Objective
Our overall objective is to determine whether urinary C-peptide relates to the development and progression of early-stage type 1 diabetes. Specifically, we aim to characterise the relationship between urinary C-peptide and first: islet antibody status, second: blood C-peptide and other measures of glucose control and third: continuous glucose monitoring measures. Continuous glucose monitoring metrics allow accurate determination of time in different glucose ranges and above and below different glucose thresholds.
Background Rationale
The ENDIA study provides a globally unique opportunity to investigate the accuracy and relevance of self-collected urine samples to measure C-peptide as a marker of insulin production in young children at risk of type 1 diabetes. Several properties of urine C-peptide warrant testing of its potential as a feasible biomarker of insulin production in early-stage (pre-symptomatic) type 1 diabetes. Urine C-peptide is stable at room temperature for 3 days and then at <20 degrees C. In people with type 1 diabetes, urine C-peptide relates robustly to blood C-peptide after a standard liquid meal and correlates with glucose time in target range during continuous glucose monitoring.
Description of Project
Children at risk of type 1 diabetes need simple and acceptable tests to measure their insulin production and so select the most effective therapies and most appropriate trials at the different stages of type 1 diabetes. We propose to leverage our experience in urine C-peptide measurement and the established Environmental determinants of Islet Autoimmunity (ENDIA) cohort of young at-risk children. C-peptide is a measure of the body’s own production of insulin and its production falls as the destruction of insulin-producing cells progresses. We will determine the usefulness of urine C-peptide in disease staging of progression in conjunction with continuous glucose monitoring. The Environmental Determinants of Islet Autoimmunity (ENDIA) cohort follows children with a first-degree relative with type 1 diabetes from the pregnancy until 10 years of age. Two studies will be performed. The first will measure urine C-peptide and other markers of insulin production and glucose status over time in about 250 children who have or have not developed early-stage type 1 diabetes or type 1 diabetes. The second study will look more closely at the 71 children who have also had continuous glucose monitoring during approximately 200 two-week monitoring periods to investigate whether declines in urine C-peptide relate to changes in the measures of continuous glucose monitoring. The relationship between urine C-peptide and blood C-peptide will also be investigated in this group. By these investigations, the utility of measuring C-peptide in children at high risk for type 1 diabetes will be defined for the first time. Understanding the correlation between urine C-peptide and glucose markers in the progression of early-stage type 1 diabetes will provide new knowledge to translate into monitoring pathways for these children. Self–collected urine samples would provide a highly feasible, acceptable, non–invasive, low burden and low-cost approach.
Anticipated Outcome
In the first study we will measure urine C-peptide in stored samples over time in all children who developed early–stage type 1 diabetes while followed in the ENDIA study and in children matched for age and sex who have not developed early–stage type 1 diabetes. The totals are 248 children and approximately 2,400 urine samples. Associations between urine C-peptide and early–stage type 1 diabetes will be investigated, as well as with other measures of disease risk including post-food blood glucose, blood C-peptide, and HbA1c. We anticipate that a decline in urine C-peptide will occur after the first development of early-stage type 1 diabetes at a similar time to a decline in blood C-peptide and before a rise in HbA1c.
In the second study, 200 continuous glucose monitoring profiles have been collected at intervals from a subset of 47 children with early–stage type 1 diabetes and matched children who have not developed early–stage type 1 diabetes. We will investigate associations between urine C-peptide and a number of continuous glucose monitoring measures in 544 urine samples collected over time. We anticipate that a decline in urine C-peptide will occur from around the time that continuous glucose monitoring measures show an increase in the percentage time that glucose levels are above 7.8mmol/L.
The urine C-peptide assay we will use is clinically accredited in South Australia for use in islet transplant patients. The assay is the same assay as that used in Exeter, UK for both blood and urine where the majority of the work relating blood and urine C-peptide has been performed.
Relevance to T1D
Understanding the correlation between urine C-peptide measures and progression of early–stage type 1 diabetes with accompanying changes in continuous glucose monitoring metrics will provide new knowledge. These findings could be readily translated into clinical pathways for monitoring of children with early-stage type 1 diabetes. Self-collected urine samples would provide a highly feasible, acceptable, low-burden and low-cost approach. Increasingly it is recognised that people progressing to type 1 diabetes require different interventions at different stages. Therefore, an easier non-invasive way of monitoring insulin production would be very welcome in the quest to delay or prevent type 1 diabetes in as many people as possible.