Pub Date : 2025-12-11DOI: 10.1007/s00125-025-06591-4
Jennifer J Couper,Helena Oakey,Megan A S Penno,John M Wentworth,Kelly Watson,James D Brown,Dao Huynh,Rebecca L Thomson,Maria E Craig,Elizabeth A Davis,Aveni Haynes,Tony Huynh,Peter J Vuillermin,Georgia Soldatos,Prudence E Lopez,Grant Morahan,Kelly McGorm,Ki Wook Kim,Simon Barry,Emma E Hamilton-Williams,William D Rawlinson,Richard Sinnott,Leonard C Harrison,Peter Achenbach,Peter G Colman,
AIMS/HYPOTHESISIslet autoantibodies herald early type 1 diabetes. However, less is known of the evolution of autoantibodies to the islet autoantigen ZnT8. Our primary aim was to characterise the development of islet autoantibodies in a pregnancy-birth at-risk cohort and to provide new knowledge about ZnT8A.METHODSIslet autoantibodies were measured every 3-6 months in 1277/1473 children with a first-degree relative with type 1 diabetes who were followed prospectively from pregnancy in the Environmental Determinants of Islet Autoimmunity (ENDIA) cohort for 7.0 (IQR 5.8-8.3) years. Islet autoantibodies were also measured in the mothers and/or in cord blood in 901 pregnancies with type 1 diabetes.RESULTSThe development of persistent IAA reached a probability of 0.02 by 2 years of age. A combination of IAA- and GADA-first, GADA-first and ZnT8A-first all reached a similar probability by 5 years of age. ZnT8A appeared as the first islet autoantibody, alone or in combination, in 43 (32%) of the 134/1473 children with persistent islet autoantibodies. Persistent single ZnT8A, detected only by ELISA, usually appeared after 4 years of age. ZnT8A that progressed to multiple islet autoantibodies or type 1 diabetes were detected in younger children (p=0.006) and in multiple assay formats. ZnT8A were confirmed in additional assay formats when present with multiple islet autoantibodies, but not when remaining as a single islet autoantibody, unlike IAA and GADA. Maternal islet GADA were detected until 15 months of age and transmission of any islet antibody/autoantibody did not relate to islet autoantibody development in the offspring (χ2=3.32, df=2, p=0.19).CONCLUSIONS/INTERPRETATIONPersistent single ZnT8A, which are detected only by ELISA and no other test format, appear not to confer an increased risk of progression to type 1 diabetes.
{"title":"Evolution of islet autoantibodies in the Environmental Determinants of Islet Autoimmunity (ENDIA) prospective cohort.","authors":"Jennifer J Couper,Helena Oakey,Megan A S Penno,John M Wentworth,Kelly Watson,James D Brown,Dao Huynh,Rebecca L Thomson,Maria E Craig,Elizabeth A Davis,Aveni Haynes,Tony Huynh,Peter J Vuillermin,Georgia Soldatos,Prudence E Lopez,Grant Morahan,Kelly McGorm,Ki Wook Kim,Simon Barry,Emma E Hamilton-Williams,William D Rawlinson,Richard Sinnott,Leonard C Harrison,Peter Achenbach,Peter G Colman, ","doi":"10.1007/s00125-025-06591-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06591-4","url":null,"abstract":"AIMS/HYPOTHESISIslet autoantibodies herald early type 1 diabetes. However, less is known of the evolution of autoantibodies to the islet autoantigen ZnT8. Our primary aim was to characterise the development of islet autoantibodies in a pregnancy-birth at-risk cohort and to provide new knowledge about ZnT8A.METHODSIslet autoantibodies were measured every 3-6 months in 1277/1473 children with a first-degree relative with type 1 diabetes who were followed prospectively from pregnancy in the Environmental Determinants of Islet Autoimmunity (ENDIA) cohort for 7.0 (IQR 5.8-8.3) years. Islet autoantibodies were also measured in the mothers and/or in cord blood in 901 pregnancies with type 1 diabetes.RESULTSThe development of persistent IAA reached a probability of 0.02 by 2 years of age. A combination of IAA- and GADA-first, GADA-first and ZnT8A-first all reached a similar probability by 5 years of age. ZnT8A appeared as the first islet autoantibody, alone or in combination, in 43 (32%) of the 134/1473 children with persistent islet autoantibodies. Persistent single ZnT8A, detected only by ELISA, usually appeared after 4 years of age. ZnT8A that progressed to multiple islet autoantibodies or type 1 diabetes were detected in younger children (p=0.006) and in multiple assay formats. ZnT8A were confirmed in additional assay formats when present with multiple islet autoantibodies, but not when remaining as a single islet autoantibody, unlike IAA and GADA. Maternal islet GADA were detected until 15 months of age and transmission of any islet antibody/autoantibody did not relate to islet autoantibody development in the offspring (χ2=3.32, df=2, p=0.19).CONCLUSIONS/INTERPRETATIONPersistent single ZnT8A, which are detected only by ELISA and no other test format, appear not to confer an increased risk of progression to type 1 diabetes.