Pub Date : 2025-12-19DOI: 10.1007/s00125-025-06637-7
João Sérgio Neves,Ana Rita Leite,Catarina Vale,Pedro Marques,Francisco Vasques-Nóvoa,Adelino Leite-Moreira,João Pedro Ferreira
AIMS/HYPOTHESISSimultaneous control of HbA1c, lipid profile, BP and body weight is essential for preventing chronic complications of type 2 diabetes. Glucagon-like peptide-1 (GLP-1)-based therapies improve all these variables but whether the dual GLP-1 / glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide is superior to semaglutide in attaining therapeutic targets remains unclear.METHODSWe performed a post hoc analysis of the SURPASS-2 trial, a randomised phase 3 study including 1879 adults with type 2 diabetes. Participants were randomised to receive tirzepatide (5, 10 or 15 mg) or semaglutide (1 mg). In this analysis, we compared the effects of tirzepatide vs semaglutide on the attainment of standard (HbA1c <53 mmol/mol [7%], BP <140/90 mmHg, LDL-cholesterol <1.8 mmol/l, >10% weight loss) and intensive (HbA1c <48 mmol/mol [6.5%], BP <130/80 mmHg, LDL-cholesterol <1.4 mmol/l , >15% weight loss) therapeutic targets at 40 weeks.RESULTSIn the SURPASS-2 trial, at baseline, 19% of participants were on target for attaining no standard goals, 59% for one goal and 21% for two or more goals. For intensive therapeutic targets, 58% of participants were on target for attaining zero goals, 38% for one goal and 4% for two goals. All doses of tirzepatide increased the number of achieved standard and intensive targets compared with semaglutide. For standard targets, 34% of participants treated with semaglutide met three or more targets, compared with 42%, 53% and 57% with tirzepatide 5, 10 and 15 mg, respectively. For intensive targets, 8% of participants treated with semaglutide met three or more targets, vs 15%, 20% and 29% with tirzepatide. Regarding specific therapeutic goals, tirzepatide increased the odds of achieving standard and intensive targets for HbA1c (HbA1c <53 mmol/mol [7%], OR 1.50 [95% CI 1.12, 2.00]; HbA1c <48 mmol/mol [6.5%], OR 1.88 [95%CI 1.49, 2.36]) and weight loss (weight loss >10%, OR 2.72 [95% CI 2.14, 3.47]; weight loss >15%, OR 3.86 [95% CI 2.69, 5.55]) and the intensive target for BP (OR 1.45 [95% CI 1.17, 1.81]).CONCLUSIONS/INTERPRETATIONTirzepatide improves therapeutic target attainment compared with semaglutide in type 2 diabetes. Longer trials are needed to confirm benefits on long-term prognosis.DATA AVAILABILITYData for this post hoc analysis was accessed through the Vivli (Center for Global Clinical Research Data) platform ( https://vivli.org ) with the Vivli ID 00009964.
目的/假设同时控制HbA1c、血脂、血压和体重对于预防2型糖尿病的慢性并发症至关重要。以胰高血糖素样肽-1 （GLP-1）为基础的治疗改善了所有这些变量，但GLP-1 /葡萄糖依赖性胰岛素多肽（GIP）激动剂替西帕肽在达到治疗目标方面是否优于半马鲁肽尚不清楚。方法：我们对SURPASS-2试验进行了事后分析，该试验是一项包括1879名2型糖尿病成人患者的随机3期研究。参与者随机接受替西帕肽（5、10或15毫克）或西马鲁肽（1毫克）治疗。在这项分析中，我们比较了替西帕肽和西马鲁肽在40周时达到标准（HbA1c减轻10%体重）和强化（HbA1c减轻15%体重）治疗目标的效果。结果在SURPASS-2试验中，在基线时，19%的参与者没有达到标准目标，59%达到一个目标，21%达到两个或更多目标。对于强化治疗目标，58%的参与者达到了零目标，38%达到了一个目标，4%达到了两个目标。与西马鲁肽相比，所有剂量的替西帕肽都增加了达到标准和强化目标的数量。对于标准目标，接受西马鲁肽治疗的参与者中有34%达到了三个或更多的目标，而接受替西帕肽5、10和15mg治疗的参与者分别为42%、53%和57%。对于强化靶标，8%的接受西马鲁肽治疗的受试者达到三个或更多靶标，而接受替西帕肽治疗的受试者达到15%、20%和29%。关于特定的治疗目标，替西帕肽增加了HbA1c标准和强化目标（HbA1c 10%, OR 2.72 [95% CI 2.14, 3.47]；体重减轻15%，OR 3.86 [95% CI 2.69, 5.55]）和BP强化目标（OR 1.45 [95% CI 1.17, 1.81]）的实现几率。结论/解释：与西马鲁肽相比，替西帕肽可提高2型糖尿病患者的治疗目标。需要更长时间的试验来证实对长期预后的益处。数据可用性通过Vivli（全球临床研究数据中心）平台（https://vivli.org）访问该事后分析的数据，Vivli ID为00009964。
