Pub Date : 2025-03-01Epub Date: 2024-11-19DOI: 10.1007/s00125-024-06323-0
Alfonso Galderisi, Emily K Sims, Carmella Evans-Molina, Alessandra Petrelli, David Cuthbertson, Brandon M Nathan, Heba M Ismail, Kevan C Herold, Antoinette Moran
Aims/hypothesis: We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate.
Methods: OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8+ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group.
Results: Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance significantly decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1+ CD8+ T effector memory cells.
Conclusions/interpretation: OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.
目的/假设:我们旨在使用口服最小模型(OMM)得出的指数分析TrialNet抗CD3预防(TN10)数据,以描述安慰剂治疗个体的2期1型糖尿病自然病史,描述对替普利珠单抗的早期代谢反应,并探索OMM指标对无病生存率的预测能力:方法: 对安慰剂组和替普利珠单抗治疗组的基线、随机化后3、6和12个月的OMM估计胰岛素分泌量、敏感性和清除率以及处置指数进行评估,并在每组中对缓慢进展者和快速进展者(疾病3期时间大于2年或小于2年)进行评估。OMM 指标还与标准 AUC C 肽进行了比较。评估了各组 CD8+ T 记忆细胞和程序性死亡-1(PD-1)表达的百分比变化:结果:28 名安慰剂治疗者和 39 名替普利珠单抗治疗者的基线代谢特征相似。在12个月内,安慰剂治疗组的胰岛素分泌下降,而替普利珠单抗治疗组的胰岛素分泌上升。在各组中,安慰剂慢进展者(14 人)保持了胰岛素分泌和敏感性,而安慰剂快进展者(14 人)的胰岛素分泌和敏感性均有所下降。替普利珠单抗缓慢进展组(28 人)保持了胰岛素分泌的升高,而替普利珠单抗快速进展组(11 人)则出现了轻微的代谢下降。与快速进展组相比,在两个治疗组中,缓慢进展组的胰岛素清除率在基线与 3、6 和 12 个月之间显著下降。总体而言,基线胰岛素分泌较高(p=0.027)和 12 个月胰岛素清除率降低(p=0.045)都预示着病情进展较慢。3 个月时胰岛素分泌量下降 >25% 的特异性为 0.95 (95% CI 0.86, 1.00),可识别快速进展者,并能正确划分 92% 参与者的 2 年进展风险,灵敏度为 0.19 (95% CI 0.08, 0.30)。在按治疗方法区分组别或预测病情进展方面,OMM 估算的胰岛素分泌量优于 AUC C 肽。代谢变化与 PD-1+ CD8+ T 效应记忆细胞的相对变化频率同步:OMM测量表征了2期糖尿病的代谢异质性,确定了快速进展者和缓慢进展者之间的差异,以及免疫疗法的异质性影响,表明在设计和解释临床试验时需要考虑这些差异。
{"title":"Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab.","authors":"Alfonso Galderisi, Emily K Sims, Carmella Evans-Molina, Alessandra Petrelli, David Cuthbertson, Brandon M Nathan, Heba M Ismail, Kevan C Herold, Antoinette Moran","doi":"10.1007/s00125-024-06323-0","DOIUrl":"10.1007/s00125-024-06323-0","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate.</p><p><strong>Methods: </strong>OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or <math><mo>≤</mo></math> 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8<sup>+</sup> T memory cell and programmed death-1 (PD-1) expression were evaluated in each group.</p><p><strong>Results: </strong>Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance significantly decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1<sup>+</sup> CD8<sup>+</sup> T effector memory cells.</p><p><strong>Conclusions/interpretation: </strong>OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"646-661"},"PeriodicalIF":8.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-11-06DOI: 10.1007/s00125-024-06292-4
Cyndya A Shibao, Vivek S Peche, Terri A Pietka, Dmitri Samovski, Ian M Williams, Naji N Abumrad, Eric R Gamazon, Ira J Goldberg, David H Wasserman, Nada A Abumrad
Aims/hypothesis: Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal.
Methods: Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36-/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion.
Results: Insulin clamps showed that Cd36-/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal.
Conclusions/interpretation: CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism.
Trial registration: Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ).
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Pub Date : 2025-02-28DOI: 10.1007/s00125-025-06388-5
Dea H. Kofod, Søren Z. Diederichsen, Tobias Bomholt, Mads Ø. Andersen, Andreas Andersen, Ebba Mannheimer, Marianne Rix, Ylian S. Liem, Kristine Lindhard, Henrik P. Hansen, Casper Rydahl, Morten Lindhardt, Julie Brøsen, Kristine Schandorff, Theis Lange, Kirsten Nørgaard, Thomas P. Almdal, Jesper H. Svendsen, Bo Feldt-Rasmussen, Mads Hornum
Aims/hypothesis
We aimed to examine arrhythmias and hypoglycaemia among individuals with and without diabetes who are receiving haemodialysis and to investigate the association between arrhythmias and hypoglycaemia, hyperglycaemia and glycaemic variability.
Methods
This prospective multicentre cohort study included 70 participants on maintenance haemodialysis (35 with diabetes and 35 without diabetes). We employed implantable cardiac monitors for continuous heart rhythm monitoring in combination with periodic use of continuous glucose monitoring. Logistic-regression-type linear mixed models were used to examine associations between arrhythmias and glycaemic measures.
Results
During 18 months of follow-up, clinically significant arrhythmias (bradyarrhythmia and ventricular tachycardia) were identified in 12 (34%) participants with diabetes and 11 (31%) without diabetes. Atrial fibrillation was detected in 13 (37%) participants with diabetes and 14 (40%) without, while other supraventricular tachycardia was detected in seven (20%) and 11 (31%) participants with and without diabetes, respectively. Hypoglycaemia (sensor glucose <3.9 mmol/l) was observed in 27 (77%) participants with diabetes and 32 (91%) without diabetes. Compared with euglycaemia, hypoglycaemia was associated with an increased rate of arrhythmias among participants without diabetes (incidence rate ratio [IRR] 3.13 [95% CI 1.49, 6.55]), while hyperglycaemia (sensor glucose >10.0 mmol/l) was associated with a decreased rate of arrhythmias among participants with diabetes (IRR 0.58 [95% CI 0.37, 0.92]). Glycaemic variability showed no association with arrhythmias regardless of the presence of diabetes.
Conclusions/interpretation
Arrhythmias and hypoglycaemia were common in those undergoing haemodialysis regardless of diabetes status. Our data suggest a temporal relationship between arrhythmias and glucose level in both individuals with and without diabetes.