt;1c&lt;/sub&gt; cutoffs resulted in the proportion of individuals being diagnosed with diabetes remaining the same but the proportion diagnosed with prediabetes rose from 8.2% (ADA crite","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946227","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":"61^st EASD Annual Meeting of the European Association for the Study of Diabetes : Vienna, Austria, 15 - 19 September 2025.","authors":"","doi":"10.1007/s00125-025-06497-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06497-1","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"68 Suppl 1","pages":"1-754"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946312","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":"Differences in biopsy-proven diabetic kidney disease in individuals from Polynesia vs mainland France: a retrospective cohort study.","authors":"Mathis Michel, Adrien Flahault, Vladimir Coliche, Asma Alla, Pascale Testevuide, Ronan Delaval, Christos Chatziantoniou, Luc Frimat, Hervé Sartelet, Raphaël Kormann","doi":"10.1007/s00125-025-06471-x","DOIUrl":"10.1007/s00125-025-06471-x","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Māori, a Polynesian population, have an earlier age of onset of type 2 diabetes and higher risk of diabetes-related complications compared with New Zealanders of European descent, and an increased incident rate ratio for end stage kidney disease. No data are available regarding the evolutive characteristics of diabetic kidney disease (DKD) in individuals living in French Polynesia.</p><p><strong>Methods: </strong>We aimed to compare the retrospectively collected characteristics and outcomes of 92 and 63 individuals from French Polynesia and mainland France, respectively, presenting type 2 diabetes and biopsy-confirmed DKD, focusing on kidney survival, analysis of the Renal Pathology Society (RPS) score and participant survival.</p><p><strong>Results: </strong>At the time of biopsy, Polynesian participants were younger (56.5 vs 66.9 years, p<0.001) and had a higher urinary protein/creatinine ratio (uPCR) (792 vs 452 mg/mmol, p<0.001), despite similar anti-proteinuria treatments and eGFR, and shorter time since diabetes diagnosis (8.7 vs 11.1 years, p=0.008). Polynesian participants had a more severe RPS classification (p<0.001). Median time from biopsy to kidney failure with replacement therapy was 1.59 years in the Polynesian population and 6.06 years in the mainland French population, accounting for death as a competing risk. Polynesian participants were at a higher risk of end stage kidney disease after adjustment for uPCR, eGFR, BMI and age at baseline (HR 2.45 [95% CI 1.23, 4.88]). In a clinical and histological reduced multivariable model, Polynesian origin, higher uPCR, lower eGFR, more severe RPS classification and presence of chronic vascular lesions were all independently associated with poorer kidney survival. The RPS classification was more strongly associated with kidney survival in participants from Polynesia (p value for interaction, 0.048), while a higher uPCR was more strongly associated with kidney survival in participants from mainland France (p value for interaction, <0.001). Older age and Polynesian origin were also independent risk factors for death.</p><p><strong>Conclusions/interpretation: </strong>Starting at an earlier age, the evolutive course of DKD is also more severe in individuals from French Polynesia than from mainland Western Europe. Strong differences in clinical, histological and predictive outcomes of diabetic nephropathy were found in these different ethnic groups.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1947-1957"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511680","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":"Comparative effectiveness of alternative second-line oral glucose-lowering therapies for type 2 diabetes: a precision medicine approach applied to routine data.","authors":"Stephen O'Neill, Patrick Bidulka, David G Lugo-Palacios, Orlagh Carroll, Ignacio Leiva-Escobar, Richard Silverwood, Andrew Briggs, Amanda I Adler, Kamlesh Khunti, Richard Grieve","doi":"10.1007/s00125-025-06447-x","DOIUrl":"10.1007/s00125-025-06447-x","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>National clinical guidelines recommend that second-line treatment for type 2 diabetes mellitus is chosen according to individuals' characteristics but there is limited evidence available to inform this choice. This paper's aim is to compare the effects on HbA_1c of sulfonylureas (SU), dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose cotransporter-2 inhibitors (SGLT2i) added to metformin as second-line oral glucose-lowering treatments according to an individual's age, baseline HbA_1c and presence of multiple long-term conditions (MLTCs).</p><p><strong>Methods: </strong>We accessed primary care-hospital linked data for 41,790 individuals from the Clinical Practice Research Datalink (CPRD) in England who initiated second-line treatment after metformin between 2015 and 2021. We combined target trial emulation with instrumental variable analysis to reduce the risk of confounding. The outcome was change in HbA_1c between baseline and 1 year follow-up. We reported results stratified by age (18-49 years, 50-69 years and ≥70 years), baseline HbA_1c (<67 mmol/mol [<8.3%], 67-77 mmol/mol [8.3-9.2%] and >77 mmol/mol [>9.2%]) and presence of MLTCs.