We demonstrated that a 2-week course of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) delayed T1D progression by a median of 24 months in high risk relatives of patients with T1D (76 multiple islet autoantibody positive dysglycemic relatives; 912 day median follow-up). Over the study 72% of the placebo-treated and 43% of the teplizumab-treated participants were diagnosed with T1D. We hypothesized that teplizumab treatment would also result in a secondary outcome of improved C-peptide responses to oral glucose tolerance tests (OGTT) compared to placebo. The C-peptide, 1 hr insulin secretory rate (early ISR), and glucose area under the curve (AUC) means were calculated for each study timepoint. Results were modeled using ANCOVA, regressing on treatment group, age and the baseline value of the dependent variable. Teplizumab treatment was associated with a greater on-study C-peptide AUC (teplizumab vs. placebo adjusted means: 1.94 vs. 1.73 nmol/L; p=0.009). For both groups, C-peptide AUC mean slopes over a mean of 7.9 months preceding study entry were similar and significantly less than zero (declining; p=0.03). In the placebo group, this decline continued over the 6 months after study entry. By contrast, the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.003 relative to study entry). Insulin secretion during the 1st hr of the OGTT also declined in participants treated with placebo, but increased in those treated with teplizumab at 6 months (p=0.007). Increases in C-peptide AUC were correlated with increases in partially exhausted KLRG1+TIGIT+ CD8+ T cells (r=0.403; p=0.018). Although rates of diabetes were reduced in teplizumab-treated participants, OGTTs showed persistent dysglycemia.

In conclusion, we found declines in C-peptide responses to OGTTs in high risk individuals prior to study treatment that were abrogated in the 6 month period after immunomodulation with teplizumab.

Disclosure

E.K. Sims: None. B.N. Bundy: None. K.D. Stier: None. E. Serti: None. N. Lim: None. G.T. Nepom: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. K.C. Herold: Consultant; Self; Provention Bio, Inc.

Funding

National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.