Diabetologia最新文献

{"title":"Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice.","authors":"Megan Beetch,Eunice Oribamise,Seokwon Jo,Briana Clifton,Sarah Larson,Alex Hausmann,Alicia Wong,Brian Akhaphong,Elizabeth Morgan,Emilyn U Alejandro","doi":"10.1007/s00125-025-06542-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06542-z","url":null,"abstract":"AIMS/HYPOTHESISFetal programming of metabolic health is influenced by the in utero environment. The placental nutrient sensor mechanistic target of rapamycin (mTOR) is implicated in regulating fetal growth and programming of offspring metabolic health, but the mechanisms are unknown.METHODSUsing a placental mTOR deficiency model to induce fetal growth restriction (FGR), we investigated mTOR-modulated placental mitochondrial function, nutrient transport and developmental programming of pancreatic beta cells, which are exquisitely sensitive to nutrient levels in utero.RESULTSWe found defects in placental mitochondria function and morphology that were specific to placentas of mTOR knockout (mTORKO) mice. Despite smaller placentas and FGR in both sexes, nutrient transporter expression and leucine flux were paradoxically increased in female mTORKO placentas. Female fetuses exposed to placental mTOR deficiency (mTORKOpl) displayed significantly reduced circulating insulin without neonatal perturbations in insulin secretion. However, average beta cell size and proliferation were increased in mTORKOpl female fetuses, possibly driven by system A (SNAT) amino acids, suggesting an immature beta cell phenotype. Adult mTORKOpl female offspring exhibit increased susceptibility to diet-induced obesity, insulin resistance and inability to mount a beta cell mass response to a hypernutrient environment.CONCLUSIONS/INTERPRETATIONOur novel in vivo model of direct placental mTOR-driven FGR provides strong evidence linking placental dysfunction and amino acid transport to proper programming of beta cells in early life.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"82 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246617","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":"Methodological considerations for interpreting long-term statin use and diabetes incidence.","authors":"Chenxi Ma,Han Zeng","doi":"10.1007/s00125-025-06568-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06568-3","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"12 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246934","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":"DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease.","authors":"Lucy Sinke,Thomas Delerue,Rory Wilson,Xueling Lu,Yujing Xia,Ricardo Costeira,M Kamal Nasr,Marian Beekman,Lude Franke,Alexandra Zhernakova,Jingyuan Fu,Christian Gieger,Christian Herder,Wolfgang Koenig,Annette Peters,José M Ordovas,Marcus Dörr,Hans J Grabe,Matthias Nauck,Jordana T Bell,Alexander Teumer,Harold Snieder,Melanie Waldenberger,P Eline Slagboom,Bastiaan T Heijmans","doi":"10.1007/s00125-025-06549-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06549-6","url":null,"abstract":"AIMS/HYPOTHESISDespite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.METHODSWe conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.RESULTSOur findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.CONCLUSIONS/INTERPRETATIONTaken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"10 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240892","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":"Acute brain responses to hypoglycaemia and hyperglycaemia in adolescents with type 1 diabetes.","authors":"Michele A O'Connell,Richard Beare,Betty Messazos,Elisabeth A Northam,Myles Clarkson Fletcher,Marc L Seal,Fergus J Cameron","doi":"10.1007/s00125-025-06548-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06548-7","url":null,"abstract":"AIMS/HYPOTHESISThe physiological basis of the well-described neurocognitive decrements and structural brain changes in type 1 diabetes is unclear. We aimed to assess differences in cerebral blood flow (CBF) and neural activity before, during and after induced hypoglycaemia and hyperglycaemia in adolescents with type 1 diabetes.METHODSAn observational hyperinsulinaemic clamp and functional MRI study was conducted. Parallel study arms assessed participants during three consecutive glycaemic phases: baseline euglycaemia (5.0±0.5 mmol/l), either hypoglycaemia (2.6±0.5 mmol/l) or