Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab
Year: 2024
Type: article
Abstract: 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 $$\le$$ ≤ 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. Graphical Abstract
Source: Diabetologia
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,290
Funders: American Diabetes Association, John Templeton Foundation, Leona M. and Harry B. Helmsley Charitable Trust, Immune Tolerance Network, MacroGenics, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Diabetes, Endocrinology, and Metabolic Diseases, JDRF
Awards: G1044130170, G1058663374, G1232883401, G1236451951, G1267130690, G1302676432, G1335891746, G1416531886, G1589937986, G1636177350, G1667355478, G1679780777, TrialNet: University of Florida Clinical Center and Network, G180872007, G1838118559, G1852839119, University of Minnesota Clinical and Translational Science Institute (UMN CTSI), Type 1 Diabetes-A Proposal for Prevention & Intervention, CLINICAL AFFILIATE OF THE TYPE 1 DIABETES TRIALNET, G2024037102, G2078056140, G215709867, G2266930470, G2270259115, G2275974395, G2325591987, G2380330539, G2579296307, G2636971422, G270828768, G3345811275, G3563640007, G3581515176, Continuation of UCSF as a Clinical Center for TrialNet, G3726356400, G3933238600, G3958151055, G3998258134, Prediction and Prevention of Type 1 Diabetes (TrialNet), UF Clinical and Translational Science Award, Northwest Clinical Center for Type 1 Diabetes - TrialNet, G4326787791, G4404410777, G451000312, G4552347576, G457535738, G4577920071, G4914271708, G491993124, Type 1 Diabetes TrialNet: Clinical Center at Berrie Center, Columbia University, G5078567877, Type 1 Diabetes TrialNet: Toronto Clinical Center, G5381970115, G5514976981, G5747062680, TrialNet at Stanford University, Mechanisms of Beta Cell Function in Health and Disease, G6173851391, G6215388834, G6276495445, G6335646514, G6558795104, G66187487, G6861125775, G6862536402, G6934766893, G695377212, G701880105, G70843923, G7500853074, G7719837979, G7739156517, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G7792937286, SECRETED SOD AND HAEMOPHILUS DUCREYI PATHOGENESIS, Yale University Clinical and Translational Science Award Program, G8002352242, G80537916, TrialNet: Diabetes Type 1 Prevention, G8114795067, G812494088, G8141590293, G8347393642, Texas Children's Hospital and Baylor College of Medicine TrialNet Clinical Center, COVID-19 Fund to Retain Clinical Scientists, G8857125704, Frontiers Clinical and Translational Science Institute at the University of Kansas, University of Pittsburgh Clinical and Translational Science Institute, Yale Clinical and Translational Science Award, Clinical and Translational Science Institute, Modulating pathogenic T cells in Type 1 diabetes
OpenAlex ID: W4404507213