Pub Date : 2025-12-15DOI: 10.1007/s00125-025-06636-8
Wonsuk Choi
{"title":"Impact of normoglycaemia and prediabetes definitions on the estimated benefits of regression from prediabetes to normoglycaemia for type 2 diabetes risk","authors":"Wonsuk Choi","doi":"10.1007/s00125-025-06636-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06636-8","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"20 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759764","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/HYPOTHESISGestational diabetes mellitus (GDM) is associated with placental hormone-induced insulin resistance; however, the mechanisms connecting hyperglycaemia to mitochondrial dysfunction remain incompletely understood. This study aimed to investigate the role of the α7 nicotinic acetylcholine receptor (α7nAChR) in regulating mitochondrial Ca2⁺ homeostasis in trophoblasts under hyperglycaemic stress, and to explore whether its dysregulation contributes to placental mitochondrial pathology in GDM.METHODSClinical placental samples from GDM pregnancies were analysed to assess α7nAChR expression, mitochondrial morphology and Ca2⁺ signalling pathways. Complementary in vitro and murine models of hyperglycaemia were employed to examine molecular interactions involving α7nAChR, voltage-dependent anion channel 1 (VDAC1) and p66Shc. Mitochondrial-associated endoplasmic reticulum membranes were studied to evaluate pathological Ca2⁺ transfer mechanisms. Pharmacological activation of α7nAChR was performed using PNU-282987 (PNU) or GTS-21, and RNA-seq was conducted to analyse downstream transcriptional changes related to mitochondrial dysfunction and cellular senescence.RESULTSClinical analysis revealed reduced α7nAChR expression, mitochondrial vacuolisation and dysregulated Ca2⁺ signalling pathways in GDM placentas. Under hyperglycaemic conditions, disrupted α7nAChR-VDAC1 interactions facilitated competitive binding of the pro-oxidant p66Shc to VDAC1, promoting pathological Ca2⁺ transfer from the endoplasmic reticulum to mitochondria via mitochondrial-associated endoplasmic reticulum membranes. This led to mitochondrial permeability transition pore overactivation, loss of mitochondrial membrane potential and induction of cellular senescence. Pharmacological activation of α7nAChR with PNU or GTS-21 restored α7nAChR-VDAC1 coupling, attenuated p66Shc-mediated oxidative stress and reversed mitochondrial Ca2⁺ overload. RNA-seq confirmed that PNU treatment normalised gene expression profiles associated with endoplasmic reticulum stress and cellular senescence.CONCLUSIONS/INTERPRETATIONThis study identifies a non-canonical role for α7nAChR in maintaining mitochondrial Ca2⁺ homeostasis by competitively regulating VDAC1-p66Shc interactions under hyperglycaemic conditions. The findings reveal a mechanistic link between α7nAChR dysfunction, mitochondrial Ca2⁺ overload and cellular senescence in GDM placentas. Targeting α7nAChR with pharmacological agents such as GTS-21 may offer a novel therapeutic approach to ameliorate mitochondrial dysfunction and placental pathology in GDM by restoring Ca2⁺ dynamics.