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"22 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717574","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/HYPOTHESISDiet switch during weaning induces gut microbiome maturation, accompanied by the formation of adequate functional beta cell mass. Bile acid (BA), an essential microbial metabolite, regulates host glucose homeostasis by binding to its main receptor, farnesoid X receptor (FXR, encoded by NR1H4). However, the precise roles of microbial BA metabolism and FXR signalling in neonatal beta cell development are still unclear.METHODSIslet FXR levels were determined at different perinatal stages. Postnatal changes in gut microbiome and BA profiles were examined in mice, with changes in germ-free mouse BAs serving as the control. We genetically modified beta cells to sustain FXR expression after birth (using Nr1h4-knockin [βFxrKI] mice) and performed morphological and functional analysis on murine islets. Single-cell RNA-seq and single-cell assay for transposase-accessible chromatin sequencing of islet cells were used to study FXR-mediated downstream regulation in islets. Lineage tracing was performed to evaluate beta cell fate transition. Mendelian randomisation (MR) and human islet proteomics data analysis were applied to study the pathological relevance in human diabetes.RESULTSFXR expression in beta cells declined after birth (positive cell proportion, 29.1 ± 3.1% at embryonic day 18.5 vs 4.2 ± 2.4% at 3 weeks postnatal in mice, p<0.001). This physiological change paralleled the ascending of FXR-agonistic BAs derived from gut microbiome maturation (unconjugated BA proportion, 0.9 ± 0.6% at 1 week vs 14.0 ± 5.6% at 3 weeks, p<0.05). βFxrKI mice had limited beta cell mass growth (approximately 70% of the control level at 1 week of age and only 15% of the control level at 8 weeks of age) and developed high blood glucose levels by weaning (random blood glucose, 15.2 ± 1.7 mmol/l in βFxrKI vs 7.7 ± 0.5 mmol/l in control, p<0.001), mainly resulting from elevated cell apoptosis (1.95-, 1.79-, and 3.27-fold increase vs control at 1, 2 and 3 weeks, respectively) and altered beta cell identity. Casp6 was identified as a key downstream target in beta cell FXR. Intervention with antibiotics or a specific caspase-6 (CASP6) inhibitor partially recovered the phenotypes of βFxrKI mice. Further validation in humans showed that islet FXR/CASP6 levels were elevated in individuals with type 2 diabetes (FXR, -0.039 ± 1.257 a.u. in donors without diabetes vs 0.646 ± 1.140 a.u. in donors with diabetes, p=0.0371; CASP6, -1.575 ± 0.307 a.u. in donors without diabetes vs -1.325 ± 0.381 a.u. in donors with diabetes, p=0.011). MR analysis further supported the effect of human islet FXR expression in elevating HbA1c (β=0.006, p<0.001) with lowering fasting insulin level (β=-0.009, p=0.02) and the effect of CASP6 expression in enhancing 2 h glucose (β=0.039, p=0.01).CONCLUSIONS/INTERPRETATIONThe declining FXR-CASP6 signals in neonatal beta cells could serve as a programmed host response to the maturing gut microbial BA metabolism to maintain normal postnatal beta cell
{"title":"Declining FXR expression coordinates neonatal beta cell mass development with microbial bile acid metabolism maturation in mice.","authors":"Chenyang Fu,Tingting Li,Yiming Hao,Yiting Lin,Yixuan Qiu,Yangyang Jia,Jie Yang,Bei Liu,Duanyi Hua,Chengyang Wang,Tao Chen,Anthony Piron,Miriam Cnop,Qicheng Ni,Jie Zheng,Guang Ning,Yanyun Gu","doi":"10.1007/s00125-025-06618-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06618-w","url":null,"abstract":"AIMS/HYPOTHESISDiet switch during weaning induces gut microbiome maturation, accompanied by the formation of adequate functional beta cell mass. Bile acid (BA), an essential microbial metabolite, regulates host glucose homeostasis by binding to its main receptor, farnesoid X receptor (FXR, encoded by NR1H4). However, the precise roles of microbial