{"title":"Efficacy of tirzepatide versus semaglutide in achieving therapeutic targets in type 2 diabetes: a post hoc analysis of the SURPASS-2 Trial.","authors":"João Sérgio Neves,Ana Rita Leite,Catarina Vale,Pedro Marques,Francisco Vasques-Nóvoa,Adelino Leite-Moreira,João Pedro Ferreira","doi":"10.1007/s00125-025-06637-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06637-7","url":null,"abstract":"AIMS/HYPOTHESISSimultaneous control of HbA1c, lipid profile, BP and body weight is essential for preventing chronic complications of type 2 diabetes. Glucagon-like peptide-1 (GLP-1)-based therapies improve all these variables but whether the dual GLP-1 / glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide is superior to semaglutide in attaining therapeutic targets remains unclear.METHODSWe performed a post hoc analysis of the SURPASS-2 trial, a randomised phase 3 study including 1879 adults with type 2 diabetes. Participants were randomised to receive tirzepatide (5, 10 or 15 mg) or semaglutide (1 mg). In this analysis, we compared the effects of tirzepatide vs semaglutide on the attainment of standard (HbA1c <53 mmol/mol [7%], BP <140/90 mmHg, LDL-cholesterol <1.8 mmol/l, >10% weight loss) and intensive (HbA1c <48 mmol/mol [6.5%], BP <130/80 mmHg, LDL-cholesterol <1.4 mmol/l , >15% weight loss) therapeutic targets at 40 weeks.RESULTSIn the SURPASS-2 trial, at baseline, 19% of participants were on target for attaining no standard goals, 59% for one goal and 21% for two or more goals. For intensive therapeutic targets, 58% of participants were on target for attaining zero goals, 38% for one goal and 4% for two goals. All doses of tirzepatide increased the number of achieved standard and intensive targets compared with semaglutide. For standard targets, 34% of participants treated with semaglutide met three or more targets, compared with 42%, 53% and 57% with tirzepatide 5, 10 and 15 mg, respectively. For intensive targets, 8% of participants treated with semaglutide met three or more targets, vs 15%, 20% and 29% with tirzepatide. Regarding specific therapeutic goals, tirzepatide increased the odds of achieving standard and intensive targets for HbA1c (HbA1c <53 mmol/mol [7%], OR 1.50 [95% CI 1.12, 2.00]; HbA1c <48 mmol/mol [6.5%], OR 1.88 [95%CI 1.49, 2.36]) and weight loss (weight loss >10%, OR 2.72 [95% CI 2.14, 3.47]; weight loss >15%, OR 3.86 [95% CI 2.69, 5.55]) and the intensive target for BP (OR 1.45 [95% CI 1.17, 1.81]).CONCLUSIONS/INTERPRETATIONTirzepatide improves therapeutic target attainment compared with semaglutide in type 2 diabetes. Longer trials are needed to confirm benefits on long-term prognosis.DATA AVAILABILITYData for this post hoc analysis was accessed through the Vivli (Center for Global Clinical Research Data) platform ( https://vivli.org ) with the Vivli ID 00009964.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"29 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785767","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 : 2025-12-19DOI: 10.1007/s00125-025-06635-9
Markus Mattila,Peppi Haario,Leena Hakola,Hanna-Mari Takkinen,Essi J Peltonen,Tuuli E Korhonen,Suvi Ahonen,Jorma Ilonen,Jorma Toppari,Mikael Knip,Riitta Veijola,Sari Niinistö,Suvi M Virtanen
AIMS/HYPOTHESISIn this prospective birth cohort study, we examined whether the dietary intake of A, B, C, D and E vitamins is associated with the risk of islet autoimmunity or type 1 diabetes in children who are genetically at risk for type 1 diabetes.METHODSData on vitamin intakes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available for 5674 children born between September 1996 and September 2004 in Oulu University Hospital or Tampere University Hospital. Diet was assessed using 3-day food records at the age of 3 and 6 months, and annually from 1 to 6 years. The primary outcomes were: (1) islet autoimmunity defined as repeated positivity for islet cell autoantibodies and at least one out of three type 1 diabetes-related biochemical autoantibodies or a diagnosis of type 1 diabetes; and (2) a diagnosis of type 1 diabetes.RESULTSDuring the 6-year follow-up, 247 children (4.4%) developed islet autoimmunity and 94 (1.7%) developed type 1 diabetes. When adjusted for total energy