HJ Aanstoot, R Varkevisser, D Mul, P Dekker, E Birnie, L Boesten, M Brugts, P van Dijk, N Duijvestijn, S Dutta, C Fransman, R Gonera, K Hoogenberg, A Kooy, E Latres, S Loves, G Nefs, T Sas, C Vollenbrock, M Vosjan-Noeverman, M de Vries-Velraeds, H Veeze, B Wolffenbuttel, M van der Klauw

Cohort profile: The ‘Biomarkers of heterogeneity in type 1 diabetes’ study – a national prospective cohort study of clinical and metabolic phenotyping of individuals with long-standing type 1 diabetes in the Netherlands. BMJ Open 2024 Jun 19;14(6):e082453.

Achieving glycemic targets still remains a challenge for many people with type 1 diabetes (PWDs), leading to long-term complications that significantly impact life expectancy and quality of life. The decline in beta-cell function, indicated by decreasing C-peptide levels, is progressive, going through four stages: two pre-symptomatic stages (1 and 2), followed by the onset of clinical symptoms (stage 3), and long-standing T1D (stage 4). Although many individuals with long-term T1D exhibit only minimal C-peptide secretion, residual C-peptide production in long-standing T1D can still provide clinical benefits.

 

There is extensive heterogeneity between PWDs in terms of clinical symptoms and severity of metabolic disturbance at onset, autoimmune markers before and after onset, initial glycemic outcomes and the efficacy of therapeutic interventions. Understanding this heterogeneity, including factors influencing complications and quality of life, is essential for developing personalized interventions and improving outcomes. Many studies on heterogeneity include, or have included, PWDs in stages 1-3. This study, co-authored by Henk-Jan Aanstoot, Pim Dekker, Erwin Birnie, Christine Fransman, Giesje Nefs, Theo Sas and Henk Veeze and of Diabeter, aimed to explore heterogeneity among PWDs with stage 4 T1D.

The “Biomarkers of heterogeneity in type 1 diabetes” study was a prospective cohort study involving 611 participants with T1D duration of ≥ 5 years (Biomarker cohort) and an additional long-term cohort including participants with T1D duration of ≥35 years (LTD cohort). It collected longitudinal data and biosamples with the aim to analyze glycemic, hormonal, immune, and metabolic markers, alongside psychosocial outcomes. A subset of 169 participants of the Biomarker cohort also underwent mixed meal tolerance tests (MMTT) to assess C-peptide levels (MMTT cohort). This paper describes the study setup and characteristics of the cohorts. Analyses using samples and data of this study have been published previously.

 

Key findings:

• Age of the Biomarker and MMTT cohorts was around 30 years, and around 65 years for the LTD cohort
• More women than men were included in the Biomarker and MMTT cohorts (59%), whereas the LTD included fewer women than men (45%)
• PWDs in the Biomarker and MMTT cohorts had a lower total daily insulin dose than participants of the LTD cohort (~50 U/day vs 30 U/day)
• Around 25% of the Biomarker cohort showed detectable C-peptide levels, with median C-peptide level of 30 pmol/L for those with detectable levels (data not available for the LTD cohort)
• About two thirds of participants of the Biomarker and MMTT cohorts and half of the participants of the LTD cohort were using an insulin pump
• Fewer than 25% of participants from Biomarker and MMTT cohorts and more than 80% of participants of the LTD cohort were using CGM
• Residual C- peptide secretion was associated with a lower risk of impaired awareness of hypoglycemia (IAH) and a higher BMI, the presence of microvascular complications and a higher age at diabetes onset were independent risk factors for IAH in PWDs (click here for more information and publication)
• Metabolomics and genome-wide association methodologies identified 12 metabolites that showed higher expression in PWDs with IAH. These were sphingomyelins and glycerophospholipids, suggesting differences in nerve functioning (click here for more information and publication)
• About 10% of participants who did not show fasting residual C- peptide production did still show meal- stimulated residual C- peptide production. The 90- min and 120- min MMTT time points showed good concordance with the MMTT total AUC. Overall, there was a decrease in C- peptide at 1- year follow- up (click here for more information and publication)

 

 

Concluding, the authors state

Please click here for the full-text version of the paper. We welcome collaboration with other research groups interested in the data/samples of this cohort. Researchers can contact us at research@diabeter.nl.