Biomarkers of heterogeneity in type 1 diabetes: an integrated approach to clinical and metabolic phenotyping of individuals with established Type 1 diabetes

Type 1 diabetes is an autoimmune disease which is far more heterogeneous than
previously assumed. This could explain why intervention studies aimed at
inhibiting or curing the disease, have only had limited success. In
intervention studies at the onset of the disease, patients of different ages
and with different pathophysiological parameters are still combined in a study
group, despite clear differences in the severity of clinical symptoms, levels
of auto-immune markers, the severity of metabolic disturbance at onset, HbAc1
(high vs. low, reflecting a long vs. short preclinical phase), etc.. Although
these studies did not show any overall benefit, beneficial effects could often
be observed in subgroups of patients. For new studies, therefore, it is
important to map the heterogeneity of type 1 diabetes. By a better staging and
selection of patients, new, personalized therapies can be developed in the
future. Previous studies showed examples of these heterogeneity in newly
diagnosed type 1 diabetes patients, both in clinical and immunological
parameters. These studies also showed an important role for hormones, such as
glucagon, GLP-1 and pro-insulin, in influencing the duration of the remission
phase.
Through biomarker research, we want to study differences in hormonal,
immune/inflammatory markers, metabolic markers and (epi)genetic factors in
patients with long-standing (at least 5 years of) diabetes. In both
participating centers, the UMCG and Diabeter, extensive clinical data on the
entire treatment period of the patients are available. By this integrated
approach of clinical and metabolic phenotyping, we want to gain insight in the
clinical heterogeneity of type 1 diabetes.

The aim of project is to map the heterogeneity of type 1 diabetes by
identifying existing and new biomarkers. To this end, a group of 600 patients
with at least 5 years of type 1 diabetes will be followed for a period of 3
years. By identifying clinically relevant biomarkers, the current staging and
phenotyping of patients can be improved and clinical heterogeneity between
groups of patients and the respective alterations during longstanding T1D can
be compared. This is essential for successful intervention studies in the
future and the development of new therapies, both for treatments that aim at
reducing beta cell damage, and for treatments that focus on the improvement of
glycemic control, reduction of complications and improvement of clinical
outcome.

The study consists of the following parts:
1. Longitudinal and cross-sectional biomarker research on the heterogeneity of
type 1 diabetes, which will be carried out for the next 3 years in 600 patients
(minimum age 16 years) with at least 5 years of type 1 diabetes. The project
focuses on hormonal, immune/inflammatory and metabolic markers.
2. Detailed test: Mixed Meal Tolerance Test (twice in 3 years) in a subgroup of
150 patients: 75 with a short diabetes duration (<15 years) and 75 with a long
diabetes duration (>15 years). With this test, glucosemanagement (insuline,
glucagon, GLP-1 etc.) can be measured and it can accurately be assessed whether
somebody is capable of naturally producing insulin (again).

1. Blood sampling (combined with regular blood drawing for the standard yearly
visit). Limited risk of pain, bruise. The volume taken is limited (114 ml in 3
years) and does not cause problems in (young) adults.
2. MMTT: same as for blood sampling. The insertion of an IV-line is not a risky
procedure. Having the needle taped to the arm for 2,5 hours can be of minor
discomfort to the patient. Also, being in a fasting state (from 12:00 midnight
on the night before the test) can be uncomfortable. The raising blood glucose
level after ingestion of the mixed meal might cause some discomfort in some
patients. The total amount of blood drawn for the MMTT is within reasonable
limits (90 ml) and does not cause any problems.
3. The storage of data and body material (also including DNA) for future
research can be considered as a potential risk. However, with the existing
technical possibilities of protecting storage of data and body material, we
consider this risk as minimal, especially since prof. Wolffenbuttel UMCG is
involved in the *String-of-pearls initiative* (PSI) and LifeLines. The
guidelines of the PSI and Lifelines will be followed to garantee confidential
handling and responsible use of the data/body material.