intake, sex, HLA genotype and family history of diabetes, the intakes of retinol (HR 0.91; 95% credible interval [CrI] 0.86, 0.97 per 10 µg/MJ increase in intake), vitamin C (HR 0.70; 95% CrI 0.54, 0.90 per 10 µg/MJ) and vitamin E (HR 0.93; 95% CrI 0.89, 0.97 per 0.1 mg/MJ) were associated with decreased risk of islet autoimmunity and also with the risk of type 1 diabetes (retinol: HR 0.83; 95% CrI 0.74, 0.96 per 10 µg/MJ; vitamin C: HR 0.45; 95% CrI 0.23, 0.84 per 10 µg/MJ; vitamin E: HR 0.89; 95% CrI 0.80, 0.99 per 0.1 mg/MJ). The associations remained statistically significant after multiple testing correction for the risk of islet autoimmunity but not for type 1 diabetes. The association between retinol intake and islet autoimmunity risk was not significant when the 3-month age point, during which the child is primarily breastfed, was excluded. We observed a weak inverse association for vitamin D and islet autoimmunity, and no associations for B vitamins.CONCLUSIONS/INTERPRETATIONHigh intake of vitamin C and vitamin E was associated with a decreased risk of islet autoimmunity.
{"title":"Dietary intake of vitamins A, B, C, D and E and risk of islet autoimmunity and type 1 diabetes in genetically at-risk children: a prospective study from the DIPP birth cohort.","authors":"Markus Mattila,Peppi Haario,Leena Hakola,Hanna-Mari Takkinen,Essi J Peltonen,Tuuli E Korhonen,Suvi Ahonen,Jorma Ilonen,Jorma Toppari,Mikael Knip,Riitta Veijola,Sari Niinistö,Suvi M Virtanen","doi":"10.1007/s00125-025-06635-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06635-9","url":null,"abstract":"AIMS/HYPOTHESISIn this prospective birth cohort study, we examined whether the dietary intake of A, B, C, D and E vitamins is associated with the risk of islet autoimmunity or type 1 diabetes in children who are genetically at risk for type 1 diabetes.METHODSData on vitamin intakes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available for 5674 children born between September 1996 and September 2004 in Oulu University Hospital or Tampere University Hospital. Diet was assessed using 3-day food records at the age of 3 and 6 months, and annually from 1 to 6 years. The primary outcomes were: (1) islet autoimmunity defined as repeated positivity for islet cell autoantibodies and at least one out of three type 1 diabetes-related biochemical autoantibodies or a diagnosis of type 1 diabetes; and (2) a diagnosis of type 1 diabetes.RESULTSDuring the 6-year follow-up, 247 children (4.4%) developed islet autoimmunity and 94 (1.7%) developed type 1 diabetes. When adjusted for total energy intake, sex, HLA genotype and family history of diabetes, the intakes of retinol (HR 0.91; 95% credible interval [CrI] 0.86, 0.97 per 10 µg/MJ increase in intake), vitamin C (HR 0.70; 95% CrI 0.54, 0.90 per 10 µg/MJ) and vitamin E (HR 0.93; 95% CrI 0.89, 0.97 per 0.1 mg/MJ) were associated with decreased risk of islet autoimmunity and also with the risk of type 1 diabetes (retinol: HR 0.83; 95% CrI 0.74, 0.96 per 10 µg/MJ; vitamin C: HR 0.45; 95% CrI 0.23, 0.84 per 10 µg/MJ; vitamin E: HR 0.89; 95% CrI 0.80, 0.99 per 0.1 mg/MJ). The associations remained statistically significant after multiple testing correction for the risk of islet autoimmunity but not for type 1 diabetes. The association between retinol intake and islet autoimmunity risk was not significant when the 3-month age point, during which the child is primarily breastfed, was excluded. We observed a weak inverse association for vitamin D and islet autoimmunity, and no associations for B vitamins.CONCLUSIONS/INTERPRETATIONHigh intake of vitamin C and vitamin E was associated with a decreased risk of islet autoimmunity.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"21 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777436","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 : 2025-12-19DOI: 10.1007/s00125-025-06630-0
