Pub Date : 2025-12-08DOI: 10.1007/s00125-025-06613-1
Riitta Veijola,Roy N Tamura,Joanna L Clasen,Helena Elding Larsson,Katharina Warncke,Andrea K Steck,Michael J Haller,Berglind Jonsdottir,Beena Akolkar,William A Hagopian,Marian J Rewers,Jin-Xiong She,Anette-Gabriele Ziegler,Jeffrey P Krischer,Jorma Toppari,
AIMS/HYPOTHESISThe aetiology of type 1 diabetes remains elusive. Family history of type 1 diabetes increases the disease risk but the role of other autoimmune diseases or type 2 diabetes in the family are unclear. Here, we aimed to analyse the effect of family history of diabetes and autoimmune diseases on development of islet autoimmunity and progression to type 1 diabetes.METHODSThe Environmental Determinants of Diabetes in the Young (TEDDY) study is a prospective observational cohort study of children recruited as newborns in 2004-2010 at clinical centres in Finland, Germany, Sweden and the USA. A total of 8676 children with high-risk HLA-DR-DQ genotype for type 1 diabetes fulfilled the eligibility criteria for regular follow-up. Questionnaire-based family history of all types of diabetes and autoimmune diseases among first- and second-degree relatives (FDRs and SDRs; data available for 8558 and 7479 children, respectively) was collected. The main outcomes were development of islet autoimmunity and progression from autoimmunity to type 1 diabetes. Data until 31 January 2016 were analysed.RESULTSPersistent islet autoantibodies were found in 669 children and type 1 diabetes in 233 children (45% and 46% female sex, respectively). The median follow-up time after seroconversion was 6.5 years (IQR 3.3-8.5). Having an FDR with type 1 diabetes increased the child's risk of islet autoimmunity (HR 2.2 [95% CI 1.8, 2.8]; p<0.001), particularly if the father or sibling had type 1 diabetes. Islet autoimmunity was also associated with family history of type 1 diabetes in an SDR when participants having an FDR with type 1 diabetes were excluded from the analysis (HR 1.4 [95% CI 1.1, 1.8]; p=0.017). Notably, progression from autoantibody positivity to type 1 diabetes was significantly delayed in children having type 2 diabetes in an SDR (HR 0.61 [95% CI 0.44, 0.86]; p=0.004). Islet autoimmunity or progression to type 1 diabetes were not associated with other types of diabetes or autoimmune diseases in the family.CONCLUSIONS/INTERPRETATIONFamily history of diabetes is differentially associated with development of islet autoimmunity and progression to type 1 diabetes. The contribution made by familial, genetic and environmental factors to the two phases of the disease pathogenesis deserves distinct analyses.DATA AVAILABILITYData reported here can be obtained by request at the NIDDK Central Repository website, Resources for Research (R4R), https://repository.niddk.nih.gov/ .
目的/假设1型糖尿病的病因仍然难以捉摸。1型糖尿病家族史增加患病风险，但其他自身免疫性疾病或2型糖尿病在家族中的作用尚不清楚。在这里，我们的目的是分析糖尿病家族史和自身免疫性疾病对胰岛自身免疫发展和发展为1型糖尿病的影响。年幼期糖尿病的环境决定因素（TEDDY）研究是一项前瞻性观察队列研究，在芬兰、德国、瑞典和美国的临床中心招募了2004-2010年的新生儿。共有8676例1型糖尿病高危HLA-DR-DQ基因型患儿符合常规随访标准。收集了所有类型糖尿病和自身免疫性疾病的家族史（FDRs和SDRs，可获得数据分别为8558和7479名儿童）。主要结局是胰岛自身免疫的发展和从自身免疫到1型糖尿病的进展。分析截至2016年1月31日的数据。结果669例儿童检测到持久性胰岛自身抗体，233例1型糖尿病儿童检测到持久性胰岛自身抗体，其中女性占45%，女性占46%。血清转换后的中位随访时间为6.5年（IQR 3.3-8.5）。患有1型糖尿病的FDR增加了儿童胰岛自身免疫的风险（HR 2.2 [95% CI 1.8, 2.8]; p<0.001），特别是如果父亲或兄弟姐妹患有1型糖尿病。当FDR合并1型糖尿病的参与者被排除在分析之外时，胰岛自身免疫也与SDR患者的1型糖尿病家族史相关（风险比为1.4 [95% CI 1.1, 1.8]; p=0.017）。值得注意的是，在SDR中，患有2型糖尿病的儿童从自身抗体阳性到1型糖尿病的进展明显延迟（HR 0.61 [95% CI 0.44, 0.86]; p=0.004）。胰岛自身免疫或进展为1型糖尿病与家族中其他类型的糖尿病或自身免疫性疾病无关。结论/解释糖尿病家族史与胰岛自身免疫的发展和1型糖尿病的进展存在差异相关。家族性、遗传和环境因素对疾病发病的两个阶段的贡献值得进行不同的分析。数据可用性这里报告的数据可以通过NIDDK中央存储库网站，研究资源（R4R）， https://repository.niddk.nih.gov/请求获得。