hyperglycaemia (18-20 mmol/l), and euglycaemic recovery (5.0±0.5 mmol/l). During each glycaemic phase, CBF/brain perfusion was measured with arterial spin labelling and brain neural activity was measured with fractional amplitude of low frequency fluctuations. Comparative analyses were based on the seven regional functional parcellation areas (networks) of the cerebral cortex. A Bayesian multi-level regression model was employed to test regional differences in CBF and brain neural activity between the various glycaemic conditions.RESULTSTwenty adolescents with type 1 diabetes participated: ten in each of the hypoglycaemic and hyperglycaemic study arms. Relative to baseline, acute hypoglycaemia was associated with substantially reduced brain neural activity (six of seven functional networks); no significant differences in CBF were evident. By contrast, acute hyperglycaemia was associated with widespread increases in brain activity (five of seven functional networks) and decreased perfusion (six of seven functional networks). Hypoglycaemia and hyperglycaemia had symmetrically opposite effects on brain neural activity in the visual, ventral attention, dorsal attention, frontoparietal and default networks. Recovery from both hypoglycaemia and hyperglycaemia was associated with persistent alterations in both brain perfusion and neural activity, relative to baseline, despite >45 min of sustained euglycaemia.CONCLUSIONS/INTERPRETATIONAcross widespread areas of the brain, both brain perfusion and neural metabolic activity are altered by acute hypoglycaemia and hyperglycaemia in adolescents with type 1 diabetes. Recovery from glycaemic extremes is delayed. These findings offer important further insights into the acute cerebral responses to abnormal blood glucose levels.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240901","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":"Beyond pain relief: the effects of chronic opioid use on brain structure and function in diabetic neuropathy-a multimodal neuroimaging study.","authors":"Gordon Sloan,Kevin Teh,Marni Greig,Pallai Shillo,Sharon Caunt,Iain D Wilkinson,Solomon Tesfaye,Dinesh Selvarajah","doi":"10.1007/s00125-025-06529-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06529-w","url":null,"abstract":"AIMS/HYPOTHESISDespite being commonly prescribed to treat painful diabetic peripheral neuropathy (DPN), the impact on the brain of long-term opioid use as analgesia is unknown. The aim of this study was to determine the structural and functional brain alterations associated with prescription opioid use in a large cohort of people with painful DPN.METHODSA total of 82 patients with diabetes were enrolled: 57 with painful DPN (18 with long-term opioid prescription [O+ individuals] and 39 who were not prescribed opioids [O- individuals]) and a control group of 25 patients with diabetes but without DPN (no DPN) matched for age (± 2 years), sex and type of diabetes. All participants underwent detailed clinical/neurophysiological assessment and brain MRI at 3 T, and a subset (14 in each group, n=42) also underwent resting-state functional MRI.RESULTSO+ individuals had greater caudate volume (ANOVA, p=0.03) compared with O- individuals (p=0.03) and those with no DPN (p=0.01). Functional connectivity was lower between the caudate and thalamus (r β = -0.24, seed-level correction -3.9, pFDR ≤0.05) in O+ individuals compared to those with no DPN. Moreover, seed-to-voxel analysis using caudate as the seed showed a significantly lower functional connectivity in O+ individuals compared with O- individuals in a cluster encompassing the superior frontal gyri bilaterally.CONCLUSIONS/INTERPRETATIONWe demonstrate that disruption of dopaminergic pathways occurs within the brain when opioids are used for analgesic purposes for painful DPN, which may reflect alterations in reward systems. This study has important clinical implications, as the measures of dopaminergic pathways found in this study may represent neuroimaging biomarkers that could be used to diagnose and monitor the negative consequences of prescription opioid use.