Javad Anjom-Shoae,Penelope C E Fitzgerald,Braden D Rose,Vida Bitarafan,Jens F Rehfeld,Michael Horowitz,Christine Feinle-Bisset
AIMS/HYPOTHESISIn healthy men, lauric acid (C12) and L-tryptophan (Trp), when administered intraduodenally in loads of 1.26 and 0.42 kJ/min (0.3 and 0.1 kcal/min), respectively, that are individually ineffective, stimulate glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK), when combined. Both hormones slow gastric emptying, suppress energy intake and lower postprandial glucose. We have now investigated the hypothesis that combined intraduodenal administration of these nutrients reduces postprandial glucose in type 2 diabetes.METHODSIn a randomised, blinded (investigators and participants), crossover study performed in the University of Adelaide Clinical Research Facility, 11 men with type 2 diabetes (age: 69 ± 7 years; HbA1c: 51 ± 5 mmol/mol [6.8 ± 0.3%]; BMI: 28 ± 1 kg/m2), each received, on four separate occasions, 45 min intraduodenal infusions of C12 (1.26 kJ/min), Trp (0.42 kJ/min), C12+Trp (1.68 kJ/min), or 0.9% saline (control), 30 min before a mixed-nutrient drink (350 ml, 2092 kJ (500 kcal), 74 g carbohydrate) containing 100 mg 13C-acetate. Plasma glucose, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and CCK concentrations were measured at baseline, following treatments alone, and for 180 min post-drink. Gastric emptying was assessed via 13C-acetate breath test.RESULTSC12+Trp, but not C12 or Trp, reduced overall (p=0.02) and peak (mmol/l; control: 11.1 ± 0.6, Trp: 10.3 ± 0.5, C12: 10.7 ± 0.6, C12+Trp: 9.8 ± 0.5; p=0.01) plasma glucose. C12+Trp slowed gastric emptying (p=0.001), and increased pre-drink plasma GLP-1, GIP and CCK (all p<0.05), without affecting insulin or C-peptide. No treatment effects were observed postprandially.CONCLUSIONS/INTERPRETATIONIn type 2 diabetes, intraduodenal C12+Trp lowers postprandial glucose, probably primarily by slowing of gastric emptying and mediated by GLP-1 and CCK. These findings support further exploration of nutrient-based gastrointestinal strategies to optimise glycaemic management in type 2 diabetes.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry ( www.anzctr.org.au ) ACTRN12623000778684 FUNDING: JAS and VB were each supported by Adelaide Scholarship International stipends, provided by the University of Adelaide (JAS, 2021-2025; VB, 2017-2020) and CFB by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (Grant 1103020, 2016-2023). The research was supported by a Diabetes Australia Research Project Grant (2021-2022) to CFB.
{"title":"Effects of combined intraduodenal administration of lauric acid and L-tryptophan on postprandial plasma glucose, glucoregulatory hormones and gastric emptying in type 2 diabetes: a double-blind, randomised, crossover study.","authors":"Javad Anjom-Shoae,Penelope C E Fitzgerald,Braden D Rose,Vida Bitarafan,Jens F Rehfeld,Michael Horowitz,Christine Feinle-Bisset","doi":"10.1007/s00125-025-06630-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06630-0","url":null,"abstract":"AIMS/HYPOTHESISIn healthy men, lauric acid (C12) and L-tryptophan (Trp), when administered intraduodenally in loads of 1.26 and 0.42 kJ/min (0.3 and 0.1 kcal/min), respectively, that are individually ineffective, stimulate glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK), when combined. Both hormones slow gastric emptying, suppress energy intake and lower postprandial glucose. We have now investigated the hypothesis that combined intraduodenal administration of these nutrients reduces postprandial glucose in type 2 diabetes.METHODSIn a randomised, blinded (investigators and participants), crossover study performed in the University of Adelaide Clinical Research Facility, 11 men with type 2 diabetes (age: 69 ± 7 