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

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 individuals (age 5-39 years), in comparison with single autoantibody-positive individuals 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:

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) individuals 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 individuals 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 individuals?

Study Overview

• Status: Recruiting
• Conditions: Type1 Diabetes Mellitus
• Intervention / Treatment: Diagnostic test: Oral glucose tolerance test (OGTT); Diagnostic test: Hyperglycemic clamp test; Diagnostic test: Continuous glucose monitoring

Detailed Description

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 userfriendly real-time CGM technology at regular intervals (every 6 months) during follow-up of multiple autoantibody-positive first-degree individuals (age 5-39 years; n>50) of type 1 diabetes patients, in comparison with single autoantibody-positive individuals (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 individuals 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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Belgian Diabetes Registry; Phone Number: +32 02 477 45 46; Email: contact@bdronline.be

Study Locations

• Belgium
  • Antwerp, Belgium, 2650
    • Recruiting
    • Universitair Ziekenhuis Antwerpen
    • Principal Investigator: Christophe De Block, MD, PhD
    • Contact: Rie Braspenning; Phone Number: +32 3 821 4002; Email: Rie.Braspenning@uza.be
    • Principal Investigator: Marieke den Brinker, MD, PhD
    • Sub-Investigator: Niels Bochanen, MD
    • Contact: Beeldens Jente; Phone Number: +3 436 8409; Email: Jente.Beeldens@uza.be
  • Ghent, Belgium, 9000
    • Recruiting
    • Universitair Ziekenhuis Gent
    • Contact: Nancy Platteau; Phone Number: +329 332 6394; Email: Nancy.Platteau@uzgent.be
    • Contact: Els Feyen; Email: Els.Feyen@uzgent.be
    • Principal Investigator: Bruno Lapauw, MD, PhD
    • Sub-Investigator: Joke Marlier, MD
    • Sub-Investigator: Sara Van Aken, MD
    • Sub-Investigator: Hasan Kahya, MD, PhD
  • Jette, Belgium, 1090
    • Recruiting
    • Universitair Ziekenhuis Brussel
    • Contact: Karen Hanssens; Phone Number: +322 477 77 60; Email: CTU-diabeteskliniek@uzbrussel.be
    • Principal Investigator: Aster Desouter, MD
    • Sub-Investigator: Willem Staels, MD PhD
  • Leuven, Belgium, 3000
    • Recruiting
    • Universitair Ziekenhuis Leuven
    • Contact: Natalie Van den Driessche; Phone Number: +3216 34 85 54; Email: natalie.vandendriessche@uzleuven.be
    • Principal Investigator: Pieter Gillard, MD, PhD
    • Sub-Investigator: Kristina Casteels, MD, PhD
  • Liège
    • Liège, Liège, Belgium, 4000
      • Recruiting
      • Clinique CHC MontLégia
      • Contact: Alexandra Van Eyck; Phone Number: 04 355 42 14; Email: Alexandra.VANEYCK@chc.be
      • Principal Investigator: Nicole Seret, MD
  • West-Vlaanderen
    • Bruges, West-Vlaanderen, Belgium, 8000
      • Recruiting
      • A.Z. Sint-Jan Brugge
      • Contact: Fabienne Beyaert; Email: Fabienne.Beyaert@azsintjan.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 39 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. aged 5-39 years at inclusion;
2. absence of diabetes meeting the clinical diagnostic American Diabetes Association (ADA) criteria;
3. persistently positive for one or multiple types of autoantibodies among IAA, GADA, IA-2A and ZnT8A.

Exclusion Criteria:

1. Pregnancy or lactation in women; <6 months postpartum
2. Diabetes meeting the clinical diagnostic ADA criteria;
3. Use of illicit drugs, or overconsumption of alcohol, or history of drug or alcohol abuse;
4. Being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders;
5. 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;
6. Gastric bypass or banding;
7. History of acute or chronic pancreatitis, or (partial) pancreatectomy
8. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Autoantibody-positive individuals

Diagnostic test: Oral glucose tolerance test (OGTT); Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals 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.; Other Names: OGTT; Diagnostic test: Hyperglycemic clamp test; Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals 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.; Other Names: clamp; Diagnostic test: Continuous glucose monitoring; Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals 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.; Other Names: CGM; Dexcom G6

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Universitair Ziekenhuis Brussel
• Collaborators: Breakthrough T1D
• Investigators: Principal Investigator: Bart Keymeulen, Vrije Universiteit Brussel

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2023
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: March 8, 2023
• First Submitted That Met QC Criteria: March 8, 2023
• First Posted (Actual): March 21, 2023

Study Record Updates

• Last Update Posted (Estimated): September 2, 2025
• Last Update Submitted That Met QC Criteria: August 25, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hyperglycemia; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Chemistry Techniques, Analytical; Blood Chemical Analysis; Clinical Chemistry Tests; Diagnostic Techniques, Endocrine; Monitoring, Physiologic; Continuous Glucose Monitoring; Glucose Tolerance Test; Glucose Clamp Technique
• Other Study ID Numbers: PredicT1D

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

We opt to restrict data access as the project involves personal and sensitive data.

A specific data use agreement could be considered for data sharing after the end of the project.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes