Objective
This study aims to determine the metabolic changes associated with the presence of islet autoantibodies in the very early stages of type 1 diabetes. The metabolic changes will be described over time by using both metabolic tests and minimally invasive subcutaneous continuous glucose sensors. The ultimate result will be to define new screening tools to identify those who may benefit the most from interventions targeting specific metabolic alterations to prevent the clinical onset of type 1 diabetes.
Background Rationale
We have previously shown that children and adolescents with one or more islet autoantibodies have lower insulin production and sensitivity than healthy peers. These early metabolic changes may accompany the appearance of islet autoantibodies and contribute to the progression of the autoimmune destruction of the islets (the cells that produce insulin).
Description of Project
Clinical onset of type 1 diabetes (T1D) is preceded by a pre-symptomatic phase characterized by the presence of one or more islet autoantibodies with normal glucose. About 3 out of 4 kids with islet autoantibodies progress to overt diabetes in 10 years. The greater the number of islet autoantibodies, the higher the risk of progression. Recognizing the ability to detect antibodies, relatives of those living with type 1 diabetes have been offered the opportunity to have screening studies conducted. To date, there has been no disease-modifying agent available to avoid onset of diabetes. However, this is expected to change soon as a drug targeting the immune system has been shown to delay the onset of diabetes up to ~2 years in those with positive antibodies and some mild elevations in glucose levels, and this agent is currently under review by the FDA.
As a disease-modifying agent is anticipated to be available, more individuals may choose to screen for antibodies. Indeed, work is also being done to allow for general population screening. Yet, little is known about the very early stages of the disease, where antibodies are present, but glucose levels are almost entirely normal. The present study seeks to characterize those with antibodies better but do not meet the thresholds to define mildly elevated glucose levels. To better describe this population, we propose to conduct a series of studies to identify the metabolic profile of those with very early stages of the disease. As glucose levels are normal, this may be an ideal group to target for interventions.
Metabolic alterations may include insulin production and the body response to insulin action, the production of gut hormones – the incretins which stimulate insulin production and also increase the effectiveness of insulin.
Using state-of-the-art metabolic tests, we will quantify these metabolic changes over time along with minimally invasive procedures like using a continuous glucose monitoring sensor. These sensor readings may be associated with metabolic alterations. Thus, a small device that can be worn at home can help determine risk for progression to disease and identify those who may be best suited for prevention trials.
Combining our metabolic measures and characterization of sensor glucose data will provide important information for those with positive islet autoantibodies and help identify the natural course of disease progression. This will inform future intervention, which may be able to halt the progression of the disease.
Anticipated Outcome
We expect to identify metabolic changes in the early stages of T1D that might help identify unique screening approaches relying on simple metabolic tests, such as the oral glucose tolerance test or continuous subcutaneous glucose sensors (CGM).
Relevance to T1D
This study is expected to shift the paradigm of diabetes staging and screening and inform future prevention trials. First, we hope that we will be able to identify metabolic subgroups within the early stages of T1D and that CGM-based screening procedures will complement this metabolic subgroup characterization. Both these approaches will allow minimally invasive characterizations of persons at risk for diabetes who may benefit from specific metabolic therapeutic interventions based on individual metabolic profiles. By further defining this group, we seek to individualize treatment strategies to halt the progression to overt type 1 diabetes where daily insulin therapy is necessary.