years; HbA1c: 51 ± 5 mmol/mol [6.8 ± 0.3%]; BMI: 28 ± 1 kg/m2), each received, on four separate occasions, 45 min intraduodenal infusions of C12 (1.26 kJ/min), Trp (0.42 kJ/min), C12+Trp (1.68 kJ/min), or 0.9% saline (control), 30 min before a mixed-nutrient drink (350 ml, 2092 kJ (500 kcal), 74 g carbohydrate) containing 100 mg 13C-acetate. Plasma glucose, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and CCK concentrations were measured at baseline, following treatments alone, and for 180 min post-drink. Gastric emptying was assessed via 13C-acetate breath test.RESULTSC12+Trp, but not C12 or Trp, reduced overall (p=0.02) and peak (mmol/l; control: 11.1 ± 0.6, Trp: 10.3 ± 0.5, C12: 10.7 ± 0.6, C12+Trp: 9.8 ± 0.5; p=0.01) plasma glucose. C12+Trp slowed gastric emptying (p=0.001), and increased pre-drink plasma GLP-1, GIP and CCK (all p<0.05), without affecting insulin or C-peptide. No treatment effects were observed postprandially.CONCLUSIONS/INTERPRETATIONIn type 2 diabetes, intraduodenal C12+Trp lowers postprandial glucose, probably primarily by slowing of gastric emptying and mediated by GLP-1 and CCK. These findings support further exploration of nutrient-based gastrointestinal strategies to optimise glycaemic management in type 2 diabetes.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry ( www.anzctr.org.au ) ACTRN12623000778684 FUNDING: JAS and VB were each supported by Adelaide Scholarship International stipends, provided by the University of Adelaide (JAS, 2021-2025; VB, 2017-2020) and CFB by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (Grant 1103020, 2016-2023). The research was supported by a Diabetes Australia Research Project Grant (2021-2022) to CFB.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"1 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785768","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 : 2025-12-19DOI: 10.1007/s00125-025-06628-8
Xinran Qin,Shuli Chen,Yu Sun,Zhenglin Ma,Chen Niu,Fangzhou Lou,Haidong Zou
AIMS/HYPOTHESISDiabetic retinopathy is a common complication of diabetes mellitus that is characterised by neurovascular dysfunction and chronic inflammation. The stimulator of IFN genes (STING) signalling pathway plays a key role in inflammatory diseases. However, its cell-specific function and value as an early-intervention target for diabetic retinopathy remain unclear.METHODSWe analysed public single-cell (sc)RNA-seq datasets from fibrous membranes of individuals with proliferative diabetic retinopathy and idiopathic macular hole, normal post-mortem retinas and retinal endothelial cells from diabetic and non-diabetic mice. A type 2 diabetes mouse model was established using a high-fat diet and streptozocin to assess STING localisation and expression differences. Using adeno-associated virus (serotype 2/1), siRNA or STING inhibitor H-151, we evaluated the effects of STING on inflammation and cell function both in vivo and in vitro.RESULTSscRNA-seq analysis revealed increased STING expression and enriched IFN signalling in endothelial cells from samples of both humans and mice with diabetes. Our mouse model exhibited increased STING expression, along with its co-localisation with CD31, and upregulated IFNs in retinal tissues. Flow cytometry confirmed diabetes-induced endothelial cell-specific phosphorylation of TBK1, a downstream effector of STING. Genetic deletion or pharmacological inhibition of STING significantly ameliorated retinal inflammation and neurovascular dysfunction in diabetic mice.CONCLUSIONS/INTERPRETATIONOur findings demonstrate endothelial-intrinsic activation of the cyclic GMP-AMP synthase (cGAS)/STING/IFN pathway as a key driver of retinal inflammation and neurovascular dysfunction in diabetes. Targeting this pathway may offer a potential therapeutic approach for early intervention in diabetic retinopathy.