{"title":"Family history of type 2 diabetes delays development of type 1 diabetes in TEDDY children with islet autoimmunity.","authors":"Riitta Veijola,Roy N Tamura,Joanna L Clasen,Helena Elding Larsson,Katharina Warncke,Andrea K Steck,Michael J Haller,Berglind Jonsdottir,Beena Akolkar,William A Hagopian,Marian J Rewers,Jin-Xiong She,Anette-Gabriele Ziegler,Jeffrey P Krischer,Jorma Toppari, ","doi":"10.1007/s00125-025-06613-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06613-1","url":null,"abstract":"AIMS/HYPOTHESISThe aetiology of type 1 diabetes remains elusive. Family history of type 1 diabetes increases the disease risk but the role of other autoimmune diseases or type 2 diabetes in the family are unclear. Here, we aimed to analyse the effect of family history of diabetes and autoimmune diseases on development of islet autoimmunity and progression to type 1 diabetes.METHODSThe Environmental Determinants of Diabetes in the Young (TEDDY) study is a prospective observational cohort study of children recruited as newborns in 2004-2010 at clinical centres in Finland, Germany, Sweden and the USA. A total of 8676 children with high-risk HLA-DR-DQ genotype for type 1 diabetes fulfilled the eligibility criteria for regular follow-up. Questionnaire-based family history of all types of diabetes and autoimmune diseases among first- and second-degree relatives (FDRs and SDRs; data available for 8558 and 7479 children, respectively) was collected. The main outcomes were development of islet autoimmunity and progression from autoimmunity to type 1 diabetes. Data until 31 January 2016 were analysed.RESULTSPersistent islet autoantibodies were found in 669 children and type 1 diabetes in 233 children (45% and 46% female sex, respectively). The median follow-up time after seroconversion was 6.5 years (IQR 3.3-8.5). Having an FDR with type 1 diabetes increased the child's risk of islet autoimmunity (HR 2.2 [95% CI 1.8, 2.8]; p<0.001), particularly if the father or sibling had type 1 diabetes. Islet autoimmunity was also associated with family history of type 1 diabetes in an SDR when participants having an FDR with type 1 diabetes were excluded from the analysis (HR 1.4 [95% CI 1.1, 1.8]; p=0.017). Notably, progression from autoantibody positivity to type 1 diabetes was significantly delayed in children having type 2 diabetes in an SDR (HR 0.61 [95% CI 0.44, 0.86]; p=0.004). Islet autoimmunity or progression to type 1 diabetes were not associated with other types of diabetes or autoimmune diseases in the family.CONCLUSIONS/INTERPRETATIONFamily history of diabetes is differentially associated with development of islet autoimmunity and progression to type 1 diabetes. The contribution made by familial, genetic and environmental factors to the two phases of the disease pathogenesis deserves distinct analyses.DATA AVAILABILITYData reported here can be obtained by request at the NIDDK Central Repository website, Resources for Research (R4R), https://repository.niddk.nih.gov/ .","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"11 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696693","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}
Pub Date : 2025-12-06DOI: 10.1007/s00125-025-06623-z
Camille E. Powe, Frederique White, Catherine Allard, Lydia Shook, Andrea Edlow, Luigi Bouchard, Francois Aguet, Pierre-Etienne Jacques, Kristin Ardlie, Jose C. Florez, S. Ananth Karumanchi, Marie-France Hivert
{"title":"Placental expression of GKN1 and diminished pancreatic beta cell function during pregnancy","authors":"Camille E. Powe, Frederique White, Catherine Allard, Lydia Shook, Andrea Edlow, Luigi Bouchard, Francois Aguet, Pierre-Etienne Jacques, Kristin Ardlie, Jose C. Florez, S. Ananth Karumanchi, Marie-France Hivert","doi":"10.1007/s00125-025-06623-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06623-z","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"26 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680156","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}
Pub Date : 2025-12-01Epub Date: 2025-09-29DOI: 10.1007/s00125-025-06530-3
Lindsey B Lamarche, Christopher Koch, Shareef Khalid, Maleeha Zaman Khan, Richard Zessis, Matthew E Clement, Daniel P Denning, Allison B Goldfine, Igor Splawski, Ali Abbasi, Jennifer L Harrow, Christina Underwood, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Juan L Rodriguez-Flores, Alan R Shuldiner, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Usman Abdulsalam, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, Allan M Gurtan, John E Dominy, Danish Saleheen
Aims/hypothesis: Genetic association studies have demonstrated that partial loss of SLC30A8 Function protects against type 2 diabetes in humans. We investigated the impact of complete loss of SLC30A8 Function on type 2 diabetes risk and related phenotypes in humans.