BA metabolism and FXR signalling in neonatal beta cell development are still unclear.METHODSIslet FXR levels were determined at different perinatal stages. Postnatal changes in gut microbiome and BA profiles were examined in mice, with changes in germ-free mouse BAs serving as the control. We genetically modified beta cells to sustain FXR expression after birth (using Nr1h4-knockin [βFxrKI] mice) and performed morphological and functional analysis on murine islets. Single-cell RNA-seq and single-cell assay for transposase-accessible chromatin sequencing of islet cells were used to study FXR-mediated downstream regulation in islets. Lineage tracing was performed to evaluate beta cell fate transition. Mendelian randomisation (MR) and human islet proteomics data analysis were applied to study the pathological relevance in human diabetes.RESULTSFXR expression in beta cells declined after birth (positive cell proportion, 29.1 ± 3.1% at embryonic day 18.5 vs 4.2 ± 2.4% at 3 weeks postnatal in mice, p<0.001). This physiological change paralleled the ascending of FXR-agonistic BAs derived from gut microbiome maturation (unconjugated BA proportion, 0.9 ± 0.6% at 1 week vs 14.0 ± 5.6% at 3 weeks, p<0.05). βFxrKI mice had limited beta cell mass growth (approximately 70% of the control level at 1 week of age and only 15% of the control level at 8 weeks of age) and developed high blood glucose levels by weaning (random blood glucose, 15.2 ± 1.7 mmol/l in βFxrKI vs 7.7 ± 0.5 mmol/l in control, p<0.001), mainly resulting from elevated cell apoptosis (1.95-, 1.79-, and 3.27-fold increase vs control at 1, 2 and 3 weeks, respectively) and altered beta cell identity. Casp6 was identified as a key downstream target in beta cell FXR. Intervention with antibiotics or a specific caspase-6 (CASP6) inhibitor partially recovered the phenotypes of βFxrKI mice. Further validation in humans showed that islet FXR/CASP6 levels were elevated in individuals with type 2 diabetes (FXR, -0.039 ± 1.257 a.u. in donors without diabetes vs 0.646 ± 1.140 a.u. in donors with diabetes, p=0.0371; CASP6, -1.575 ± 0.307 a.u. in donors without diabetes vs -1.325 ± 0.381 a.u. in donors with diabetes, p=0.011). MR analysis further supported the effect of human islet FXR expression in elevating HbA1c (β=0.006, p<0.001) with lowering fasting insulin level (β=-0.009, p=0.02) and the effect of CASP6 expression in enhancing 2 h glucose (β=0.039, p=0.01).CONCLUSIONS/INTERPRETATIONThe declining FXR-CASP6 signals in neonatal beta cells could serve as a programmed host response to the maturing gut microbial BA metabolism to maintain normal postnatal beta cell ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"42 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728542","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/HYPOTHESISPancreatic beta cell dedifferentiation underlies the reversible reduction in beta cell mass and function in diabetes. Exploratory research into interventional targets and adjuvant therapies to prevent or reverse beta cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, although the underlying molecular mechanism remains elusive.METHODSLactate dehydrogenase A (LDHA) expression and activity were analysed in islets obtained from human donors with type 2 diabetes, hyperglycaemic db/db mice and a high-fat diet (HFD)-induced mouse model of diabetes. The impact of LDHA inhibition on beta cell function and identity was also investigated in HFD-fed mice and db/db mice. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on histone H3 lysine 9 lactylation (H3K9la) increases and beta cell function under glucotoxic conditions.RESULTSWe demonstrate that inhibition of LDHA effectively preserves beta cell identity, which not only delays disease progression in individuals with impaired fasting glucose, but also improves insulin output and glucose homeostasis in diabetic models. Mechanistically, activation of LDHA led to a marked increase in H3K9la in the promoter region of the beta cell dedifferentiation marker genes Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering beta cell dedifferentiation as well as impaired glucose homeostasis and beta cell function in mice.CONCLUSIONS/INTERPRETATIONWe unravelled the role of LDHA-mediated metabolic and epigenetic reprogramming in beta cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.
