Cohort profile: the ‘Biomarkers of heterogeneity in type 1 diabetes’ study – a prospective cohort study of clinical and metabolic phenotyping of individuals with long-standing type 1 diabetes
Authors: Mul Dick , Varkevisser Rita D.M. , Aanstoot Henk-Jan , Dekker Pim , Birnie Erwin , Boersma Erik , Boesten Lianne S.M. , Brugts Michael P. , van Dijk Peter R. , Duijvestijn Petronella H.L.M. , Dutta Sanjoy , Fransman Christine , Gonera Rob K. , Hoogenberg Klaas , Kooy Adriaan , Latres Esther , Loves Sandra , Nefs Giesje , Sas Theo , Verburg Frederik A.J. , Vollenbrock Charlotte E. , Vosjan-Noeverman Marleen J. , de Vries-Velraeds Martine M.C. , Veeze Henk J. , Wolffenbuttel Bruce H.R. , van der Klauw Melanie M. 
Published: August 2023

Purpose

The ‘Biomarkers of heterogeneity in type 1 diabetes’ study cohort was set up to identify genetic, physiological and psychosocial factors explaining the observed heterogeneity in disease progression and the development of complications in people with long-standing type 1 diabetes (T1D). Data and samples are available for new studies and collaborations.

Participants

Data- and samples were collected in two subsets. 1) A prospective cohort of 611 participants aged ≥16 years with ≥5 years T1D duration was recruited from four Dutch Diabetes clinics between June 2016 and March 2021. At baseline and 1- and 2-year follow-up visits, physical assessments were performed, and blood and urine samples were collected. Participants completed questionnaires about diabetes-related problems, quality of life, neuropathy and impaired awareness of hypoglycaemia at baseline and at the last follow-up visit. A subgroup of participants underwent mixed-meal tolerance tests (MMTT) at baseline (n=169) and at 1-year follow-up (n=104). Genetic data and linkage to medical and administrative records were also available. 2) A second cross-sectional cohort, aiming to include 200 participants aged ≥18 years with ≥35 years T1D duration, was recruited from 7 centres, collecting measurements and samples plus 5-year retrospective data.

Findings to date

Fasting residual C-peptide secretion associated with decreased risk of impaired awareness of hypoglycaemia. Stimulated residual C-peptide was detectable in an additional 10% of individuals compared with fasting residual C-peptide secretion. MMTT measurements at 90 minutes and 120 minutes showed good concordance with the MMTT total area under the curve. An overall decrease of C-peptide at 1-year follow-up was observed.

Future plans

Research groups are invited to consider the use of this data and sample collection. Future work will include additional hormones, beta-cell-directed autoimmunity, specific immune markers, microRNA’s, metabolomics and gene expression data, combined with glucometrics, anthropometric/clinical data and additional markers of residual beta-cell function.

Strengths and limitations of this study

Strengths

- The Biomarker cohort is a large longitudinal prospective cohort study with three time points, collecting biosamples and clinical data from participants with well-established and long-standing type 1 diabetes (≥5 years).

- A subgroup with detailed clinical data underwent MMTT tests at two timepoints allowing further residual beta-cell marker studies.

- The Biomarker and Long-Term type 1 Diabetes cohorts represent a “real-world” population, also including participants from non-academic/-specialised centres.

Limitations

- Despite the fact that data and biosamples were collected from more than 600 participants, this number may be too low for (sub) stratification of the data (e.g. insulin delivery modality, different treating centres and therapies etc.).

- In the prospective group there was a relatively high dropout rate of 25% after 2 years, largely affected by the Covid-19 outbreak.