Methods: The Pakistan Genome Resource (PGR), a biobank comprising whole-exome and whole-genome sequences of 145,037 participants, was analysed for phenotypic associations with SLC30A8 loss-of-function (LoF) variants. To follow up on the observations in the PGR, we conducted recall-by-genotype analyses of SLC30A8 LoF heterozygotes and homozygotes, as well as their participating family members, using OGTTs.
Results: We identified 18 SLC30A8 knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter), and 1024 heterozygotes for LoF variants. Type 2 diabetes risk was lower in SLC30A8 LoF heterozygotes and homozygotes relative to non-carriers, and the protective effect strengthens in a gene dose-dependent manner (ORadditive=0.62; 95% CI 0.53, 0.72; p=1.1×10-9; ORrecessive=0.34; 95% CI 0.12, 0.93; p=0.04). OGTTs in recall-by-genotype studies showed a gene dose-dependent reduction in glucose levels, coupled with elevated insulin.
Conclusions/interpretation: The corrected insulin response, disposition index and insulin sensitivity index in LoF heterozygotes and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function that was independent of BMI. These data suggest that therapeutic inhibition of SLC30A8, up to and including complete knockout, may treat type 2 diabetes safely and effectively.
目的/假设：遗传关联研究表明，SLC30A8功能的部分丧失可以预防人类2型糖尿病。我们研究了SLC30A8功能完全丧失对人类2型糖尿病风险和相关表型的影响。方法：巴基斯坦基因组资源（PGR）是一个包含145,037名参与者的全外显子组和全基因组序列的生物库，分析了与SLC30A8功能丧失（LoF）变异的表型关联。为了跟进PGR的观察结果，我们使用ogtt对SLC30A8 LoF杂合子和纯合子及其参与家族成员进行了回忆-基因型分析。结果：我们确定了18个SLC30A8敲除，包括南亚人富集的变体（Gln174Ter）的纯合子和LoF变体的1024个杂合子。SLC30A8 LoF杂合子和纯合子与非携带者相比，2型糖尿病风险较低，且保护作用呈基因剂量依赖性增强（或加性=0.62;95% CI 0.53, 0.72; p=1.1×10-9；或隐性=0.34;95% CI 0.12, 0.93; p=0.04）。在基因型回忆研究中，ogtt显示出基因剂量依赖性的葡萄糖水平降低，并伴有胰岛素升高。结论/解释：校正后的LoF杂合子和纯合子的胰岛素反应、处置指数和胰岛素敏感性指数表明，葡萄糖刺激的胰岛素分泌较高，并保留了独立于BMI的β细胞功能。这些数据表明，治疗性抑制SLC30A8，直至完全敲除，可能安全有效地治疗2型糖尿病。
{"title":"Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function.","authors":"Lindsey B Lamarche, Christopher Koch, Shareef Khalid, Maleeha Zaman Khan, Richard Zessis, Matthew E Clement, Daniel P Denning, Allison B Goldfine, Igor Splawski, Ali Abbasi, Jennifer L Harrow, Christina Underwood, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Juan L Rodriguez-Flores, Alan R Shuldiner, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Usman Abdulsalam, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, Allan M Gurtan, John E Dominy, Danish Saleheen","doi":"10.1007/s00125-025-06530-3","DOIUrl":"10.1007/s00125-025-06530-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Genetic association studies have demonstrated that partial loss of SLC30A8 Function protects against type 2 diabetes in humans. We investigated the impact of complete loss of SLC30A8 Function on type 2 diabetes risk and related phenotypes in humans.</p><p><strong>Methods: </strong>The Pakistan Genome Resource (PGR), a biobank comprising whole-exome and whole-genome sequences of 145,037 participants, was analysed for phenotypic associations with SLC30A8 loss-of-function (LoF) variants. To follow up on the observations in the PGR, we conducted recall-by-genotype analyses of SLC30A8 LoF heterozygotes and homozygotes, as well as their participating family members, using OGTTs.</p><p><strong>Results: </strong>We identified 18 SLC30A8 knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter), and 1024 heterozygotes for LoF variants. Type 2 diabetes risk was lower in SLC30A8 LoF heterozygotes and homozygotes relative to non-carriers, and the protective effect strengthens in a gene dose-dependent manner (OR<sub>additive</sub>=0.62; 95% CI 0.53, 0.72; p=1.1×10<sup>-9</sup>; OR<sub>recessive</sub>=0.34; 95% CI 0.12, 0.93; p=0.04). OGTTs in recall-by-genotype studies showed a gene dose-dependent reduction in glucose levels, coupled with elevated insulin.</p><p><strong>Conclusions/interpretation: </strong>The corrected insulin response, disposition index and insulin sensitivity index in LoF heterozygotes and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function that was independent of BMI. These data suggest that therapeutic inhibition of SLC30A8, up to and including complete knockout, may treat type 2 diabetes safely and effectively.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2754-2766"},"PeriodicalIF":10.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12594714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184964","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}
Pub Date : 2025-11-28DOI: 10.1007/s00125-025-06617-x
Patrick J Highton,Mark P Funnell,Pankaj Gupta,Francesco Zaccardi,Lee-Ling Lim,Samuel Seidu,Kamlesh Khunti
