Continuous Monitoring of Glycemic Variability to Predict Dys- and Hyperglycemia in Asymptomatic Type 1 Diabetes

Study Overview
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Brief Summary
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The goal of this longitudinal clinical trial is to measure variability of interstitial glucose levels with a user-friendly real-time continuous glucose monitoring (CGM) technology at regular intervals in 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. Participants will asked to undergo repeated oral glucose tolerance tests (OGTTs) (age 5-39 years) and hyperglycemic clamp tests (age 12-39 years) in parallel for a period of at least 2-3 years. In case of confirmed dysglycemia, we propose to perform CGM and OGTT every 3 months. The main questions the study aims to answer are: 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? 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? 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? 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?

Official Title
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Continuous Monitoring of Glycemic Variability to Predict Dys- and Hyperglycemia in Asymptomatic Type 1 Diabetes

Conditions
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Type1 Diabetes Mellitus

Intervention / Treatment
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* Diagnostic Test: Oral glucose tolerance test (OGTT)
* Diagnostic Test: Hyperglycemic clamp test
* Diagnostic Test: Continuous glucose monitoring


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: aged 5-39 years at inclusion; being a sibling, offspring or parent of a patient with confirmed auto-immune type 1 diabetes; absence of diabetes according to American Diabetes Association (ADA) criteria; persistently positive for one or multiple types of autoantibodies among IAA, GADA, IA-2A and ZnT8A. Exclusion Criteria: Pregnancy or lactation in women; <6 months postpartum Diabetes according to ADA criteria; Use of illicit drugs, or overconsumption of alcohol, or history of drug or alcohol abuse; Being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders; Treatment with immune modulating or diabetogenic medication (e.g. corticosteroids) or medication that act to lower glycemia (oral antidiabetics) or agents that may influence insulin sensitivity or secretion; Gastric bypass or banding; History of acute or chronic pancreatitis, or (partial) pancreatectomy History of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risks to the subjects.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Autoantibody-positive first-degree relatives of type 1 diabetes patients<br> | Diagnostic Test: Oral glucose tolerance test (OGTT)<br>* Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in first-degree relatives at moderate, high and very high risk of clinical onset of type 1 diabetes. OGTT is performed every 6 months (every 3 months in case of dysglycemia) in all participants.<br>* Other names: OGTT;Diagnostic Test: Hyperglycemic clamp test<br>* Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in first-degree relatives at moderate, high and very high risk of clinical onset of type 1 diabetes. Clamp test is performed every 12 months in single autoantibody-positive participants and every 6 months in multiple autoantibody-positive participants. Clamp tests are not performed in participants aged between 5-11 years.<br>* Other names: clamp;Diagnostic Test: Continuous glucose monitoring<br>* Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in first-degree relatives at moderate, high and very high risk of clinical onset of type 1 diabetes. A 10-day CGM recording is performed every 6 months (every 3 months in case of dysglycemia) in all participants.<br>* Other names: CGM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression to persistent dysglycemia | In initially normoglycemic (single or multiple) autoantibody-positive relatives | 2-3 years | 
| Progression to persistent dysglycemia and stage 3 type 1 diabetes | In all multiple autoantibody-positive relatives | 2-3 years |