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Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab

Diabetologia, ISSN: 1432-0428
2024
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  • Captures
    4
  • Mentions
    1
    • News Mentions
      1
      • 1

Most Recent News

New Findings on Type 1 Diabetes from Yale University Summarized (Trajectory of Beta Cell Function and Insulin Clearance In Stage 2 Type 1 Diabetes: Natural History and Response To Teplizumab)

2024 DEC 16 (NewsRx) -- By a News Reporter-Staff News Editor at Immunotherapy Daily -- Investigators publish new report on Nutritional and Metabolic Diseases and

Article Description

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. Graphical Abstract: (Figure presented.)

Bibliographic Details

Galderisi, Alfonso; Sims, Emily K; Evans-Molina, Carmella; Petrelli, Alessandra; Cuthbertson, David; Nathan, Brandon M; Ismail, Heba M; Herold, Kevan C; Moran, Antoinette

Springer Science and Business Media LLC

Medicine

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