{"title":"LDHA induces beta cell dedifferentiation in diabetes through metabolic and epigenetic reprogramming.","authors":"Xirui Li,Haoqiang Gong,Can Xiong,Xinyue Huang,Mei He,Liangjun Sun,Wenyue Yin,Suyun Zou,Min Sha,Wanhua Guo,Tijun Wu,Xiao Han,Qingguo Li,Yaqin Zhang,Fang Chen","doi":"10.1007/s00125-025-06626-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06626-w","url":null,"abstract":"AIMS/HYPOTHESISPancreatic beta cell dedifferentiation underlies the reversible reduction in beta cell mass and function in diabetes. Exploratory research into interventional targets and adjuvant therapies to prevent or reverse beta cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, although the underlying molecular mechanism remains elusive.METHODSLactate dehydrogenase A (LDHA) expression and activity were analysed in islets obtained from human donors with type 2 diabetes, hyperglycaemic db/db mice and a high-fat diet (HFD)-induced mouse model of diabetes. The impact of LDHA inhibition on beta cell function and identity was also investigated in HFD-fed mice and db/db mice. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on histone H3 lysine 9 lactylation (H3K9la) increases and beta cell function under glucotoxic conditions.RESULTSWe demonstrate that inhibition of LDHA effectively preserves beta cell identity, which not only delays disease progression in individuals with impaired fasting glucose, but also improves insulin output and glucose homeostasis in diabetic models. Mechanistically, activation of LDHA led to a marked increase in H3K9la in the promoter region of the beta cell dedifferentiation marker genes Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering beta cell dedifferentiation as well as impaired glucose homeostasis and beta cell function in mice.CONCLUSIONS/INTERPRETATIONWe unravelled the role of LDHA-mediated metabolic and epigenetic reprogramming in beta cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"6 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728544","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 : 2025-12-10DOI: 10.1007/s00125-025-06625-x
Chittaranjan S Yajnik,Souvik Bandyopadhyay,Dattatray S Bhat,Rucha S H Wagh,Pallavi C Yajnik,Rasika Ladkat,Kurus Coyaji,Caroline H D Fall
AIMS/HYPOTHESISTraditionally, gestational diabetes mellitus (GDM) (defined here as hyperglycaemia first detected during pregnancy) has been considered to be a transient condition of pregnancy, but evidence suggests it is often a pre-existing chronic condition. Studies have reported that women diagnosed with GDM were hyperglycaemic, obese and insulin-resistant from before pregnancy. However, little is known about the life-course evolution of glycaemia before pregnancy. Participants in the Pune Maternal Nutrition Study (PMNS) birth cohort underwent serial measurements of glycaemia from early childhood, through puberty, young adulthood, pregnancy and later, providing a unique opportunity to test the hypothesis that pregnancy glycaemia (fasting plasma glucose and/or OGTT AUC) is only a window on a lifetime glycaemic trajectory.METHODSFemale participants in the PMNS birth cohort, established in 1993, underwent serial glucose measurements at ages 6, 12 and 18 years, and during pregnancy and post-delivery follow-up. Of 366 female cohort members, 171 became pregnant and delivered by February 2020. Given the small number of GDM cases (n=20, IADPSG criteria), we divided women into quartiles of fasting plasma glucose (FPG) and AUC during an OGTT at 28 weeks' gestation to study life-course tracking of pregnancy glycaemia.RESULTSAt 28 weeks' gestation, the women (mean age 20.9 years) had a median BMI of 21.7 kg/m2 (IQR 20.0-23.8). Forty-four women were in the highest quartile (Q4) of FPG (>4.7 mmol/l) and 39 were in Q4 of OGTT AUC (>8.57 × 102 mmol/l x min). Both Q4 groups had higher glycaemia from childhood through to post-delivery compared with those in lower quartiles (Q1+2+3), and higher HbA1c pre-pregnancy. Being in Q4 of FPG from childhood increased the odds of being in Q4 of FPG during pregnancy 2.22-fold (95% CI 1.45, 3.38) and increased the odds of post-delivery glucose intolerance (prediabetes + diabetes) 5.22-fold (95% CI 2.40, 11.33). For Q4 of OGTT AUC, the corresponding ORs were 2.88 (95% CI 1.32, 6.28) and 3.50 (95% CI 1.36, 8.97), respectively.CONCLUSIONS/INTERPRETATIONIn this cohort of rural lean Indian women, higher pregnancy glycaemia reflects persistently higher glycaemia since childhood. Coupled with the existing evidence that women with GDM have higher glycaemia from before pregnancy, our results suggest that pregnancy hyperglycaemia is only a window on a life-course of hyperglycaemia and not a de novo phenomenon. This has implications for the timing of diagnosis and management of pregnancy hyperglycaemia (GDM).