</p><p><strong>Results: </strong>The mean (95% CI) difference in HbA_1c change for SGLT2i vs SU was larger for people aged 18-49 years (-5.74 mmol/mol [-7.47, -4.01]) (-0.5% [-0.7, -0.4]) than for those aged 50-69 years (-4.03 mmol/mol [-5.61, -2.44]) (-0.4% [-0.5, -0.2]) and for those aged 70 years or over (-2.68 mmol/mol [-4.50, -0.86]) (-0.3% [-0.4, -0.07]). The mean (95% CI) difference in HbA_1c change for SGLT2i vs DPP4i was -5.80 mmol/mol (-7.60, -4.00) (-0.5% [-0.7, -0.4]) for those aged 18-49 years, -4.13 mmol/mol (-5.82, -2.45) (-0.4% [-0.5, -0.2]) for those aged 50-69 years and -3.13 mmol/mol (-5.01, -1.24) (-0.3% [-0.4, -0.1]) for those aged ≥70 years. The mean difference (improvement) in HbA_1c was similar across subgroups defined by baseline HbA_1c or presence of MLTCs. For SGLT2i vs SU, the mean (95% CI) difference was -5.37 mmol/mol (-7.13, -3.62) (-0.5% [-0.6, -0.3]) for people without MLTC and -3.72 mmol/mol (-5.34, -2.10]) (-0.3% [-0.5, -0.2]) for people with MLTC. For SGLT2i vs DPP4i the corresponding estimated differences (95% CI) were -5.44 mmol/mol (-7.27, -3.61) (-0.5% [-0.7, -0.3]) for those without MLTC and -3.93 mmol/mol (-5.64, -2.21) (-0.3% [-0.5, -0.2]) for those with MLTC.</p><p><strong>Conclusions/interpretation: </strong>Second-line treatment with SGLT2i is more effective than SU or DPP4i in reducing HbA_1c across subgroups of people defined by age, baseline HbA_1c and presence of MLTCs. Our evidence complements RCTs in using routinely available information on demographic characteristics, biomarkers and comorbidities to inform an individualised approach.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1908-1923"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191631","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":"ApoC-III and ectopic fat accumulation in individuals with type 2 diabetes: an exploratory analysis from the MEDEA randomised controlled study.","authors":"Giuseppina Costabile, Dominic Salamone, Giuseppe Della Pepa, Roberta Testa, Marilena Vitale, Valentina Brancato, Marco Salvatore, Andrea Soricelli, Giovanni Annuzzi, Angela A Rivellese, Lutgarda Bozzetto","doi":"10.1007/s00125-025-06464-w","DOIUrl":"10.1007/s00125-025-06464-w","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>We aimed to investigate the effects of an isoenergetic multifactorial diet, previously shown to reduce liver and pancreatic fat content, compared with a monounsaturated fatty acid (MUFA)-rich diet, on plasma apolipoprotein C-III (ApoC-III) levels and their relationship with ectopic fat and beta cell function in people with type 2 diabetes.</p><p><strong>Methods: </strong>In this randomised controlled, parallel group study, 36 individuals with type 2 diabetes (20 men, 16 women), aged 35-75 years, were assigned to an 8 week intervention with either an isoenergetic MUFA-rich diet (n=16) or a multifactorial diet rich in MUFA, polyunsaturated fats, fibre, polyphenols and vitamins (n=20). Fasting and postprandial (3 h test meal reflecting the assigned diet) plasma glucose, insulin and ApoC-III concentrations were measured before and after the intervention. Beta cell function was assessed as the insulin-to-glucose total AUC ratio. Liver and pancreatic fat content were quantified using magnetic resonance techniques.</p><p><strong>Results: </strong>Compared with the MUFA diet, the multifactorial diet led to a decrease (8 week minus baseline) in fasting ApoC-III levels (-0.006 ± 0.040 vs +0.007 ± 0.048 g/l, p=0.070) and postprandial ApoC-III AUC (-1.34 ± 6.01 vs +1.60 ± 5.56 g/l × 180 min, p=0.043). Regardless of dietary intervention, changes in fasting ApoC-III positively correlated with changes in liver fat (r=0.357, p=0.032) and pancreatic fat (r=0.385, p=0.020). Both fasting and postprandial ApoC-III changes were inversely correlated with beta cell function (r=-0.384, p=0.026; r=-0.402, p=0.018, respectively).</p><p><strong>Conclusions/interpretation: </strong>A multifactorial diet significantly reduced plasma ApoC-III levels in individuals with type 2 diabetes. Independent of dietary intervention, lower ApoC-III levels were associated with reduced liver and pancreatic fat accumulation and improved beta cell function.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov NCT03380416.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2036-2041"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224604","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 heterogeneity of type 1 diabetes: implications for pathogenesis, prevention, and treatment-2024 Diabetes, Diabetes Care, and Diabetologia Expert Forum.","authors":"Carmella Evans-Molina, Yuval Dor, Åke Lernmark, Chantal Mathieu, Jeffrey R Millman, Raghavendra G Mirmira, Flemming Pociot, Maria J Redondo, Stephen S Rich, Sarah J Richardson, Michael R Rickels, R David Leslie","doi":"10.1007/s00125-025-06462-y","DOIUrl":"10.1007/s00125-025-06462-y","url":null,"abstract":"<p><p>This article summarises the current understanding of the heterogeneity of type 1 diabetes from a June 2024 international Expert Forum organised by the editors of Diabetes, Diabetes Care, and Diabetologia. The Forum reviewed key factors contributing to the development