{"title":"α7 Nicotinic acetylcholine receptor activation rescues mitochondrial dysfunction in gestational diabetes mellitus by competing with p66Shc for VDAC1 binding.","authors":"Lulu Ji,Yaru Nai,Zhiguo Chen,Yu Zhong,Hengxuan Zhu,Yanyi Huang,Xiaoli Zhang,Yuexiao Wang,Xiting Yang,Qiongtao Wang,Hanyang Hu,Lin Wang","doi":"10.1007/s00125-025-06640-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06640-y","url":null,"abstract":"AIMS/HYPOTHESISGestational diabetes mellitus (GDM) is associated with placental hormone-induced insulin resistance; however, the mechanisms connecting hyperglycaemia to mitochondrial dysfunction remain incompletely understood. This study aimed to investigate the role of the α7 nicotinic acetylcholine receptor (α7nAChR) in regulating mitochondrial Ca2⁺ homeostasis in trophoblasts under hyperglycaemic stress, and to explore whether its dysregulation contributes to placental mitochondrial pathology in GDM.METHODSClinical placental samples from GDM pregnancies were analysed to assess α7nAChR expression, mitochondrial morphology and Ca2⁺ signalling pathways. Complementary in vitro and murine models of hyperglycaemia were employed to examine molecular interactions involving α7nAChR, voltage-dependent anion channel 1 (VDAC1) and p66Shc. Mitochondrial-associated endoplasmic reticulum membranes were studied to evaluate pathological Ca2⁺ transfer mechanisms. Pharmacological activation of α7nAChR was performed using PNU-282987 (PNU) or GTS-21, and RNA-seq was conducted to analyse downstream transcriptional changes related to mitochondrial dysfunction and cellular senescence.RESULTSClinical analysis revealed reduced α7nAChR expression, mitochondrial vacuolisation and dysregulated Ca2⁺ signalling pathways in GDM placentas. Under hyperglycaemic conditions, disrupted α7nAChR-VDAC1 interactions facilitated competitive binding of the pro-oxidant p66Shc to VDAC1, promoting pathological Ca2⁺ transfer from the endoplasmic reticulum to mitochondria via mitochondrial-associated endoplasmic reticulum membranes. This led to mitochondrial permeability transition pore overactivation, loss of mitochondrial membrane potential and induction of cellular senescence. Pharmacological activation of α7nAChR with PNU or GTS-21 restored α7nAChR-VDAC1 coupling, attenuated p66Shc-mediated oxidative stress and reversed mitochondrial Ca2⁺ overload. RNA-seq confirmed that PNU treatment normalised gene expression profiles associated with endoplasmic reticulum stress and cellular senescence.CONCLUSIONS/INTERPRETATIONThis study identifies a non-canonical role for α7nAChR in maintaining mitochondrial Ca2⁺ homeostasis by competitively regulating VDAC1-p66Shc interactions under hyperglycaemic conditions. The findings reveal a mechanistic link between α7nAChR dysfunction, mitochondrial Ca2⁺ overload and cellular senescence in GDM placentas. Targeting α7nAChR with pharmacological agents such as GTS-21 may offer a novel therapeutic approach to ameliorate mitochondrial dysfunction and placental pathology in GDM by restoring Ca2⁺ dynamics.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"112 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752613","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 : 2025-12-12DOI: 10.1007/s00125-025-06641-x
Najmeh Davoodian,Mojtaba Lotfaliany,Rachel R Huxley,Crystal M Y Lee,Julie A Pasco,Robert J Adams,Fereidoun Azizi,Alain G Bertoni,Stephen Colagiuri,Edward W Gregg,Tiffany K Gill,Farzad Hadaegh,Davood Khalili,Dianna J Magliano,Morgana Mongraw-Chaffin,Gita D Mishra,Jonathan E Shaw,Masaru Sakurai,Hiroshi Yatsuya,Mohammadreza Mohebbi