目的/假设传统上，妊娠期糖尿病（GDM）（这里定义为妊娠期间首次检测到的高血糖）被认为是一种短暂的妊娠状态，但有证据表明，它通常是一种预先存在的慢性疾病。有研究报道，被诊断为GDM的女性在怀孕前就患有高血糖、肥胖和胰岛素抵抗。然而，对妊娠前血糖的生命过程演变知之甚少。普纳产妇营养研究（PMNS）出生队列的参与者从儿童早期、青春期、青年期、妊娠期及以后进行了一系列血糖测量，提供了一个独特的机会来检验妊娠血糖（空腹血糖和/或OGTT AUC）只是一生血糖轨迹的一个窗口。方法：在1993年建立的PMNS出生队列中，女性参与者在6岁、12岁和18岁时以及怀孕和分娩后随访期间进行了连续的血糖测量。在366名女性队列成员中，有171人在2020年2月之前怀孕并分娩。考虑到GDM病例较少（n=20， IADPSG标准），我们在妊娠28周OGTT期间将女性空腹血糖（FPG）和AUC分为四分位数，以研究妊娠血糖的生命历程跟踪。结果在妊娠28周时，这些女性（平均年龄20.9岁）的中位BMI为21.7 kg/m2 （IQR为20.0-23.8）。FPG最高四分位数（Q4） 44例（>4.7 mmol/l）， OGTT AUC最高四分位数（Q4） 39例（>8.57 × 102 mmol/l x min）。与低四分位数组（Q1+2+3）相比，Q4组从儿童期到分娩后血糖都较高，孕前HbA1c也较高。儿童期患有FPG Q4的患者在妊娠期出现FPG Q4的几率增加了2.22倍（95% CI 1.45, 3.38），分娩后出现葡萄糖耐受不良（前驱糖尿病+糖尿病）的几率增加了5.22倍（95% CI 2.40, 11.33）。对于第四季度OGTT AUC，相应的or分别为2.88 （95% CI 1.32, 6.28）和3.50 （95% CI 1.36, 8.97）。结论/解释：在印度农村瘦弱妇女队列中，较高的妊娠血糖反映了自童年以来持续较高的血糖。结合现有证据表明，妊娠期糖尿病女性在怀孕前血糖较高，我们的研究结果表明，妊娠期高血糖只是高血糖生命过程中的一个窗口，而不是一种新生现象。这对妊娠期高血糖（GDM）的诊断和治疗具有重要意义。
{"title":"Gestational glycaemia reflects lifelong glycaemia: the Pune Maternal Nutrition Study.","authors":"Chittaranjan S Yajnik,Souvik Bandyopadhyay,Dattatray S Bhat,Rucha S H Wagh,Pallavi C Yajnik,Rasika Ladkat,Kurus Coyaji,Caroline H D Fall","doi":"10.1007/s00125-025-06625-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06625-x","url":null,"abstract":"AIMS/HYPOTHESISTraditionally, gestational diabetes mellitus (GDM) (defined here as hyperglycaemia first detected during pregnancy) has been considered to be a transient condition of pregnancy, but evidence suggests it is often a pre-existing chronic condition. Studies have reported that women diagnosed with GDM were hyperglycaemic, obese and insulin-resistant from before pregnancy. However, little is known about the life-course evolution of glycaemia before pregnancy. Participants in the Pune Maternal Nutrition Study (PMNS) birth cohort underwent serial measurements of glycaemia from early childhood, through puberty, young adulthood, pregnancy and later, providing a unique opportunity to test the hypothesis that pregnancy glycaemia (fasting plasma glucose and/or OGTT AUC) is only a window on a lifetime glycaemic trajectory.METHODSFemale participants in the PMNS birth cohort, established in 1993, underwent serial glucose measurements at ages 6, 12 and 18 years, and during pregnancy and post-delivery follow-up. Of 366 female cohort members, 171 became pregnant and delivered by February 2020. Given the small number of GDM cases (n=20, IADPSG criteria), we divided women into quartiles of fasting plasma glucose (FPG) and AUC during an OGTT at 28 weeks' gestation to study life-course tracking of pregnancy glycaemia.RESULTSAt 28 weeks' gestation, the women (mean age 20.9 years) had a median BMI of 21.7 kg/m2 (IQR 20.0-23.8). Forty-four women were in the highest quartile (Q4) of FPG (>4.7 mmol/l) and 39 were in Q4 of OGTT AUC (>8.57 × 102 mmol/l x min). Both Q4 groups had higher glycaemia from childhood through to post-delivery compared with those in lower quartiles (Q1+2+3), and higher HbA1c pre-pregnancy. Being in Q4 of FPG from childhood increased the odds of being in Q4 of FPG during pregnancy 2.22-fold (95% CI 1.45, 3.38) and increased the odds of post-delivery glucose intolerance (prediabetes + diabetes) 5.22-fold (95% CI 2.40, 11.33). For Q4 of OGTT AUC, the corresponding ORs were 2.88 (95% CI 1.32, 6.28) and 3.50 (95% CI 1.36, 8.97), respectively.CONCLUSIONS/INTERPRETATIONIn this cohort of rural lean Indian women, higher pregnancy glycaemia reflects persistently higher glycaemia since childhood. Coupled with the existing evidence that women with GDM have higher glycaemia from before pregnancy, our results suggest that pregnancy hyperglycaemia is only a window on a life-course of hyperglycaemia and not a de novo phenomenon. This has implications for the timing of diagnosis and management of pregnancy hyperglycaemia (GDM).","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"239 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710986","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 : 2025-12-09DOI: 10.1007/s00125-025-06619-9
