biostudies-literatureSims EKNCATS NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSJuvenile Diabetes Research Foundation InternationalJohn Templeton Foundation2283-2291https://www.ebi.ac.uk/biostudies/studies/S-EPMC10914155biostudies-literatureUnknown66(12)<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions/interpretation</h4>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.DiabetologiaHigh 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.PMC10914155U01 DK061042R01DK129523U01 DK085476U01 DK085453R01 DK057846U01 DK085499UL1 TR001863U01 DK103180U01 DK085509R01DK057846R01 DK129523UC4 DK106993U01 DK106993U01 DK106994U01 DK103266R01 DK133881R01 DK121929U01DK127382U01 DK103282U01 DK061010U01 DK085461U01 DK061034U01 DK08546562288R01 DK121843P30DK097512U01 DK085466U01 DK061058P30 DK097512U01 DK085504SRA-2019-833-S-BR01DK121929U01 DK107013U01 DK107014UC4 DK097835U01 DK106984U01 DK103153U01 DK127382R01DK133881Herold KCLong SAGeyer SMSims EKfalseHigh 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.<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions/interpretation</h4>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.2023-01-01T00:00:00Z2023 Dec2026-06-03T00:44:51.745Z2025-04-06T15:08:50.184ZS-EPMC109141553766710610.1007/s00125-023-06003-5