Objective
The overall aim of this proposal is to develop a new way to monitor individuals with stage 1 and 2 and predict progression to more advanced stages of T1D, using a home-based tool. This tool consists of a combination of fasting and post-glucose load C-peptide and proinsulin levels using dried blood spot (DBS) cards that only require a finger prick blood sample along with continuous glucose monitoring using a glucose sensor.
This tool could be used in clinical practice to stratify individuals identified through screening programs in different risk categories and guide their long-term monitoring needs. In addition, it could be used to select individuals for future enrolment in preventive trials.
The proposal will address two specific objectives:
Objective 1: To evaluate the ability of markers of beta-cell function, as assessed by repeated home-collected DBS fasting and post-glucose load C-peptide, alone or in combination with proinsulin, in predicting changes in glycemic status, from normal levels to hyperglycemia, in children, adolescents and adults with stage 1 and 2 T1D.
Objective 2: to explore if measures of glucose, based on continuous glucose monitoring ('glucose sensors or CGM) can identify early changes in glucose profile in pre-symptomatic individuals in stage 1 and 2 predictive of progression over time, and how CGM metrics reflect beta cell function changes in this population.
Background Rationale
Symptomatic type 1 diabetes (stage 3 T1D) is preceded by a prolonged pre-symptomatic phase characterized by progressive loss of the insulin producing cells (pancreatic beta-cells). While stage 3 T1D can be recognized from clinical symptoms, changes in earlier stages will require sensitive and reliable markers in the absence of symptoms. In particular, the ability to monitor changes in beta-cell function is critical to identify individuals most at risk of progression to stage 3 T1D and for the evaluation of interventions to prevent clinical T1D in pre-symptomatic individuals. To limit the burden on pre-symptomatic individuals, measures of beta-cell function should preferably be home-based.
Our group has developed a dried blood spot (DBS) method to assess C-peptide in the home setting, which can be easily repeated over time. DBS C-peptide measurements have been shown to be a viable tool for early detection of changes in beta-cell function in individuals with stage 3 T1D.
Further work is needed to establish whether measures of beta-cell function based on DBS, fasting and after a glucose load, and their combination with measures of glucose levels (through continuous glucose monitoring systems, known as glucose sensors), could predict disease progression in pre-symptomatic individuals.
Description of Project
Type 1 diabetes (T1D) is the third most common chronic condition in children, affecting around 1.5 million young people under the age of 18 years worldwide. It is caused by the immune system damaging the pancreas, an organ responsible for making insulin, which impacts every aspect of a person’s life. Previous research has shown that the development of T1D occurs through different stages. This starts with a phase where there are no symptoms (presymptomatic), which can last months or years (stages 1 and 2), before symptoms of T1D develop and someone becomes unwell (stage 3 T1D or clinical T1D). The progression to clinical T1D is associated with a progressive loss of the beta-cells, which are insulin producing cells. The best biomarker to measure decline in beta-cells is a protein in the blood called C-peptide, but taking this blood sample requires hospital attendance. Our research group previously developed a new way of measuring C-peptide using dried blood spot (DBS) cards that only require a finger prick blood sample taken at home. We now aim to assess whether home assessment of DBS C-peptide is a reliable tool to identify presymptomatic individuals at risk of progressing to clinical T1D. We also plan to combine this measurement with assessments of glucose levels using continuous glucose monitoring (glucose sensors), which are commonly used in people with clinical T1D. This study is important because we need non-invasive tools to frequently monitor asymptomatic individuals that allow us to reliably predict their risk of progression. Such tool could be implemented in clinical practice to guide long-term monitoring needs and to avoid late presentation of clinical T1D. This tool could also be used to select individuals for future enrolment in clinical trials or to offer them new interventions to prevent progression to symptomatic (stage 3) T1D.
Anticipated Outcome
The proposed assessment tool could be used to identify individuals who are most at risk of developing clinical type 1 diabetes for future enrolment in preventive trials. In addition, it could be implemented in clinical practice to stratify individuals identified through screening programs in different risk categories to guide their long-term monitoring needs and prevent late presentation with diabetic ketoacidosis and improve.
Relevance to T1D
This proposal focuses on how to prevent Type 1 diabetes (T1D), the third most common chronic disease in childhood, but which can occur also in adults. Often people present with complications such as diabetic ketoacidosis (DKA) which are associated with significant morbidity, mortality and high costs related to admissions and treatment. Therefore, preventing this condition is a priority. We now know that the clinical onset of T1D (stage 3 T1D) is preceded by a pre-symptomatic phase featured by the presence of autoantibodies against the insulin-producing beta cells. While autoantibodies are the hallmark of the underlying autoimmune process, very little evidence is available for the metabolic changes that accompany the loss of insulin producing beta-cells. Thus, there is a need for reliable, non-invasive and acceptable methods to identify key changes in beta cell function in presymptomatic individuals before progression to stage 3 T1D.