{"title":"Impact of normoglycaemia and prediabetes definitions on the estimated benefits of regression from prediabetes to normoglycaemia for type 2 diabetes risk. Reply to Choi W [Letter].","authors":"Najmeh Davoodian,Mojtaba Lotfaliany,Rachel R Huxley,Crystal M Y Lee,Julie A Pasco,Robert J Adams,Fereidoun Azizi,Alain G Bertoni,Stephen Colagiuri,Edward W Gregg,Tiffany K Gill,Farzad Hadaegh,Davood Khalili,Dianna J Magliano,Morgana Mongraw-Chaffin,Gita D Mishra,Jonathan E Shaw,Masaru Sakurai,Hiroshi Yatsuya,Mohammadreza Mohebbi","doi":"10.1007/s00125-025-06641-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06641-x","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"231 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732750","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 : 2025-12-12DOI: 10.1007/s00125-025-06632-y
Yiying Wang,Jagannathan Ram,Cristina Bianchi,Teresa Vanessa Fiorentino,Sang Soo Kim,Jinmi Kim,Soree Ryang,Stefano Del Prato,Giorgio Sesti,Leontine Sandforth,Hubert Preissl,Reiner Jumpertz von Schwartzenberg,Norbert Stefan,Andreas Fritsche,Joon Ha,Andreas L Birkenfeld,Michael Bergman
AIMS/HYPOTHESISThe IDF has proposed 1 h plasma glucose (1 h PG) as a diagnostic test for type 2 diabetes. This study evaluated the utility of 1 h PG in diagnosing type 2 diabetes, compared with fasting plasma glucose (FPG), 2 h plasma glucose (2 h PG), HbA1c and the combination of HbA1c plus FPG.METHODSAnalyses were conducted using data from five independent cohorts: KoGES, CATAMERI, GENFIEV, PLIS (follow-up) and TULIP (follow-up). Type 2 diabetes was defined according to ADA criteria (FPG ≥7.0 mmol/l [≥126 mg/dl], 2 h PG ≥11.1 mmol/l [≥200 mg/dl] or HbA1c ≥48 mmol/mol [≥6.5%]) or IDF criteria (1 h PG ≥11.6 mmol/l [≥209 mg/dl]). Area under of the receiver operating characteristic curves (AUC-ROCs) were used to assess the performance of 1 h PG relative to FPG and HbA1c, individually and in combination, for diagnosing diabetes. Random-effects meta-analyses were applied to pooled data to summarise the overall diagnostic accuracy across studies.RESULTSCohort-specific analyses demonstrated consistently higher AUCs for 1 h PG in KoGES (AUC 0.96 vs 0.88; Δ 0.08; sensitivity 84.2 vs 77.0; specificity 98.6 vs 87.0), CATAMERI (AUC 0.98 vs 0.86; Δ 0.12; sensitivity 75.0 vs 69.4; specificity: 98.4 vs 78.9), GENFIEV (AUC 0.97 vs 0.89; Δ 0.08; sensitivity 89.5 vs 69.4; specificity 100.0 vs 88.3), PLIS follow-up (AUC 0.98 vs 0.76; Δ 0.22; sensitivity 94.9 vs 46.8; specificity 100.0 vs 92.3) and TULIP follow-up (AUC 0.98 vs 0.83; Δ 0.15; sensitivity 90.2 vs 90.2; specificity 100.0 vs 65.0) compared with FPG plus HbA1c (all p<0.001). Meta-analysis of five cohorts (N=11,968) revealed superior diagnostic performance of 1 h PG compared with FPG plus HbA1c, with pooled AUCs (95% CI) of 0.97 (0.96, 0.98) vs 0.85 (0.82, 0.88).CONCLUSIONS/INTERPRETATIONThese findings support the superior utility of the IDF-recommended 1 h PG vs FPG, 2 h PG, HbA1c and FPG plus HbA1c for diagnosing type 2 diabetes.