Medication adherence is critical for optimal glycaemic management and the prevention of complications in type 2 diabetes mellitus. Despite its importance, non-adherence remains a prevalent issue, with global estimates suggesting that approximately 38% of people with type 2 diabetes do not take their medications as prescribed, although estimates vary widely due to a range of patient-related, socioeconomic, condition-related (e.g. chronicity, severity of comorbidities) and healthcare system factors. This review synthesises the current evidence on the prevalence of non-adherence in type 2 diabetes, as well as risk factors and clinical and economic consequences, and evaluates interventions designed to improve adherence in this population. Medication non-adherence is associated with increased HbA1c levels and risks of micro- and macrovascular complications, hospitalisation and mortality, while also incurring substantial healthcare costs. Methods for assessing medication adherence range from subjective self-report tools to objective measures such as biochemical testing, which are gaining prominence in both research and clinical practice. Numerous interventions to increase medication adherence have been investigated, including educational, technological, pharmacist-led, behavioural and financial strategies and fixed-dose combination (FDC) therapies. While interventions such as pharmacist-led care and FDC therapies are beneficial, outcomes from technology-based and motivational strategies remain mixed. Shared decision making and behavioural interventions, such as cognitive behavioural therapy, may provide additional benefits, particularly for individuals with multiple long-term conditions or psychological comorbidities. Multifaceted interventions tailored to individual barriers and sustained over time appear most effective. Given the significant impact of non-adherence on both patient outcomes and healthcare systems, future research is needed to design personalised, multicomponent interventions that are scalable and equitable across diverse healthcare settings.
{"title":"Improving medication adherence in type 2 diabetes: strategies for better clinical and economic outcomes.","authors":"Patrick J Highton,Mark P Funnell,Pankaj Gupta,Francesco Zaccardi,Lee-Ling Lim,Samuel Seidu,Kamlesh Khunti","doi":"10.1007/s00125-025-06617-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06617-x","url":null,"abstract":"Medication adherence is critical for optimal glycaemic management and the prevention of complications in type 2 diabetes mellitus. Despite its importance, non-adherence remains a prevalent issue, with global estimates suggesting that approximately 38% of people with type 2 diabetes do not take their medications as prescribed, although estimates vary widely due to a range of patient-related, socioeconomic, condition-related (e.g. chronicity, severity of comorbidities) and healthcare system factors. This review synthesises the current evidence on the prevalence of non-adherence in type 2 diabetes, as well as risk factors and clinical and economic consequences, and evaluates interventions designed to improve adherence in this population. Medication non-adherence is associated with increased HbA1c levels and risks of micro- and macrovascular complications, hospitalisation and mortality, while also incurring substantial healthcare costs. Methods for assessing medication adherence range from subjective self-report tools to objective measures such as biochemical testing, which are gaining prominence in both research and clinical practice. Numerous interventions to increase medication adherence have been investigated, including educational, technological, pharmacist-led, behavioural and financial strategies and fixed-dose combination (FDC) therapies. While interventions such as pharmacist-led care and FDC therapies are beneficial, outcomes from technology-based and motivational strategies remain mixed. Shared decision making and behavioural interventions, such as cognitive behavioural therapy, may provide additional benefits, particularly for individuals with multiple long-term conditions or psychological comorbidities. Multifaceted interventions tailored to individual barriers and sustained over time appear most effective. Given the significant impact of non-adherence on both patient outcomes and healthcare systems, future research is needed to design personalised, multicomponent interventions that are scalable and equitable across diverse healthcare settings.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"107 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613364","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}