{"title":"Aberrant STING signalling promotes endothelial dysfunction and neurovascular injury in diabetic retinopathy.","authors":"Xinran Qin,Shuli Chen,Yu Sun,Zhenglin Ma,Chen Niu,Fangzhou Lou,Haidong Zou","doi":"10.1007/s00125-025-06628-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06628-8","url":null,"abstract":"AIMS/HYPOTHESISDiabetic retinopathy is a common complication of diabetes mellitus that is characterised by neurovascular dysfunction and chronic inflammation. The stimulator of IFN genes (STING) signalling pathway plays a key role in inflammatory diseases. However, its cell-specific function and value as an early-intervention target for diabetic retinopathy remain unclear.METHODSWe analysed public single-cell (sc)RNA-seq datasets from fibrous membranes of individuals with proliferative diabetic retinopathy and idiopathic macular hole, normal post-mortem retinas and retinal endothelial cells from diabetic and non-diabetic mice. A type 2 diabetes mouse model was established using a high-fat diet and streptozocin to assess STING localisation and expression differences. Using adeno-associated virus (serotype 2/1), siRNA or STING inhibitor H-151, we evaluated the effects of STING on inflammation and cell function both in vivo and in vitro.RESULTSscRNA-seq analysis revealed increased STING expression and enriched IFN signalling in endothelial cells from samples of both humans and mice with diabetes. Our mouse model exhibited increased STING expression, along with its co-localisation with CD31, and upregulated IFNs in retinal tissues. Flow cytometry confirmed diabetes-induced endothelial cell-specific phosphorylation of TBK1, a downstream effector of STING. Genetic deletion or pharmacological inhibition of STING significantly ameliorated retinal inflammation and neurovascular dysfunction in diabetic mice.CONCLUSIONS/INTERPRETATIONOur findings demonstrate endothelial-intrinsic activation of the cyclic GMP-AMP synthase (cGAS)/STING/IFN pathway as a key driver of retinal inflammation and neurovascular dysfunction in diabetes. Targeting this pathway may offer a potential therapeutic approach for early intervention in diabetic retinopathy.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"13 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785766","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 : 2025-12-18DOI: 10.1007/s00125-025-06643-9
Martina Chiriacò,Domenico Tricò,John R Petrie,Rafael Gabriel,Amalia Gastaldelli,John Nolan,Nebojsa Lalic,Geltrude Mingrone,Andrea Mari,Andrea Natali
AIMS/HYPOTHESISFasting hyperinsulinaemia is a key feature of obesity and is implicated in diabetes progression. However, the following aspects of insulin secretion remain unclear: (1) which index of obesity is most important; (2) what is the shape of the dose-response curve between obesity and insulin secretion; (3) what physiological mechanisms sustain insulin hypersecretion; (4) what are the underlying causes; and (5) whether sex-related differences exist.METHODSWe analysed data from 1250 healthy participants (547 men, 703 women) of the EGIR-RISC cohort followed up for 3.5 years, with age 30-60 years and BMI 18.5-40.0 kg/m2. Assessments included body composition, insulin secretion, beta cell function modelling from an OGTT and clamp-derived insulin sensitivity. Endogenous glucose production (EGP) was measured in a subset of 368 participants. Multivariable regression models and stratifications for BMI, body fat per cent, WHR and fat mass were applied to evaluate the effect of obesity on insulin secretion and beta cell function.RESULTSThe impact of obesity on fasting insulin secretion (FIS) was continuous across the full spectrum of BMI and WHR values and was greater in men than women. Among adiposity indices, fat mass (standardised β coefficient [Stβ] 0.27, p<0.0001) and waist circumference (Stβ 0.21, p<0.0001) were the strongest predictors of FIS. Insulin secretion increased 2.4-fold across BMI deciles, and adiposity-associated insulin hypersecretion appeared to be driven by the combination of hyperglycaemia and an increase in a specific beta cell function variable (insulin secretion rate at 5 mmol/l glucose [ISR@5]). In the follow-up cohort, weight gain (mean ± SD ∆ weight=+5.1 ± 3.8 kg) was associated with an increase in FIS and fasting glucose (+0.20 ± 0.63 mmol/l, p<0.03), whereas weight loss (-4.7 ± 2.8 kg) led to a reduction in FIS and fasting glucose (+0.06 ± 0.55 mmol/l, p<0.006). ISR@5 declined in both weight losers and those with stable weight (-0.17 ± 1.9 and -0.16 ± 1.0 U/h, respectively; p<0.002 for both) but not in weight gainers (-0.06 ± 1.1 U/h). Peripheral insulin resistance, plasma NEFA and leptin accounted for only part of obesity's effect on insulin secretion. Subset analysis of fasting and clamp EGP data suggested a rightwards shift in the dose-response curve across fat mass quintiles, indicating progressive hepatic glucose overproduction despite a preserved hepatic insulin response.CONCLUSIONS/INTERPRETATIONThe effect of body mass on insulin secretion is continuous, more pronounced in men, driven by fat mass and waist, sustained by hyperglycaemia and by an upregulation of beta cell insulin secretion and is only partially explained by typical hormonal and metabolic consequences of obesity. We suggest that hepatic glucose overproduction contributes to the fasting hyperinsulinaemia observed in individuals with obesity.
