Elevations in the Fasting Serum Proinsulin–to–C-Peptide Ratio Precede the Onset of Type 1 Diabetes

Abstract

OBJECTIVEWe tested whether an elevation in the serum proinsulin–to–C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes.RESEARCH DESIGN AND METHODSFasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels.RESULTSAlthough absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05).CONCLUSIONSThese data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.

Autoreactive T cells in type 1 diabetes

“…Based on these findings, Figure 1 illustrates two theoretical patterns of β cell destruction: insulitis may begin early, with destruction proceeding in a semi-linear fashion; or insulitis and β cell destruction may occur closer to diagnosis. The latter fits the observations that (i) the proportion of infiltrated islets is modest near diagnosis, and insulitis is only present in non-diabetic donors with multiple autoantibodies (16,21,23); (ii) β cell loss near diagnosis is partial in many patients (16,21,23), and no appreciable reduction in β cell mass has been reported in autoantibody-positive donors (44,45); and (iii) impaired glucose metabolism, abnormalities of insulin secretion (46,47) and insulin sensitivity (48), and increased β cell death (49) usually manifest shortly before diagnosis in longitudinal studies of at-risk relatives.…”

Biomarkers of β-Cell Stress and Death in Type 1 Diabetes

“…In the Belgian Diabetes Registry, autoantibody-positive first-degree relatives with random PI/C ratios above the 66th percentile had an increased 5-year risk of T1D development [26]. Sims et al recently reported that within the TrialNet Pathway to Prevention cohort, an international cohort of autoantibody-positive family members of individuals with T1D, fasting PI/C ratios were significantly increased ~12 months prior to onset of T1D [27••]. Elevations were most pronounced in children ≤10 years, where median PI/C ratios were 3-fold higher than those who did not progress to T1D.…”

“…Elevations were most pronounced in children ≤10 years, where median PI/C ratios were 3-fold higher than those who did not progress to T1D. However, even among the entire group, increased PI/C ratios were associated with increased odds of progression to T1D, after correction for age and BMI [27••]. …”

Combination Immunotherapy for Type 1 Diabetes

“…Prevention studies mentioned above used autoantibodies as biomarkers for T1D. Other potential biomarkers of T1D development include: genetic predisposition (13, 58, 107-109), unmethylated preproinsulin (110, 111), proinsulin-to-C-peptide ratios (112, 113), and microRNA species (114). In addition, β-cell derived neo-antigens offer another potential biomarker of T1D, but also a target for T1D prevention (115, 116).…”