Proinsulin to C-Peptide Ratio in the First Year After Diagnosis of Type 1 Diabetes

Abstract

Objectives This study examined the natural history of the proinsulin to c-peptide (PI:C) ratio and its correlation with residual β-cell function in childhood new-onset type 1 diabetes (T1D). Reputedly, this ratio is a biomarker of β-cell endoplasmic reticulum (ER) stress. Over the first year of T1D, the temporal trend in fasting and nutrient-stimulated PI data is limited. Methods PI was a secondary pre-planned analysis of our one year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4-18 years, 30 were placebo. This study only involved the 30 placebo patients; all were enrolled within 5 weeks of T1D diagnosis. A liquid mixed meal tolerance test was administered at baseline visit, 5 and 12 months for determination of c-peptide, PI, glucose, and hemoglobin A1C. Results Both the fasting (p=0.0003) and stimulated (p=0.00008) PI:C ratios increased from baseline to 12 months, inferring escalating β-cell ER stress. The baseline fasting PI correlated with the fasting change in c-peptide at 12 months (p=0.004) with a higher PI correlating with a greater decline in c-peptide. Patients with an insulin adjusted A1C > 9% (hence, not in remission) had higher fasting PI:C ratios. Younger age at diagnosis correlated with a higher PI:C ratio (p=0.04). Conclusion Children with new-onset T1D are undergoing progressive β-cell ER stress and aberrant proinsulin processing as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects a more aggressive β-cell onslaught the younger the age as well as diminished glycemic control.

GABA and Combined GABA with GAD65-Alum Treatment Alters Th1 Cytokine Responses of PBMCs from Children with Recent-Onset Type 1 Diabetes

“…Despite being a hallmark cytokine for Th1 responses, IFN-γ inhibition should not be viewed as a complete end-all, for under certain circumstances, IFN-γ can have inhibitory effects on CD8 T cell responses in T1D [40]. Our results are in concordance with another outcome measure from this study in that the escalating Th1 signature in the placebo group coincided with an increasing ratio of proinsulin to c-peptide [41].…”

Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets

“…A second common feature of islet pathology in T1D and T2D is secretion of unprocessed proinsulin (20). In fact, detectable serum proinsulin persists in a majority of individuals with longstanding T1D, even those that no longer have detectable serum C-peptide (21).…”

Approaches to Measuring Beta Cell Reserve and Defining Partial Clinical Remission in Paediatric Type 1 Diabetes

“…3a Proinsulin/C-peptide Ratio C-peptide and insulin are secreted in equal molar amounts following cleavage of proinsulin. The proinsulin/c-peptide ratio (PI:C) has been used as a biomarker of beta cell stress [122,123]. Fasting and MMTT-stimulated PI:C increased from baseline measurement early in T1D diagnosis to measurements at 12 months; demonstrating increasing beta cell stress.…”

“…Fasting and MMTT-stimulated PI:C increased from baseline measurement early in T1D diagnosis to measurements at 12 months; demonstrating increasing beta cell stress. One year after diagnosis, those with an IDAA1C > 9 (i.e., considered not be in remission) had a higher PI:C. Patients who had a higher PI:C at baseline were shown to have a greater decline in their c-peptide over the first year of disease [123]. Although these results may signify beta cell stress, PI:C has not been used to define a partial clinical remission to date.…”