and progression of type 1 diabetes and outlined specific, high-priority research questions. Knowledge gaps were identified and, notably, opportunities to harness disease heterogeneity to develop personalised therapies were outlined. Herein, we summarise our discussions and review the heterogeneity of genetic risk and immunologic and metabolic phenotypes that influence and characterise type 1 diabetes progression (presented as a palette of risk factors). We discuss how these age-related factors determine disease aggressiveness (along gradients) and describe how variable immunogenetic pathways aggregate (into networks) to affect beta cell and other pancreatic pathologies to cause clinical disease at different ages and with variable severity (described as disease-related thresholds). Heterogeneity of pathogenesis and clinical severity opens avenues to prevention and intervention, including the potential of disease-modifying immunotherapy and islet cell replacement. We conclude with a call for (1) continued research to identify more factors contributing to the disease, both overall and in specific subgroups; (2) investigations focusing on both individuals who surpass metabolic and immune thresholds and develop diabetes and those who remain disease free with the same level of immunogenetic risk; and (3) efforts to identify where the current type 1 diabetes staging system may fall short and determine how it can be improved to capture and leverage heterogeneity in prevention and intervention strategies.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1859-1878"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741612","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":"Prevention of diabetic ketoacidosis in relatives screened for islet autoantibodies and followed up in the TrialNet Pathway to Prevention study at a single institution in Italy.","authors":"Sabina Martinenghi, Aurora Merolla, Pauline Grogan, Eleonora Bianconi, Elisa Senni, Anastasia Goncharova, Francesco Massara, Francesca Ragogna, Elena Bazzigaluppi, Matteo R Pastore, Riccardo Bonfanti, Emanuele Bosi","doi":"10.1007/s00125-025-06461-z","DOIUrl":"10.1007/s00125-025-06461-z","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Screening for islet autoantibodies is an effective method for identifying individuals with pre-symptomatic (stage 1 and 2) type 1 diabetes. This approach offers a valuable opportunity for education and monitoring, which can help to reduce the severity of clinical manifestations at clinical onset (stage 3), including diabetic ketoacidosis. The aim of the study was to evaluate the progression to stage 3 and the incidence of diabetic ketoacidosis in relatives of individuals with type 1 diabetes screened and followed up at a single institution in Italy.</p><p><strong>Methods: </strong>This was a single-centre observational study conducted at San Raffaele Hospital, Milan, Italy, within the international multisite TrialNet Natural History Study-Pathway to Prevention. First-degree (aged 1-45 years) and second-degree (aged 1-20 years) relatives were screened primarily for GADA, IAA and IA-2A. In the event of a positive result, subsequent testing was conducted for ICA and ZnT8A. Periodic autoantibody testing, metabolic monitoring and educational support were offered to all autoantibody-positive participants. Participants were screened between July 2005 and February 2020, with the latest update obtained between January 2023 and June 2024.</p><p><strong>Results: </strong>In total, 4046 relatives were screened at a median (IQR) age of 17.6 (7.9-38.0) years. At first screening, 4.9% were found to be positive, with 3.1% having a single autoantibody and 1.8% multiple autoantibodies. Follow-up data were available for 78.5% of the participants, with a median (IQR) follow-up time of 9.9 (6.5-13.5) years. Progression to stage 3 was observed in 51 (1.6%) participants. Disease onset occurred in 0.4% of autoantibody-negative, 6.5% of single-positive and 43.1% of multiple-positive participants after a median (IQR) time of 7.8 (5.4-10.4), 7.9 (2.1-11.8) and 2.9 (0.9-6.5) years, respectively (p=0.012). The Kaplan-Meier survival free of clinical diabetes at 15 years was 99.5% (95% CI 99.1, 99.7), 87.3% (95% CI 74.4, 94.0) and 45.9% (95% CI 31.1, 59.6), respectively (p<0.001). At the time of disease onset, no occurrences of diabetic ketoacidosis were documented. Median (IQR) HbA_1c was 64 (52-86) mmol/mol (8.0 [6.9-10.0]%) and median (IQR) venous pH at onset was 7.37 (7.35-7.39). Hospitalisation occurred in 22 paediatric participants, as part of standard practice for newly diagnosed patients at our institution aiming to provide disease education and insulin therapy optimisation.</p><p><strong>Conclusions/interpretation: </strong>The early identification of individuals at risk for type 1 diabetes through a single-centre approach, combining autoantibody screening and regular monitoring, completely prevented diabetes-associated ketoacidosis at disease onset in relatives of individuals with type 1 diabetes.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov NCT00097292.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1889-1898"},"PeriodicalIF":10.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172930","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}