Objective
This study aims to measure variability of interstitial glucose levels with a user-friendly real-time continuous glucose monitoring (CGM) technology (Dexcom G6, San Diego, CA, USA) at regular intervals (every 6 months) during follow-up of normo- and dysglycemic multiple autoantibody-positive first-degree relatives (age 5-39 years) of type 1 diabetes patients, in comparison with single autoantibody-positive relatives in the same age range. In parallel, repeated oral glucose tolerance tests (OGTTs) (age 5-39 years) and hyperglycemic clamp tests (age 12-39 years) will be performed for a period of at least 2-3 years.
We hypothesize that CGM-derived indices of increased glucose excursions – alone or in combination – accompany or even precede OGTT-derived dysglycemia and may be used as a less cumbersome and a more frequently applicable alternative to OGTT for predicting dysglycemia (i.e. disturbed blood glucose levels after acute stimulation with a concentrated glucose solution, associated with increased risk of fast progression) and clinical onset of type 1 diabetes.
As CGM-derived indices of glycemic variability allegedly represent composite measures of beta cell function and insulin action, we also hypothesize that comparing them to OGTT- and hyperglycemic clamp-derived variables of beta cell function and insulin action will allow to better understand the relative contribution of these two components to increasing glycemic variability throughout the elusive natural history of asymptomatic type 1 diabetes.
Experiments will be conducted to answer the following research questions:
(1) Do the amplitude and time trends of CGM-derived glycemic variability indices and OGTT- and clamp-derived variables differ between the intermediate, high and very high risk groups?
(2) Can (changes in) CGM-derived glycemic variability indices predict/detect dysglycemia in initially normoglycemic (single or multiple autoantibody-positive) relatives with the same diagnostic efficiency as OGTT- or clamp-derived variables?
(3) Can (changes in) CGM-derived glycemic variability indices predict clinical onset in (stage 1 or 2) multiple autoantibody-positive relatives with the same diagnostic efficiency as OGTT- or clamp-derived variables?
(4) Can correlating (changes in) CGM-derived indices with (changes in) OGTT- and clamp-derived variables help to better understand the sequence of events leading to dysglycemia and clinical onset, as well as the relative contribution of beta cell function and insulin action to glycemic variability according to disease stage and biological and phenotypical characteristics of the relatives?
Background Rationale
Type 1 diabetes is a for now incurable disease caused by a major immune-mediated loss of insulin-producing pancreatic beta cells. When the remaining beta cells have dropped to 10-40% of normal capacity, blood glucose levels start to rise, leading to potentially severe acute and chronic complications and necessitating a demanding, lifelong insulin treatment.
Clinical onset of type 1 diabetes is preceded by an asymptomatic disease phase of highly variable duration, which is signaled by the presence of multiple (≥2) types of islet autoantibodies. Multiple autoantibody-positive children and adults, with blood glucose levels still within normal limits, have a 90% risk of developing symptomatic disease within the next 20 years, or so-called stage 1 asymptomatic type 1 diabetes. Time to clinical onset remains highly variable and unpredictable among multiple autoantibody-positive individuals and cannot be accurately estimated based solely on autoantibody profile or genetic markers.
Recognizing individuals at high risk of impending clinical onset of type 1 diabetes is important for early diagnosis, when the insulin-producing beta cells are still relatively preserved, for reducing the incidence of inaugural ketoacidosis, a possibly life-threatening acute complication, and for enrolling participants of choice in immune intervention trials before and at clinical diagnosis, aiming to develop an effective cure or even better, prevention.
The development of dysglycemia (stage 2 type 1 diabetes) – i.e. disturbed blood glucose levels during an oral glucose tolerance test or OGTT – dramatically raises the risk of impending clinical onset to 90% within 5 years. However, the ingestion of a concentrated glucose solution is not always well tolerated. The hyperglycemic clamp test is the gold standard beta cell stimulation test to measure to residual beta cell function and insulin action and has a high diagnostic ability to predict progression to symptomatic disease. However, the repeated performance of both OGTTs and clamps are cumbersome and difficult to implement on a large scale in a seemingly healthy population.
In contrast, state-of-the-art CGM methods nowadays avoid the need of frequent calibration based on capillary blood measurements obtained by finger pricks. They also allow to detect more subtle glycemic fluctuations over longer observation periods and on a more frequent basis than achievable with OGTT, and to derive a wide variety of indices of glycemic variability.
Preliminary findings suggest that repeated CGM metrics in stage 1 asymptomatic diabetes could provide a minimally invasive alternative to OGTT for early detection or prediction of stage 2 asymptomatic disease, provided that increased CGM-derived glycemic excursions can be shown to coincide with or precede OGTT-inferred dysglycemia, respectively, in a longitudinal study. In addition, it is anticipated that further increasing glycemic excursions may forecast impending clinical onset.
Description of Project
Type 1 diabetes is a for now incurable disease caused by a major immune-mediated loss of insulin-producing pancreatic beta cells, can lead to potentially severe acute and chronic complications and requires a lifelong insulin treatment.
Clinical onset of type 1 diabetes is preceded by an asymptomatic disease phase of highly variable duration, which is signaled by the presence of multiple (≥2) types of islet autoantibodies. Multiple autoantibody-positive individuals, with blood glucose levels still within normal limits (defined as stage 1 type 1 diabetes) have a 90% risk of developing symptomatic disease within the next 20 years. The development of dysglycemia (stage 2 type 1 diabetes) – i.e. disturbed blood glucose levels during an oral glucose tolerance test (OGTT) – dramatically raises the risk of impending clinical onset to 90% within 5 years.
Identifying individuals at high risk of impending clinical onset of type 1 diabetes is important for early diagnosis, for reducing the incidence of inaugural ketoacidosis, and for enrolling participants of choice in immune intervention trials before and at clinical diagnosis, aiming to develop an effective cure or even better, prevention.
The hyperglycemic clamp test is the gold standard for assessing beta cell function and has also been validated for estimating insulin action in parallel. Decreased clamp-derived measures of islet function and insulin action have been shown to outperform OGTT-derived variables for predicting progression to symptomatic disease. However, the repeated performance of both OGTTs and clamps are cumbersome and difficult to implement on a large scale in a seemingly healthy population.
In contrast, continuous glucose monitoring (CGM) methods nowadays avoid the need of frequent calibration based on capillary blood measurements obtained by finger pricks. They also allow to detect more subtle glycemic fluctuations over longer observation periods and on a more frequent basis than achievable with OGTT, and to derive a wide variety of indices of glycemic variability.
Preliminary findings suggest that repeated CGM metrics in stage 1 asymptomatic diabetes could represent a minimally invasive alternative to OGTT for early detection or prediction of stage 2 asymptomatic disease, provided that increased CGM-derived glycemic excursions can be shown to coincide with or precede OGTT-inferred dysglycemia, respectively, in a longitudinal study. In addition, it is anticipated that further increasing glycemic excursions may forecast impending clinical onset.
Using the capacity of the nationwide network of the Belgian Diabetes Registry, we therefore propose a longitudinal study to measure variability of interstitial glucose levels with a user-friendly real-time CGM technology at regular intervals (every 6 months) during follow-up of multiple autoantibody-positive first-degree relatives (age 5-39 years; n>50) of type 1 diabetes patients, in comparison with single autoantibody-positive relatives (n>25). In parallel repeated OGTTs (age 5-39 years) and hyperglycemic clamp tests (age 12-39 years) will be performed for a period of at least 2-3 years.
We anticipate that, especially when using up-to-date CGM technology, (i) the amplitude and time trends of various glycemic variability indices – alone or in combination – will differ between groups of relatives at moderate (single autoantibody-positive), high (stage 1), and very high (stage 2) risk of impending clinical onset (stage 3); (ii) (changes in) CGM-derived glycemic variability indices will be able to predict and/or diagnose stage 2 asymptomatic type 1 diabetes and clinical onset (stage 3) with a diagnostic efficiency equaling that of variables derived from (repeated) OGTT or clamp tests; (iii) correlating CGM metrics with hyperglycemic clamp- and OGTT-derived indices of beta cell function and insulin action will help to understand the relative contribution of both components to disease progression in general, and to glycemic variability in particular.
Anticipated Outcome
We anticipate that, especially when using up-to-date CGM technology, the amplitude and time trends of various glycemic variability indices – alone or in combination – will differ between groups of relatives at moderate (single autoantibody-positive), high (stage 1), and very high (stage 2) risk, and that the diagnostic efficiency of (changes in) CGM-derived variables for diagnosing/predicting stage 2 asymptomatic type 1 diabetes and clinical onset (stage 3) equals that of (changes in) variables derived from (repeated) OGTT or clamp tests.
Relevance to T1D
We anticipate that the systematical correlation of glycemic variability measures as assessed by continuous glucose monitoring, with OGTT- and clamp-derived variables during follow-up in the various stages of asymptomatic type 1 diabetes will provide a better insight in the natural history of the still incompletely understood hidden disease stage.
Efficient prediction of dysglycemia and clinical onset through repeated CGM recordings using state-of-the-art and user-friendly technology should provide a minimally invasive and widely applicable alternative to repeatedly performing cumbersome beta cell stimulation tests.
Strategies to facilitate early diagnosis of stage 3 type 1 diabetes, prevention of inaugural ketoacidosis and planning of prevention trials are likely to benefit from the proposed study.