AIMS/HYPOTHESISFerroptosis, a regulated form of cell death characterised by excessive lipid peroxidation, plays a critical role in acute kidney injury (AKI). Individuals with diabetes have an elevated risk of developing AKI. However, the contribution of ferroptosis to the heightened susceptibility to AKI in diabetic kidney disease (DKD) remains unclear. This study aimed to investigate whether DKD influences ferroptosis susceptibility in proximal tubular epithelial cells (PTECs), focusing on autophagy and AMP-activated protein kinase (AMPK) signalling.METHODSWe examined the association between ferroptotic signatures and autophagy/AMPK pathways in human kidney biopsy specimens. To explore the roles of autophagy and AMPK in modulating ferroptosis in PTECs during DKD, we subjected streptozocin (STZ)-induced type 1 diabetic mice and type 2 diabetic db/db mice to ischaemia-reperfusion injury. Primary Atg5-deficient and wild-type PTECs were used to further investigate the underlying cellular mechanisms.RESULTSAnalysis of human kidney biopsy specimens revealed an increased ferroptotic signature (4-hydroxynonenal immunostaining), impaired autophagy (SQSTM1 accumulation) and AMPK inactivation (reduced p-AMPK) in PTECs of individuals with DKD. In STZ-treated Atg5 knockout (Atg5KO) mice, experiments combining ischaemia-reperfusion injury with ferrostatin-1 treatment showed that autophagy suppressed ferroptotic susceptibility. Additionally, susceptibility to ferroptosis was heightened in db/db mice following ischaemia-reperfusion injury; however, this effect was mitigated by enhancing autophagy through rapamycin treatment. In primary PTECs isolated from Atg5KO mice, ferroptotic cell death and lipid peroxidation were significantly increased, together with elevated mitochondrial reactive oxygen species. Mitochondrial DNA/RNA depletion substantially abolished ferroptotic effects in Atg5KO cells. Furthermore, high-glucose treatment inactivated AMPK and promoted ferroptosis, whereas treatment with the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) attenuated ferroptosis in vitro and reduced vulnerability to AKI in DKD models.CONCLUSIONS/INTERPRETATIONThese findings demonstrate that impaired autophagy and inactivated AMPK heighten susceptibility to ferroptosis in DKD, suggesting that therapeutic strategies targeting autophagy and AMPK activation may reduce ferroptosis-associated kidney injury in individuals with diabetes.
{"title":"Defective autophagy and AMPK inactivation drive ferroptosis in diabetic kidney disease.","authors":"Sho Matsui,Takeshi Yamamoto,Yoshitsugu Takabatake,Atsushi Takahashi,Tomoko Namba-Hamano,Jun Matsuda,Satoshi Minami,Shinsuke Sakai,Hiroaki Yonishi,Jun Nakamura,Hideaki Kawai,Takuya Kubota,Isao Matsui,Motoko Yanagita,Yoshitaka Isaka","doi":"10.1007/s00125-025-06612-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06612-2","url":null,"abstract":"AIMS/HYPOTHESISFerroptosis, a regulated form of cell death characterised by excessive lipid peroxidation, plays a critical role in acute kidney injury (AKI). Individuals with diabetes have an elevated risk of developing AKI. However, the contribution of ferroptosis to the heightened susceptibility to AKI in diabetic kidney disease (DKD) remains unclear. This study aimed to investigate whether DKD influences ferroptosis susceptibility in proximal tubular epithelial cells (PTECs), focusing on autophagy and AMP-activated protein kinase (AMPK) signalling.METHODSWe examined the association between ferroptotic signatures and autophagy/AMPK pathways in human kidney biopsy specimens. To explore the roles of autophagy and AMPK in modulating ferroptosis in PTECs during DKD, we subjected streptozocin (STZ)-induced type 1 diabetic mice and type 2 diabetic db/db mice to ischaemia-reperfusion injury. Primary Atg5-deficient and wild-type PTECs were used to further investigate the underlying cellular mechanisms.RESULTSAnalysis of human kidney biopsy specimens revealed an increased ferroptotic signature (4-hydroxynonenal immunostaining), impaired autophagy (SQSTM1 accumulation) and AMPK inactivation (reduced p-AMPK) in PTECs of individuals with DKD. In STZ-treated Atg5 knockout (Atg5KO) mice, experiments combining ischaemia-reperfusion injury with ferrostatin-1 treatment showed that autophagy suppressed ferroptotic susceptibility. Additionally, susceptibility to ferroptosis was heightened in db/db mice following ischaemia-reperfusion injury; however, this effect was mitigated by enhancing autophagy through rapamycin treatment. In primary PTECs isolated from Atg5KO mice, ferroptotic cell death and lipid peroxidation were significantly increased, together with elevated mitochondrial reactive oxygen species. Mitochondrial DNA/RNA depletion substantially abolished ferroptotic effects in Atg5KO cells. Furthermore, high-glucose treatment inactivated AMPK and promoted ferroptosis, whereas treatment with the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) attenuated ferroptosis in vitro and reduced vulnerability to AKI in DKD models.CONCLUSIONS/INTERPRETATIONThese findings demonstrate that impaired autophagy and inactivated AMPK heighten susceptibility to ferroptosis in DKD, suggesting that therapeutic strategies targeting autophagy and AMPK activation may reduce ferroptosis-associated kidney injury in individuals with diabetes.