Type 1 diabetes (T1D) results from destruction of insulin producing beta cells by the body’s own immune system (autoimmunity) causing an individual to lose the ability to make enough insulin to control their blood sugar levels and need to have insulin injections to lower blood glucose levels. Whilst high blood sugar level is a problem for people with Type 1 diabetes, taking insulin medication to lower sugar levels, delayed meals and exercise can all result in dangerously low blood sugar levels (hypoglycaemia). The biological causes of hypoglycaemia, and ways to prevent it are poorly understood. In non-diabetic individuals, a hormone called glucagon is secreted naturally to raise blood glucose levels but it is unclear why glucagon secretion is impaired during hypoglycaemia in individuals with T1D.
The aim of this work is to study the relationship between a glucagon stimulation test and risk of hypoglycaemia in T1D. It is hoped this research will establish whether this relationship could be used as a blood test and be a clinically useful biomarker of hypoglycaemia risk and, therefore, directly inform clinical care of people with T1D, particularly those with highest risk of hypoglycaemia.
The study will recruit 75 individuals with long duration type 1 diabetes, identified from participation in the TIGI study (UK IRAS ID: 141756, REC Number: 13/SW/0312), with consent to be contacted for future research. All study visits will be carried out at the NIHR Exeter Clinical Research Facility, Royal Devon & Exeter Hospital.
Normally blood glucose levels are controlled by insulin, a hormone that lowers high blood glucose levels, and glucagon which is released into the blood to raise glucose when levels are low. For people with Type 1 diabetes (T1D), taking insulin medication to lower glucose levels, delayed meals and exercise can all result in dangerously low blood sugar levels (hypoglycaemia). The ability to release glucagon and correct blood glucose can vary, particularly in people who have had T1D for years. For some people, glucagon levels may not be able to rise quickly, reflecting an impairment in glucagon production. The study aims to find out how blood glucagon levels after a stimulus compare to a person’s own experience of hypoglycaemia, and hypoglycaemia as measured by flash glucose monitoring in T1D. We hope this research will establish whether glucagon measured after a meal could be used as a blood marker of hypoglycaemia risk and help to identify individuals at high risk, potentially identifying some people who could benefit from treatments targeting glucagon.
- To understand the relationship of stimulated glucagon secretion to hypoglycaemia, a hormone that raises blood glucose levels, in Type 1 diabetes (T1D).
- To create a blood test to predict the risk of hypoglycaemia (low blood glucose levels).
To clinically validate the relationship of both post mixed-meal and amino-acid stimulated (arginine stimulation test, AST) glucagon levels to hypoglycaemia frequency in people with long duration T1D by using continuous glucose monitoring (CGM) and hypoglycaemia questionnaire data.
- Test the longitudinal variability of glucagon levels and its relationship to episodes of hypoglycaemia in long-duration T1D (repeated stimulation and inhibition experiments within isolated islets and individuals (laboratory and clinical studies);
- Derive a mechanistic understanding of the relationship between plasma glucagon levels under basal conditions, following a stimulation (by mixed meal or arginine)
The outcome of this programme of work will be a description of the strength and reproducibility of the relationship of post-mixed meal and AST glucagon with hypoglycaemia. We will describe longitudinal stability of stimulated glucagon, its relationship with variation in hypoglycaemia frequency, and the potential to predict future hypoglycaemia.
We will describe the combined predictive power of glucagon and clinical variables to predict future hypoglycaemia risk, facilitating creation of a simple clinical prediction tool to predict hypoglycaemia.