Clinical trial NCT04977635: Biomarkers of Heterogeneity in Type 1 Diabetes
Official title: Biomarkers of Heterogeneity in Type 1 Diabetes: an Integrated Approach to Clinical and Metabolic Phenotyping of Individuals With Established Type 1 Diabetes
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Type 1 Diabetes
Keywords: Heterogeneity
Biomarkers
C-peptide
Glucagon
Impaired awareness of hypoglycemia
Mixed meal tolerance test
Genetics
Lead sponsor: Diabeter Nederland BV
Sponsor class: OTHER
Collaborators: name: University Medical Center Groningen
First posted: 2021-07-27
Enrollment: 611
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with \>= 5 years duration of type 1 diabetes, age \>= 16 years, treated for type 1 diabetes at a diabetes center participating in this study

Brief summary: Biomarkers of heterogeneity in type 1 diabetes: establishment of a biobank and an integrated approach to clinical and metabolic phenotyping of individuals with established T1DM. In this project the investigators are searching for biomarkers in 600 patients with established (\>5 years) diabetes. The inter-relation and patterns of expression in clinical, (auto)immune, metabolic, inflammatory and other parameters, and (potential) biomarkers are investogated. Blood and urine samples are collected annually (over 3 years) in standardized conditions and biobanked. In addition, 150 patients will undergo additional metabolic testing (such as mixed meal-tests).

Detailed description: Identifying biomarkers of type 1 diabetes heterogeneity can help to stage the disease, and identify risks such as the early development of damage and complications.

Type 1 diabetes has long been considered to be an autoimmune disease in which failure of immune tolerance induces a specific immune attack on insulin-producing beta-cells. Recent research shows that the pathophysiology of type 1 diabetes is heterogeneous, involving various beta-cell-specific processes, different genetic predispositions, and several disease stages. It is very important to recognize this heterogeneity as it results in an accumulation of differences in outcomes during the course of the disease.

This heterogeneity requires further elucidation as a heterogeneous disease is likely to require multiple approaches to stop or cure the pathophysiological pathways. This underscores the need for more biomarkers to identify this heterogeneity, the different phases of disease and the effects of interventions and cures.

In many countries and research groups, data and samples from newly-diagnosed individuals (i.e. within the first 6 months after diagnosis) have been collected and studied. Fewer data and samples are available from patients with longer disease duration. This prompted JDRF to grant a strategic research agreement (SRA) to Diabeter and UMC Groningen. Both clinics have access to a substantial clinical database since 1998 with medical record data of \> 3500 type 1 diabetes patients.

In this BIOMARKER project, the investigators intend to analyze hormonal, biochemical, immunological, inflammatory and psychological biomarkers of type 1 diabetes in patients with a disease duration of \> 5 years. A sample repository (serum, plasma, urine, DNA, RNA) is established which is also accessible to other interested collaborators.

The collection currently includes:

* Fasting samples (serum, plasma, urine, DNA, RNA) from 600 patients with type 1 diabetes (\> 5 years duration) taken annually at 3 timepoints
* Samples from 150 patients who underwent Mixed Meal Tolerance Tests (MMTT with 5 timepoints) at 2 occasions (1-year interval)
* Data from questionnaires on psychosocial burden, quality of life, neuropathy and hypoglycaemia completed by the patients
* Clinical datasets on their health, diabetes history, family history and clinical course during treatment

Eligibility criteria: Inclusion Criteria:

1. Type 1 diabetes determined by either autoantibodies or based on clinical and historical data or both
2. At least 5 years (1825 days) of type 1 diabetes
3. Minimum age 16 years
4. Treated for type 1 diabetes at a diabetes center participating in this study
5. Subject understands study protocol and agrees to comply with it and has been able to read the patient information sheet, has had time to ask questions and get answers and gives signed informed consent.

Exclusion Criteria:

1. Non-type 1 diabetes
2. Patients with a duration of type 1 diabetes below 5 years
3. Patients under the age of 16 years
4. Pregnancy and breastfeeding, until 3 months (12 weeks) after childbirth or breastfeeding
5. On experimental medication or participating in other studies with conflicting goals and schedules
6. Diseases or conditions that the investigator/physician believes to be a contraindication to participate
7. Unwilling to be informed on incidental findings.

Primary outcomes:
measure: Change from baseline remaining C-peptide production at 1 year and 2 years as measured by the Beckman ultrasensitive C-peptide assay
timeFrame: baseline, 1 year, 2 years
measure: Change in prevalence of impaired awareness of hypoglycaemia between baseline and 2-year timepoint as measured by adapted Clarke hypoglycaemia awareness survey
timeFrame: baseline, 2 years
measure: Genome-wide Association Study (GWAS) by Illumina 720k chip
timeFrame: cross-sectional: baseline
measure: Assessment of glucagon response after stimulation with a mixed meal tolerance test as measured by the Mercodia glucagon assay (ELISA)
timeFrame: baseline
measure: Change in patient-reported outcomes between baseline and 2 year timepoint as measured by WHO-5, PAID-20 and WHOQOL surveys
timeFrame: baseline, 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Rotterdam
country: Netherlands
facility: Martine MC de Vries
city: The Hague
country: Netherlands
facility: Haaglanden Medical Center
Study officials:
affiliation: Diabeter Nederland BV
name: Henk-Jan Aanstoot, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Groningen
name: Bruce HR Wolffenbuttel, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Haaglanden Medical Center
name: Nel PH Geelhoed-Duijvestijn, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: