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

Abstract

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 &gt;2 or $$\le$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mo>≤</mml:mo> </mml:math> 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 &gt;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

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