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"20 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229138","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":"Reassessing retinopathy risk with tirzepatide therapy.","authors":"Na Zhang,Wenzhan Wang,Guangming Wan","doi":"10.1007/s00125-025-06566-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06566-5","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"2 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229137","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":"No evidence that tirzepatide can worsen diabetic retinopathy. Reply to Fadini GP [letter]. Reassessing retinopathy risk with tirzepatide therapy. Reply to Zhang N, Wang W, Wan G [letter].","authors":"Adam J Buckley,Garry D Tan,Marta Gruszka-Goh,Peter H Scanlon,Imran Ansari,Sara G I Suliman","doi":"10.1007/s00125-025-06562-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06562-9","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"32 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229136","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":"No evidence that tirzepatide can worsen diabetic retinopathy.","authors":"Gian Paolo Fadini","doi":"10.1007/s00125-025-06564-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06564-7","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"27 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229139","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":"Methodological considerations for interpreting long-term statin use and diabetes incidence. Reply to Ma C, Zeng H [letter].","authors":"Yiwen Zhang,Edward L Giovannucci,Dong D Wang","doi":"10.1007/s00125-025-06569-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06569-2","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"126 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209138","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":"HLA-focused type 1 diabetes genetic risk prediction in populations of diverse ancestry.","authors":"Dominika A Michalek, Courtney Tern, Catherine C Robertson, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich","doi":"10.1007/s00125-025-06563-8","DOIUrl":"10.1007/s00125-025-06563-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Type 1 diabetes is characterised by the destruction of pancreatic beta cells. Genetic factors account for approximately 50% of the total risk, with variants in the HLA region contributing to half of this genetic risk. Research has historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRS_HLA) using SNPs or HLA alleles from four ancestry groups (admixed African [AFR; T1D GRS_HLA-AFR], admixed American [AMR; T1D GRS_HLA-AMR], European [EUR; T1D GRS_HLA-EUR] and Finnish [FIN; T1D GRS_HLA-FIN]). We also developed an across-ancestry GRS (ALL; T1D GRS_HLA-ALL). We assessed the performance of the GRS in each population to determine the transferability of constructed scores.</p><p><strong>Methods: </strong>A total of 41,689 samples and 13,695 SNPs in the HLA region were genotyped, with HLA alleles imputed using the HLA-TAPAS multi-ethnic reference panel. Conditionally independent SNPs and HLA alleles associated with type 1 diabetes were identified in each population group to construct T1D GRS_HLA models. Generated T1D GRS_HLA models were used to predict HLA-focused type 1 diabetes genetic risk across four ancestry groups. The performance of each T1D GRS_HLA model was assessed using receiver operating characteristic (ROC) AUCs, and compared statistically.</p><p><strong>Results: </strong>Each T1D GRS_HLA model included a different number of conditionally independent HLA-region SNPs (AFR, n=5; AMR, n=3; EUR, n=38; FIN, n=6; ALL, n=36) and HLA alleles (AFR, n=6; AMR, n=5; EUR, n=40; FIN, n=8; ALL, n=41). The ROC AUC values for the T1D GRS_HLA from SNPs or HLA alleles were similar, and ranged from 0.73 (T1D GRS_{HLA-allele-AMR} applied to FIN) to 0.88 (T1D GRS_{HLA-allele-EUR} applied to EUR). The ROC AUC using the combined set of conditionally independent SNPs (T1D GRS_HLA-SNP-ALL) or HLA alleles (T1D GRS_{HLA-allele-ALL}) performed uniformly well across all ancestry groups, with values ranging from 0.82 to 0.88 for SNPs and 0.80 to 0.87 for HLA alleles.</p><p><strong>Conclusions/interpretation: </strong>T1D GRS_HLA models derived from SNPs performed equivalently to those derived from HLA alleles across ancestries. In addition, T1D GRS_HLA-SNP-ALL and GRS_{HLA-allele-ALL} models had consistently high ROC AUC values when applied across ancestry groups. Larger studies in more diverse populations are needed to better assess the transferability of T1D GRS_HLA across ancestries.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205633","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}