{"title":"Impact of overweight and obesity on fasting insulin secretion in men and women without diabetes: effect sizes and mechanisms.","authors":"Martina Chiriacò,Domenico Tricò,John R Petrie,Rafael Gabriel,Amalia Gastaldelli,John Nolan,Nebojsa Lalic,Geltrude Mingrone,Andrea Mari,Andrea Natali","doi":"10.1007/s00125-025-06643-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06643-9","url":null,"abstract":"AIMS/HYPOTHESISFasting hyperinsulinaemia is a key feature of obesity and is implicated in diabetes progression. However, the following aspects of insulin secretion remain unclear: (1) which index of obesity is most important; (2) what is the shape of the dose-response curve between obesity and insulin secretion; (3) what physiological mechanisms sustain insulin hypersecretion; (4) what are the underlying causes; and (5) whether sex-related differences exist.METHODSWe analysed data from 1250 healthy participants (547 men, 703 women) of the EGIR-RISC cohort followed up for 3.5 years, with age 30-60 years and BMI 18.5-40.0 kg/m2. Assessments included body composition, insulin secretion, beta cell function modelling from an OGTT and clamp-derived insulin sensitivity. Endogenous glucose production (EGP) was measured in a subset of 368 participants. Multivariable regression models and stratifications for BMI, body fat per cent, WHR and fat mass were applied to evaluate the effect of obesity on insulin secretion and beta cell function.RESULTSThe impact of obesity on fasting insulin secretion (FIS) was continuous across the full spectrum of BMI and WHR values and was greater in men than women. Among adiposity indices, fat mass (standardised β coefficient [Stβ] 0.27, p<0.0001) and waist circumference (Stβ 0.21, p<0.0001) were the strongest predictors of FIS. Insulin secretion increased 2.4-fold across BMI deciles, and adiposity-associated insulin hypersecretion appeared to be driven by the combination of hyperglycaemia and an increase in a specific beta cell function variable (insulin secretion rate at 5 mmol/l glucose [ISR@5]). In the follow-up cohort, weight gain (mean ± SD ∆ weight=+5.1 ± 3.8 kg) was associated with an increase in FIS and fasting glucose (+0.20 ± 0.63 mmol/l, p<0.03), whereas weight loss (-4.7 ± 2.8 kg) led to a reduction in FIS and fasting glucose (+0.06 ± 0.55 mmol/l, p<0.006). ISR@5 declined in both weight losers and those with stable weight (-0.17 ± 1.9 and -0.16 ± 1.0 U/h, respectively; p<0.002 for both) but not in weight gainers (-0.06 ± 1.1 U/h). Peripheral insulin resistance, plasma NEFA and leptin accounted for only part of obesity's effect on insulin secretion. Subset analysis of fasting and clamp EGP data suggested a rightwards shift in the dose-response curve across fat mass quintiles, indicating progressive hepatic glucose overproduction despite a preserved hepatic insulin response.CONCLUSIONS/INTERPRETATIONThe effect of body mass on insulin secretion is continuous, more pronounced in men, driven by fat mass and waist, sustained by hyperglycaemia and by an upregulation of beta cell insulin secretion and is only partially explained by typical hormonal and metabolic consequences of obesity. We suggest that hepatic glucose overproduction contributes to the fasting hyperinsulinaemia observed in individuals with obesity.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"162 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777435","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 : 2025-12-17DOI: 10.1007/s00125-025-06629-7
Cheryl Pritlove, Christian Herder, Anna Krook, Hindrik Mulder, Jennifer L. Sargent
{"title":"Equity, Diversity and Inclusion is essential for rigorous science and good for health","authors":"Cheryl Pritlove, Christian Herder, Anna Krook, Hindrik Mulder, Jennifer L. Sargent","doi":"10.1007/s00125-025-06629-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06629-7","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"155 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770754","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 : 2025-12-15DOI: 10.1007/s00125-025-06627-9
Alessandra Kobayati,Michael A Tsoukas,Natasha Garfield,Laurent Legault,Melissa-Rosina Pasqua,Jean-François Yale,Sara J Meltzer,Simon S Wing,Stéphanie Michaud,Vanessa Tardio,Tricia Peters,Rachel Bond,Preetha Krishnamoorthy,Ivan George Fantus,Joanna Rutkowski,Anas El Fathi,Anh Ngo,Leif Erik Lovblom,Ahmad Haidar
AIMS/HYPOTHESISThere is an unmet need for automated insulin adjustments for multiple daily injections in type 1 diabetes under unsupervised use. We aimed to assess the McGill decision support system (DSS), which comprises a Bayesian algorithm, by comparing its automated insulin adjustments with those made by endocrinologists.METHODSWe surveyed 13 Canadian endocrinologists who made mock insulin adjustments in three separate parts on retrospective participants' data. Part A (weekly data) and part C (biweekly data) compared the recommendations from physicians with those of the algorithm. Part B evaluated intra-physician variability by comparing the recommendations made by the same physician over time based on an identical dataset to part A.RESULTSIn part A, the agreement rate (mean [SD]) on the direction of weekly adjustments between the algorithm and physicians was non-inferior to the agreement rate between physicians for prandial bolus (55% [5] vs 56% [7], respectively; p=0.006) and basal insulin (48% [6] vs 51% [11], respectively; p=0.037). Low full disagreement rates on weekly adjustments were also comparable between the pairs for prandial bolus (3.9% [2.3] vs 4.1% [2.3], respectively; p=0.006) and basal insulin (10.6% [4.6] vs 9.2% [7.1], respectively; p=0.23). Similar rates were observed for biweekly insulin adjustments in part C. When comparing intra-physician decisions in part A with those in part B, on average, physicians fully agreed with themselves 66% (SD 7) and 67% (SD 7) of the time for prandial bolus and basal insulin adjustments, respectively.CONCLUSIONS/INTERPRETATIONThe direction of insulin adjustments was comparable between physicians and the McGill algorithm. The large intra-physician variability further emphasises the subjective nature of insulin management.