目的/假设IDF建议将1 h血浆葡萄糖（1 h PG）作为2型糖尿病的诊断试验。本研究评估了1h PG与空腹血糖（FPG）、2h血糖（2h PG）、HbA1c以及HbA1c + FPG联合诊断2型糖尿病的效用。方法采用KoGES、CATAMERI、GENFIEV、PLIS（随访）和TULIP（随访）五个独立队列的数据进行分析。根据ADA标准（FPG≥7.0 mmol/l[≥126 mg/dl], 2 h PG≥11.1 mmol/l[≥200 mg/dl]或HbA1c≥48 mmol/mol[≥6.5%]）或IDF标准（1 h PG≥11.6 mmol/l[≥209 mg/dl]）定义2型糖尿病。采用受试者工作特征曲线下面积（auc - roc）分别或联合评估1 h PG相对于FPG和HbA1c的表现，用于诊断糖尿病。随机效应荟萃分析应用于汇总数据，以总结所有研究的总体诊断准确性。RESULTSCohort-specific分析证明持续高1 h PG的AUC KoGES (AUC 0.96 vs 0.88;Δ0.08;灵敏度84.2 vs 77.0;特异性98.6 vs 87.0), CATAMERI (AUC 0.98 vs 0.86;Δ0.12;灵敏度75.0 vs 69.4;特异性:98.4 vs 78.9), GENFIEV (AUC 0.97 vs 0.89;Δ0.08;灵敏度89.5 vs 69.4;特异性100.0 vs 88.3),刺随访(AUC 0.98 vs 0.76;Δ0.22;灵敏度94.9 vs 46.8;特异性100.0 vs 92.3)和郁金香随访(AUC 0.98 vs 0.83;Δ0.15;灵敏度90.2 vs 90.2；特异性100.0 vs 65.0)，与FPG + HbA1c相比（均p<0.001）。5个队列（N= 11968）的荟萃分析显示，与FPG + HbA1c相比，1 h PG的诊断性能更好，合并auc （95% CI）为0.97 (0.96,0.98)vs 0.85（0.82, 0.88）。结论/解释：这些发现支持idf推荐的1小时PG与FPG、2小时PG、HbA1c和FPG + HbA1c诊断2型糖尿病的优势。
{"title":"Superiority of 1 h plasma glucose vs fasting plasma glucose, 2 h plasma glucose and HbA1c for the diagnosis of type 2 diabetes.","authors":"Yiying Wang,Jagannathan Ram,Cristina Bianchi,Teresa Vanessa Fiorentino,Sang Soo Kim,Jinmi Kim,Soree Ryang,Stefano Del Prato,Giorgio Sesti,Leontine Sandforth,Hubert Preissl,Reiner Jumpertz von Schwartzenberg,Norbert Stefan,Andreas Fritsche,Joon Ha,Andreas L Birkenfeld,Michael Bergman","doi":"10.1007/s00125-025-06632-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06632-y","url":null,"abstract":"AIMS/HYPOTHESISThe IDF has proposed 1 h plasma glucose (1 h PG) as a diagnostic test for type 2 diabetes. This study evaluated the utility of 1 h PG in diagnosing type 2 diabetes, compared with fasting plasma glucose (FPG), 2 h plasma glucose (2 h PG), HbA1c and the combination of HbA1c plus FPG.METHODSAnalyses were conducted using data from five independent cohorts: KoGES, CATAMERI, GENFIEV, PLIS (follow-up) and TULIP (follow-up). Type 2 diabetes was defined according to ADA criteria (FPG ≥7.0 mmol/l [≥126 mg/dl], 2 h PG ≥11.1 mmol/l [≥200 mg/dl] or HbA1c ≥48 mmol/mol [≥6.5%]) or IDF criteria (1 h PG ≥11.6 mmol/l [≥209 mg/dl]). Area under of the receiver operating characteristic curves (AUC-ROCs) were used to assess the performance of 1 h PG relative to FPG and HbA1c, individually and in combination, for diagnosing diabetes. Random-effects meta-analyses were applied to pooled data to summarise the overall diagnostic accuracy across studies.RESULTSCohort-specific analyses demonstrated consistently higher AUCs for 1 h PG in KoGES (AUC 0.96 vs 0.88; Δ 0.08; sensitivity 84.2 vs 77.0; specificity 98.6 vs 87.0), CATAMERI (AUC 0.98 vs 0.86; Δ 0.12; sensitivity 75.0 vs 69.4; specificity: 98.4 vs 78.9), GENFIEV (AUC 0.97 vs 0.89; Δ 0.08; sensitivity 89.5 vs 69.4; specificity 100.0 vs 88.3), PLIS follow-up (AUC 0.98 vs 0.76; Δ 0.22; sensitivity 94.9 vs 46.8; specificity 100.0 vs 92.3) and TULIP follow-up (AUC 0.98 vs 0.83; Δ 0.15; sensitivity 90.2 vs 90.2; specificity 100.0 vs 65.0) compared with FPG plus HbA1c (all p<0.001). Meta-analysis of five cohorts (N=11,968) revealed superior diagnostic performance of 1 h PG compared with FPG plus HbA1c, with pooled AUCs (95% CI) of 0.97 (0.96, 0.98) vs 0.85 (0.82, 0.88).CONCLUSIONS/INTERPRETATIONThese findings support the superior utility of the IDF-recommended 1 h PG vs FPG, 2 h PG, HbA1c and FPG plus HbA1c for diagnosing type 2 diabetes.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"66 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732749","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 : 2025-12-11DOI: 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。
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