High proinsulin:C-peptide ratio identifies individuals with stage 2 type 1 diabetes at high risk for progression to clinical diagnosis and responses to teplizumab treatment

Abstract

Aims/hypothesis: Tractable precision biomarkers to identify immunotherapy responders are lacking in type 1 diabetes. We hypothesised that proinsulin:C-peptide (PI:C) ratios, a readout of beta cell stress, could provide insight into type 1 diabetes progression and responses to immunotherapy.

Methods: In this post hoc analysis, proinsulin and C-peptide levels were determined in baseline serum samples from 63 participants with stage 2 type 1 diabetes in the longitudinal TrialNet Teplizumab Prevention Study (n=41 in the teplizumab arm; n=22 in the placebo arm). In addition, previously tested demographic, C-peptide, glucose and proinsulin data were used for the new data analyses. The ratio of intact (unprocessed) proinsulin to C-peptide was analysed and relationships with progression to stage 3 diabetes were investigated.

Results: Elevated baseline PI:C was strongly associated with more rapid progression of diabetes in both the placebo and teplizumab treatment groups, but teplizumab abrogated the impact of high pre-treatment PI:C on type 1 diabetes progression. Differential responses of drug treatment in those with high vs low PI:C ratios were independent of treatment effects of teplizumab on the PI:C ratio or on relevant immune cells.

Conclusions/interpretation: High pre-treatment PI:C identified individuals with stage 2 type 1 diabetes who were exhibiting rapid progression to stage 3 disease and who displayed benefit from teplizumab treatment. These data suggest that readouts of active disease, such as PI:C ratio, could serve to identify optimal candidates or timing for type 1 diabetes disease-modifying therapies.

Keywords: Beta cell; Beta cell dysfunction; Beta cell stress; Biomarker; Precision medicine; Proinsulin; Teplizumab; Type 1 diabetes; Type 1 diabetes prevention.

Figure 1.. In individuals with stage 2 type 1 diabetes PI:C is inversely associated with age, and predicts progression to stage 3 type 1 diabetes.

A. Pre-treatment PI:C values for 63 individuals participating in the TrialNet Teplizumab prevention study. Values were not different between treatment groups (p=0.87). B. Age was inversely related to pre-treatment PI:C ratios (r = −0.36; p=0.004). C. Kaplan-Meier curve showing distribution of the time to progression to Stage 3 diabetes based on high vs. low baseline PI:C ratio of entire cohort, regardless of treatment group, to Stage 3 diabetes, with multivariable cox regression adjusting for age and baseline C-peptide area under the curve.

Figure 1.. In individuals with stage 2 type 1 diabetes PI:C is inversely associated with age, and predicts progression to stage 3 type 1 diabetes.

A. Pre-treatment PI:C values for 63 individuals participating in the TrialNet Teplizumab prevention study. Values were not different between treatment groups (p=0.87). B. Age was inversely related to pre-treatment PI:C ratios (r = −0.36; p=0.004). C. Kaplan-Meier curve showing distribution of the time to progression to Stage 3 diabetes based on high vs. low baseline PI:C ratio of entire cohort, regardless of treatment group, to Stage 3 diabetes, with multivariable cox regression adjusting for age and baseline C-peptide area under the curve.

Figure 1.. In individuals with stage 2 type 1 diabetes PI:C is inversely associated with age, and predicts progression to stage 3 type 1 diabetes.

A. Pre-treatment PI:C values for 63 individuals participating in the TrialNet Teplizumab prevention study. Values were not different between treatment groups (p=0.87). B. Age was inversely related to pre-treatment PI:C ratios (r = −0.36; p=0.004). C. Kaplan-Meier curve showing distribution of the time to progression to Stage 3 diabetes based on high vs. low baseline PI:C ratio of entire cohort, regardless of treatment group, to Stage 3 diabetes, with multivariable cox regression adjusting for age and baseline C-peptide area under the curve.

Figure 2.. Relationship between pre-treatment PI:C, type 1 diabetes progression, and teplizumab treatment.

A. Kaplan-Meier Curve showing rates of progression amongst participants from both treatment groups, stratified based on high vs. low pre-treatment PI:C ratio (above or below 0.5%). Cox regression stratified by pre-treatment ratio and treatment group showed that differences in Stage 3 progression were only statistically significant for participants starting the trial with a high pre-treatment PI:C ratio.

Figure 3.. Average study AUC PI:C ratios were not different between treatment groups.

Average study AUC PI:C ratio corrected for time in study were calculated and adjusted for pre-treatment ratio and age. A: Average study AUC PI:C ratio by treatment arm. B. Average study AUC PI:C ratio by treatment arm and progression to Stage 3 type 1 diabetes. No significant differences were present for any comparisons. n= 22 for placebo group and 41 for teplizumab treated group; 23/41 participants in the teplizumab and 18/22 participants in the placebo arm developed stage 3 type 1 diabetes.

Figure 3.. Average study AUC PI:C ratios were not different between treatment groups.

Average study AUC PI:C ratio corrected for time in study were calculated and adjusted for pre-treatment ratio and age. A: Average study AUC PI:C ratio by treatment arm. B. Average study AUC PI:C ratio by treatment arm and progression to Stage 3 type 1 diabetes. No significant differences were present for any comparisons. n= 22 for placebo group and 41 for teplizumab treated group; 23/41 participants in the teplizumab and 18/22 participants in the placebo arm developed stage 3 type 1 diabetes.