{"title":"Inter- and intra-physician variability in insulin injection adjustments compared with Bayesian algorithm recommendations in type 1 diabetes.","authors":"Alessandra Kobayati,Michael A Tsoukas,Natasha Garfield,Laurent Legault,Melissa-Rosina Pasqua,Jean-François Yale,Sara J Meltzer,Simon S Wing,Stéphanie Michaud,Vanessa Tardio,Tricia Peters,Rachel Bond,Preetha Krishnamoorthy,Ivan George Fantus,Joanna Rutkowski,Anas El Fathi,Anh Ngo,Leif Erik Lovblom,Ahmad Haidar","doi":"10.1007/s00125-025-06627-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06627-9","url":null,"abstract":"AIMS/HYPOTHESISThere is an unmet need for automated insulin adjustments for multiple daily injections in type 1 diabetes under unsupervised use. We aimed to assess the McGill decision support system (DSS), which comprises a Bayesian algorithm, by comparing its automated insulin adjustments with those made by endocrinologists.METHODSWe surveyed 13 Canadian endocrinologists who made mock insulin adjustments in three separate parts on retrospective participants' data. Part A (weekly data) and part C (biweekly data) compared the recommendations from physicians with those of the algorithm. Part B evaluated intra-physician variability by comparing the recommendations made by the same physician over time based on an identical dataset to part A.RESULTSIn part A, the agreement rate (mean [SD]) on the direction of weekly adjustments between the algorithm and physicians was non-inferior to the agreement rate between physicians for prandial bolus (55% [5] vs 56% [7], respectively; p=0.006) and basal insulin (48% [6] vs 51% [11], respectively; p=0.037). Low full disagreement rates on weekly adjustments were also comparable between the pairs for prandial bolus (3.9% [2.3] vs 4.1% [2.3], respectively; p=0.006) and basal insulin (10.6% [4.6] vs 9.2% [7.1], respectively; p=0.23). Similar rates were observed for biweekly insulin adjustments in part C. When comparing intra-physician decisions in part A with those in part B, on average, physicians fully agreed with themselves 66% (SD 7) and 67% (SD 7) of the time for prandial bolus and basal insulin adjustments, respectively.CONCLUSIONS/INTERPRETATIONThe direction of insulin adjustments was comparable between physicians and the McGill algorithm. The large intra-physician variability further emphasises the subjective nature of insulin management.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"145 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752564","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 : 2025-12-15DOI: 10.1007/s00125-025-06631-z
Xuan Zhou, Magdalena Sevilla-Gonzalez, Amanda I. Phipps, Miriam Udler, Sergi Castellví-Bel, Andrew T. Chan, Andrew J. Pellatt, Robert E. Schoen, Edward Giovannucci, Marc J. Gunter, Jose C. Florez, Ulrike Peters, Mingyang Song, Jordi Merino
{"title":"Diabetogenic processes for insulin resistance-linked hyperinsulinaemia are associated with colorectal cancer","authors":"Xuan Zhou, Magdalena Sevilla-Gonzalez, Amanda I. Phipps, Miriam Udler, Sergi Castellví-Bel, Andrew T. Chan, Andrew J. Pellatt, Robert E. Schoen, Edward Giovannucci, Marc J. Gunter, Jose C. Florez, Ulrike Peters, Mingyang Song, Jordi Merino","doi":"10.1007/s00125-025-06631-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06631-z","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"19 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760066","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 : 2025-12-15DOI: 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}
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