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"32 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613362","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}
Pub Date : 2025-11-28DOI: 10.1007/s00125-025-06614-0
Maj Bangshaab,Mads B Bengtsen,Stine Smedegaard,Esben Søndergaard,Niels Møller,Mads V Svart,Nikolaj Rittig
AIMS/HYPOTHESISPostprandial hyperglycaemia and hyperlipidaemia are independent risk factors for CVD in individuals with type 2 diabetes. We aimed to test whether a ketone monoester (KE) and ketone salts (KS) reduce postprandial glucose and lipid excursions in individuals with type 2 diabetes.METHODSIn two randomised, participant-blind crossover studies we investigated individuals with type 2 diabetes treated with either metformin monotherapy or a lifestyle intervention alone. In study 1, 14 participants received 30 g of KE, KS or placebo 30 min before a mixed meal test on three separate occasions. The primary outcome was the incremental AUC (iAUC) for glucose. In study 2, ten participants were investigated on six separate occasions, consuming various doses (0 g, 10 g, 20 g and 40 g) of KE 30 min, 60 min or immediately before an OGTT. Both studies were conducted at Aarhus University Hospital, Denmark, with the primary investigator randomly assigning the intervention order.RESULTSWe found that the iAUC for glucose decreased by 36% (95% CI 14, 57) with KE and 22% (95% CI 1, 44) with KS compared with placebo. Both ketone supplements lowered postprandial NEFA and ghrelin concentrations, and KE reduced triglycerides (n=14). Furthermore, KE dose-dependently lowered the iAUC of glucose, with the strongest effect when ingested 30 min or 60 min before the OGTT (n=10). No serious adverse events occurred; however, transient mild gastrointestinal symptoms, including nausea and diarrhoea, were reported.CONCLUSIONS/INTERPRETATIONPre-meal ketone supplementation reduced postprandial glucose, lipid and ghrelin concentrations. These findings support the therapeutic potential of KE supplementation in the management of type 2 diabetes.TRIAL REGISTRATIONClinicalTrials.gov NCT05263401 and NCT05581043 FUNDING: Novo Nordisk Foundation (NNF19OC0058872 and NNF22OC0081911), the Health Research Foundation of Central Denmark Region and the Aase Einar Danielsen Foundation (Jr. No. 23-10-0145).
目的/假设餐后高血糖和高脂血症是2型糖尿病患者心血管疾病的独立危险因素。我们的目的是测试酮单酯（KE）和酮盐（KS）是否能降低2型糖尿病患者餐后血糖和脂质漂移。方法在两项随机、参与者盲交叉研究中，我们调查了接受二甲双胍单药治疗或单独生活方式干预治疗的2型糖尿病患者。在研究1中，14名参与者在三次不同的混合餐测试前30分钟接受30克KE， KS或安慰剂。主要终点是葡萄糖的增量AUC （iAUC）。在研究2中，10名参与者在6个不同的场合接受调查，在OGTT前30分钟、60分钟或立即服用不同剂量的KE （0 g、10 g、20 g和40 g）。两项研究均在丹麦奥胡斯大学医院进行，主要研究者随机分配干预顺序。结果我们发现，与安慰剂相比，KE组葡萄糖的iAUC降低了36% (95% CI 14,57)， KS组降低了22% （95% CI 1,44）。两种酮类补充剂均可降低餐后NEFA和胃促生长素浓度，KE可降低甘油三酯（n=14）。此外，KE还能剂量依赖性地降低葡萄糖的iAUC，在OGTT前30分钟或60分钟服用效果最强（n=10）。未发生严重不良事件；然而，报告了短暂的轻度胃肠道症状，包括恶心和腹泻。餐前补充酮可降低餐后葡萄糖、脂质和胃饥饿素浓度。这些发现支持补充KE治疗2型糖尿病的治疗潜力。资助：诺和诺德基金会（NNF19OC0058872和NNF22OC0081911），丹麦中部地区卫生研究基金会和Aase Einar Danielsen基金会（Jr. No. 23-10-0145）。
{"title":"Ketone supplementation dose-dependently lowers postprandial blood glucose, lipid and ghrelin levels in individuals with type 2 diabetes: a randomised crossover study.","authors":"Maj Bangshaab,Mads B Bengtsen,Stine Smedegaard,Esben Søndergaard,Niels Møller,Mads V Svart,Nikolaj Rittig","doi":"10.1007/s00125-025-06614-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06614-0","url":null,"abstract":"AIMS/HYPOTHESISPostprandial hyperglycaemia and hyperlipidaemia are independent risk factors for CVD in individuals with type 2 diabetes. We aimed to test whether a ketone monoester (KE) and ketone salts (KS) reduce postprandial glucose and lipid excursions in individuals with type 2 diabetes.METHODSIn two randomised, participant-blind crossover studies we investigated individuals with type 2 diabetes treated with either metformin monotherapy or a lifestyle intervention alone. In study 1, 14 participants received 30 g of KE, KS or placebo 30 min before a mixed meal test on three separate occasions. The primary outcome was the incremental AUC (iAUC) for glucose. In study 2, ten participants were