Olivia M. McCarthy, Rasmus B. Brødsgaard, Sandra Tawfik, Sissel Banner Lundemose, Emilie B. Lindkvist, Sara H. Naaman, Christian Stevns Hansen, Richard M. Bracken, Kirsten Nørgaard
{"title":"Impact of cardiovascular autonomic neuropathy on cardiopulmonary, sympathoadrenal and metabolic responses to physical exercise in adults with type 1 diabetes","authors":"Olivia M. McCarthy, Rasmus B. Brødsgaard, Sandra Tawfik, Sissel Banner Lundemose, Emilie B. Lindkvist, Sara H. Naaman, Christian Stevns Hansen, Richard M. Bracken, Kirsten Nørgaard","doi":"10.1007/s00125-025-06619-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06619-9","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"134 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703880","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 : 2025-12-09DOI: 10.1007/s00125-025-06616-y
Roopameera Thirumathyam,Erik A Richter,Gerrit van Hall,Nicoline R Andersen,Per L Madsen,Jens J Holst,Sten Madsbad,Nils B Jørgensen
AIMS/HYPOTHESISSodium-glucose co-transporter 2 (SGLT2) inhibitors improve beta cell function in individuals with type 2 diabetes. It has been suggested this is due to relief of glucotoxicity, but the mechanism is unknown. The objective of the present study was to evaluate the effect of the SGLT2 inhibitor empagliflozin, compared with NPH insulin treatment, on beta cell function, and, secondarily, on insulin sensitivity.METHODSIn this open-label, randomised, cross-over study, 17 individuals with non-insulin-treated type 2 diabetes were randomised to receive 5 weeks of treatment with either empagliflozin or insulin titrated to a similar level of glycaemic control as with empagliflozin before crossing over to the other treatment. Key inclusion criteria included age ≥18 years, BMI ≥ 28 kg/m2, and a diabetes duration of more than 3 months. Treatments were preceded by a 3 week washout. Fasting and post-OGTT (5 h) metabolism were studied before and during treatments. Beta cell glucose sensitivity (bGS) was calculated as the slope of the linear relationship between the pre-hepatic insulin secretion rate and the corresponding plasma glucose value, and insulin sensitivity was calculated as glucose clearance relative to insulin concentrations. Endogenous glucose production, tissue glucose disposal and lipolysis were measured using stable isotopes. The disposition index was calculated as bGS × insulin sensitivity to assess beta cell function. Data for the present study were collected at the Department of Endocrinology, Hvidovre Hospital, Denmark.RESULTSAll participants who completed the study were included in the analyses. With equipoised glycaemic control, insulin concentrations were higher during insulin treatment than during empagliflozin treatment. bGS and insulin sensitivity were higher during empagliflozin treatment than during insulin treatment. The disposition index thus improved during empagliflozin treatment compared with insulin treatment.CONCLUSIONS/INTERPRETATIONWith similar glycaemic control, insulin sensitivity was higher and beta cell function improved during empagliflozin compared with insulin treatment, possibly due to a disinhibitory effect of lower insulin concentrations.TRIAL REGISTRATIONEudraCT 2017-002101-35.FUNDINGThis study was supported by Boehringer Ingelheim. Additional funding was provided by the Grosserer L.F. Foghts Fond, Charlottenlund, Denmark.
钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂改善2型糖尿病患者的β细胞功能有人认为这是由于糖毒性的缓解，但其机制尚不清楚。本研究的目的是评估SGLT2抑制剂恩格列净与NPH胰岛素治疗相比对β细胞功能的影响，其次是对胰岛素敏感性的影响。方法：在这项开放标签、随机、交叉研究中，17名非胰岛素治疗的2型糖尿病患者被随机分组，接受5周的恩格列净或胰岛素治疗，在转入另一种治疗之前，恩格列净或胰岛素的血糖控制水平与恩格列净相似。主要纳入标准为年龄≥18岁，BMI≥28 kg/m2，糖尿病病程超过3个月。治疗前有3周的洗脱期。在治疗前和治疗期间研究空腹和ogtt后（5 h）代谢。β细胞葡萄糖敏感性（bGS）计算为肝前胰岛素分泌率与相应血浆葡萄糖值之间线性关系的斜率，胰岛素敏感性计算为葡萄糖清除率相对于胰岛素浓度。内源性葡萄糖生成、组织葡萄糖处理和脂肪分解用稳定同位素测量。处置指数计算为bGS ×胰岛素敏感性，以评估β细胞功能。本研究的数据收集于丹麦Hvidovre医院内分泌科。结果所有完成研究的参与者均被纳入分析。在血糖控制均衡的情况下，胰岛素治疗组的胰岛素浓度高于恩格列净治疗组。依帕列净组bGS和胰岛素敏感性高于胰岛素组。因此，与胰岛素治疗相比，恩格列净治疗期间的处置指数有所改善。结论/解释在血糖控制相似的情况下，与胰岛素治疗相比，恩格列净治疗组胰岛素敏感性更高，β细胞功能得到改善，这可能是由于较低胰岛素浓度的去抑制作用。试验注册草案2017-002101-35。本研究得到勃林格殷格翰公司的支持。额外的资金由丹麦夏洛滕隆德的Grosserer L.F. fogts Fond提供。
{"title":"Empagliflozin improves beta cell function independently of relief of glucotoxicity in patients with type 2 diabetes: results from a randomised cross-over study with insulin as comparator.","authors":"Roopameera Thirumathyam,Erik A Richter,Gerrit van Hall,Nicoline R Andersen,Per L Madsen,Jens J Holst,Sten Madsbad,Nils B Jørgensen","doi":"10.1007/s00125-025-06616-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06616-y","url":null,"abstract":"AIMS/HYPOTHESISSodium-glucose co-transporter 2 (SGLT2) inhibitors improve beta cell function in individuals with type 2 diabetes. It has been suggested this is due to relief of glucotoxicity, but the mechanism is unknown. The objective of the present study was to evaluate the effect of the SGLT2 inhibitor empagliflozin, compared with NPH insulin treatment, on beta cell function, and, secondarily, on insulin sensitivity.METHODSIn this open-label, randomised, cross-over study, 17 individuals with non-insulin-treated type 2 diabetes were randomised to receive 5 weeks of treatment with either empagliflozin or insulin titrated to a similar level of glycaemic control as with empagliflozin before crossing over to the other treatment. Key inclusion criteria included age ≥18 years, BMI ≥ 28 kg/m2, and a diabetes duration of more than 3 months. Treatments were preceded by a 3 week washout. Fasting and post-OGTT (5 h) metabolism were studied before and during treatments. Beta cell glucose sensitivity (bGS) was calculated as the slope of the linear relationship between the pre-hepatic insulin secretion rate and the corresponding plasma glucose value, and insulin sensitivity was calculated as glucose clearance relative to insulin concentrations. Endogenous glucose production, tissue glucose disposal and lipolysis were measured using stable isotopes. The disposition index was calculated as bGS × insulin sensitivity to assess beta cell function. Data for the present study were collected at the Department of Endocrinology, Hvidovre Hospital, Denmark.RESULTSAll participants who completed the study were included in the analyses. With equipoised glycaemic control, insulin concentrations were higher during insulin treatment than during empagliflozin treatment. bGS and insulin sensitivity were higher during empagliflozin treatment than during insulin treatment. The disposition index thus improved during empagliflozin treatment compared with insulin treatment.CONCLUSIONS/INTERPRETATIONWith similar glycaemic control, insulin sensitivity was higher and beta cell function improved during empagliflozin compared with insulin treatment, possibly due to a disinhibitory effect of lower insulin concentrations.TRIAL REGISTRATIONEudraCT 2017-002101-35.FUNDINGThis study was supported by Boehringer Ingelheim. Additional funding was provided by the Grosserer L.F. Foghts Fond, Charlottenlund, Denmark.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"364 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710989","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/HYPOTHESISA highly specific mosaic transcriptional environment guides the fate of pancreatic progenitors during development and maintains the identity of mature endocrine cells. In mice, one such transcription factor is MNX1 (motor neuron and pancreas homeobox1). It is essential for beta cell development and identity, as its deletion in mature beta cells increases their somatostatin expression via an unknown mechanism. Here, we determined whether MNX1 plays a similar role in human beta cells. and dissected the molecular players involved in its function.METHODSWe used the human beta cell line EndoC-BH1, knocked down MNX1 expression using siRNA, and performed bulk RNA sequencing searching for MNX1 targets. We next performed loss-of-function (siRNA) and gain-of-function (transduction with lentivectors and lipofections) experiments to determine how MNX1 regulates gene expression in human beta cells.RESULTSsiRNA-mediated downregulation of MNX1 in EndoC-BH1 cells induced the upregulation of somatostatin as well as its transcriptional activator haematopoietically expressed homeobox (HHEX) by more than fivefold. RNA-seq revealed PERCC1 (encoding proline and glutamate rich with coiled coil 1) to be among one of the highest upregulated genes, with eightfold induction. siRNA-mediated partial loss of PERCC1 upon MNX1 knockdown moderately impaired the upregulation of both SST and HHEX expression, while PERCC1 overexpression upregulated the expression of both HHEX and SST. PERCC1 expression was tightly regulated by HHEX and by its own expression in a positive feedback mechanism. Moreover, downregulation of NKX2.2, whose knockout in mice induces somatostatin upregulation, led to the upregulation of PERCC1, HHEX and SST in EndoC-BH1 cells. Finally, overexpression of PERCC1 in primary mouse beta cells revealed upregulation of both mouse Hhex and Sst.CONCLUSIONS/INTERPRETATIONWe discovered a novel MNX1-PERCC1-HHEX regulatory axis in human beta cells. In these cells, MNX1 protects beta cell identity by inhibiting PERCC1, an activator of HHEX and SST expression. PERCC1 may thus be considered as a sharply tuned central hub for somatostatin regulation. Our results increase our knowledge of beta cell plasticity, and may have implications for therapeutic strategies aimed at protecting beta cell identity.
{"title":"MNX1 prevents somatostatin expression in human beta cells by repressing PERCC1.","authors":"Farah Kobaisi,Alexis Fouque,Philippe Ravassard,Olivier Albagli-Curiel,Raphael Scharfmann","doi":"10.1007/s00125-025-06620-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06620-2","url":null,"abstract":"AIMS/HYPOTHESISA highly specific mosaic transcriptional environment guides the fate of pancreatic progenitors during development and maintains the identity of mature endocrine cells. In mice, one such transcription factor is MNX1 (motor neuron and pancreas homeobox1). It is essential for beta cell development and identity, as its deletion in mature beta cells increases their somatostatin expression via an unknown mechanism. Here, we determined whether MNX1 plays a similar role in human beta cells. and dissected the molecular players involved in its function.METHODSWe used the human beta cell line EndoC-BH1, knocked down MNX1 expression using siRNA, and performed bulk RNA sequencing searching for MNX1 targets. We next performed loss-of-function (siRNA) and gain-of-function (transduction with lentivectors and lipofections) experiments to determine how MNX1 regulates gene expression in human beta cells.RESULTSsiRNA-mediated downregulation of MNX1 in EndoC-BH1 cells induced the upregulation of somatostatin as well as its transcriptional activator haematopoietically expressed homeobox (HHEX) by more than fivefold. RNA-seq revealed PERCC1 (encoding proline and glutamate rich with coiled coil 1) to be among one of the highest upregulated genes, with eightfold induction. siRNA-mediated partial loss of PERCC1 upon MNX1 knockdown moderately impaired the upregulation of both SST and HHEX expression, while PERCC1 overexpression upregulated the expression of both HHEX and SST. PERCC1 expression was tightly regulated by HHEX and by its own expression in a positive feedback mechanism. Moreover, downregulation of NKX2.2, whose knockout in mice induces somatostatin upregulation, led to the upregulation of PERCC1, HHEX and SST in EndoC-BH1 cells. Finally, overexpression of PERCC1 in primary mouse beta cells revealed upregulation of both mouse Hhex and Sst.CONCLUSIONS/INTERPRETATIONWe discovered a novel MNX1-PERCC1-HHEX regulatory axis in human beta cells. In these cells, MNX1 protects beta cell identity by inhibiting PERCC1, an activator of HHEX and SST expression. PERCC1 may thus be considered as a sharply tuned central hub for somatostatin regulation. Our results increase our knowledge of beta cell plasticity, and may have implications for therapeutic strategies aimed at protecting beta cell identity.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"30 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696691","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 : 2025-12-08DOI: 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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：