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).

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

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.

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