investigated on six separate occasions, consuming various doses (0 g, 10 g, 20 g and 40 g) of KE 30 min, 60 min or immediately before an OGTT. Both studies were conducted at Aarhus University Hospital, Denmark, with the primary investigator randomly assigning the intervention order.RESULTSWe found that the iAUC for glucose decreased by 36% (95% CI 14, 57) with KE and 22% (95% CI 1, 44) with KS compared with placebo. Both ketone supplements lowered postprandial NEFA and ghrelin concentrations, and KE reduced triglycerides (n=14). Furthermore, KE dose-dependently lowered the iAUC of glucose, with the strongest effect when ingested 30 min or 60 min before the OGTT (n=10). No serious adverse events occurred; however, transient mild gastrointestinal symptoms, including nausea and diarrhoea, were reported.CONCLUSIONS/INTERPRETATIONPre-meal ketone supplementation reduced postprandial glucose, lipid and ghrelin concentrations. These findings support the therapeutic potential of KE supplementation in the management of type 2 diabetes.TRIAL REGISTRATIONClinicalTrials.gov NCT05263401 and NCT05581043 FUNDING: Novo Nordisk Foundation (NNF19OC0058872 and NNF22OC0081911), the Health Research Foundation of Central Denmark Region and the Aase Einar Danielsen Foundation (Jr. No. 23-10-0145).","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"126 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613363","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}
Pub Date : 2025-11-26DOI: 10.1007/s00125-025-06615-z
So Hyun Cho, Seohyun Kim, Rosa Oh, Ji Yoon Kim, Myunghwa Jang, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Gyuri Kim, Jae Hyeon Kim
{"title":"High incidence of eating disorders in individuals with type 2 diabetes and their association with cardiovascular and mortality risks","authors":"So Hyun Cho, Seohyun Kim, Rosa Oh, Ji Yoon Kim, Myunghwa Jang, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Gyuri Kim, Jae Hyeon Kim","doi":"10.1007/s00125-025-06615-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06615-z","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"23 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599318","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}
Pub Date : 2025-11-25DOI: 10.1007/s00125-025-06605-1
Anup K. Nair, Katiya Barkho, Koushik Ponnanna Cheranda, Michael Traurig, Jeffrey R. Sutherland, Divya Anup, Clifton Bogardus, Leslie J. Baier
Aims/hypothesis An R1420H variation in sulfonylurea receptor 1 (SUR1), a subunit of the K ATP channel, was previously identified in an Indigenous community in Arizona where a homozygous carrier (1420HH) had hyperinsulinaemic hypoglycaemia during infancy (HHI), suggestive of a K ATP channel loss of function (LoF). Interestingly, heterozygous carriers of this variation (1420RH, occurring in 3% of the community), had a twofold increased risk of type 2 diabetes. We aimed to create an isogenic induced pluripotent stem cell (iPSC)-derived pancreatic islet (SC-islet)-based platform to test whether the R1420H variant results in K ATP channel LoF, and to examine the distinct temporal effects of SUR1 1420HH and 1420RH K ATP channel variations on insulin secretion from developing and mature SC-islets. Methods Using CRISPR-Cas9, isogenic iPSCs with all three genotypes (SUR1 1420RR, 1420RH and 1420HH) were generated from two different parental Indigenous American iPSC lines (IS1, isogenic cell lines derived from parental cell line 1; and IS2, isogenic cell lines derived from parental cell line 2). These isogenic cell lines were used to generate immature SC-islets (resembling fetal islets) and mature SC-islets (resembling adult islets), which were used to assess insulin secretion dynamics during different stages of development and identify differences in gene expression by single-cell RNA-seq. This study was consistent with the CONSIDER statement for research studies among Indigenous American communities. Results Immature SUR1 1420HH SC-islets secreted 3.4-fold (IS1, p <0.001) and 4.2-fold (IS2, p =0.001) more insulin under basal conditions than normal (SUR1 1420RR) SC-islets. Modest hyperinsulinaemia was also seen in immature SUR1 1420RH SC-islets (2.2-fold [IS1] and 2.3-fold [IS2]) but the results were not statistically significant. After maturation, the 1420HH SC-islets failed to achieve glucose responsiveness whereas the 1420RH SC-islets achieved biphasic insulin secretion but had significantly lower glucose responsiveness than normal SC-islets (AUC for insulin secretion [as a % of total insulin] under high glucose challenge: 1.04 vs 0.56 in normal vs 1420RH SC-islets, p <0.001). Diazoxide reduced hyperinsulinaemia in SUR1 1420RH and 1420HH immature SC-islets, while tolbutamide elicited a greatly diminished or undetectable insulin secretory response from mature SUR1 1420RH SC-islets (13.2-fold increase in insulin secretion) and 1420HH SC-islets (1.9-fold increase) compared with normal SC-islets (31.5-fold increase). Results were directionally comparable for both IS1 and IS2 SC-islets. SUR1 1420RH SC-islets also responded to the glucokinase activator dorzagliatin with improvement in first-phase insulin secretory response (first-phase stimulation index: 3.9-fold vs 7.3-fold, p<
{"title":"Modelling the effects of human SUR1 R1420H variation on insulin secretory function using isogenic iPSC-derived pancreatic islets","authors":"Anup K. Nair, Katiya Barkho, Koushik Ponnanna Cheranda, Michael Traurig, Jeffrey R. Sutherland, Divya Anup, Clifton Bogardus, Leslie J. Baier","doi":"10.1007/s00125-025-06605-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06605-1","url":null,"abstract":"Aims/hypothesis An R1420H variation in sulfonylurea receptor 1 (SUR1), a subunit of the K <jats:sub>ATP</jats:sub> channel, was previously identified in an Indigenous community in Arizona where a homozygous carrier (1420HH) had hyperinsulinaemic hypoglycaemia during infancy (HHI), suggestive of a K <jats:sub>ATP</jats:sub> channel loss of function (LoF). Interestingly, heterozygous carriers of this variation (1420RH, occurring in 3% of the community), had a twofold increased risk of type 2 diabetes. We aimed to create an isogenic induced pluripotent stem cell (iPSC)-derived pancreatic islet (SC-islet)-based platform to test whether the R1420H variant results in K <jats:sub>ATP</jats:sub> channel LoF, and to examine the distinct temporal effects of SUR1 1420HH and 1420RH K <jats:sub>ATP</jats:sub> channel variations on insulin secretion from developing and mature SC-islets. Methods Using CRISPR-Cas9, isogenic iPSCs with all three genotypes (SUR1 1420RR, 1420RH and 1420HH) were generated from two different parental Indigenous American iPSC lines (IS1, isogenic cell lines derived from parental cell line 1; and IS2, isogenic cell lines derived from parental cell line 2). These isogenic cell lines were used to generate immature SC-islets (resembling fetal islets) and mature SC-islets (resembling adult islets), which were used to assess insulin secretion dynamics during different stages of development and identify differences in gene expression by single-cell RNA-seq. This study was consistent with the CONSIDER statement for research studies among Indigenous American communities. Results Immature SUR1 1420HH SC-islets secreted 3.4-fold (IS1, <jats:italic>p</jats:italic> <0.001) and 4.2-fold (IS2, <jats:italic>p</jats:italic> =0.001) more insulin under basal conditions than normal (SUR1 1420RR) SC-islets. Modest hyperinsulinaemia was also seen in immature SUR1 1420RH SC-islets (2.2-fold [IS1] and 2.3-fold [IS2]) but the results were not statistically significant. After maturation, the 1420HH SC-islets failed to achieve glucose responsiveness whereas the 1420RH SC-islets achieved biphasic insulin secretion but had significantly lower glucose responsiveness than normal SC-islets (AUC for insulin secretion [as a % of total insulin] under high glucose challenge: 1.04 vs 0.56 in normal vs 1420RH SC-islets, <jats:italic>p</jats:italic> <0.001). Diazoxide reduced hyperinsulinaemia in SUR1 1420RH and 1420HH immature SC-islets, while tolbutamide elicited a greatly diminished or undetectable insulin secretory response from mature SUR1 1420RH SC-islets (13.2-fold increase in insulin secretion) and 1420HH SC-islets (1.9-fold increase) compared with normal SC-islets (31.5-fold increase). Results were directionally comparable for both IS1 and IS2 SC-islets. SUR1 1420RH SC-islets also responded to the glucokinase activator dorzagliatin with improvement in first-phase insulin secretory response (first-phase stimulation index: 3.9-fold vs 7.3-fold, <jats:italic>p<","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"6 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599319","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":"Time-dependent association between progression of arterial stiffness and risk of incident chronic kidney disease: a cohort study in China","authors":"Jing-li Gao, Hua Deng, Guo-Dong Wang, Hui-ling Deng, Dong-Yi Feng, Shou-ling Wu, Shuo-hua Chen, Yan-Feng Zhou","doi":"10.1007/s00125-025-06609-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06609-x","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"19 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575464","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}
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