Plasma proinsulin and proinsulin/C-peptide ratio to facilitate prediction for progression to type 1 diabetes in at risk individuals

Type 1 diabetes (T1D) is a chronic disease caused by a major loss of insulin-producing beta cells.
Clinical onset is preceded by an asymptomatic disease phase of variable duration. Metabolic
investigations, such as oral glucose tolerance tests (OGTT) and hyperglycemic clamp tests (HCT)
improve prediction of clinical onset, which helps reducing the occurrence of ketoacidosis and
optimizing immune intervention protocols. However, performing these standardized beta cell
stimulation tests is cumbersome, time-consuming, and costly. Plasma proinsulin (PI) and the PI/Cpeptide ratio (PI/CP) were shown to rise before clinical diagnosis. We hypothesize that in
asymptomatic T1D, PI may better reflect the functional state of beta cells than CP in conditions of
metabolic and/or inflammatory burden, and that PI and PI/CP provide composite scores of insulin
biosynthetic capacity, insulin resistance and inflammatory activity around islets. This project aims to
measure and monitor plasma PI and the PI/CP in asymptomatic T1D (1) to validate them against
OGTT and HCT, as minimally invasive predictors of clinical onset, applicable on a large scale; (2) to
correlate them with functional beta cell mass, insulin resistance, BMI, and immune and genetic
biomarkers of disease progression. This may facilitate early diagnosis, avoidance of ketoacidosis, and
development of novel prevention trials in asymptomatic T1D.