Circulating metabolomic markers in association with overall burden of microvascular complications in type 1 diabetes

Viktor Rotbain Curovic, Brede A. Sørland, Tine W. Hansen, Siddhi Y. Jain, Karolina Sulek, Ismo Matias Mattila, Marie Frimodt-Moller, Kajetan Trost, Cristina Legido-Quigley, Simone Theilade, Nete Tofte, Signe Abitz Winther, Christian Stevns Hansen, Peter Rossing, Tarunveer S. Ahluwalia

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


INTRODUCTION: Diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN) share common pathophysiology and pose an additive risk of early mortality. 

RESEARCH DESIGN AND METHODS: In adults with type 1 diabetes, 49 metabolites previously associated with either DR or DKD were assessed in relation to presence of DSPN. Metabolites overlapping in significance with presence of all three complications were assessed in relation to microvascular burden severity (additive number of complications-ie, presence of DKD±DR±DSPN) using linear regression models. Subsequently, the same metabolites were assessed with progression to endpoints: soft microvascular events (progression in albuminuria grade, ≥30% estimated glomerular filtration rate (eGFR) decline, or any progression in DR grade), hard microvascular events (progression to proliferative DR, chronic kidney failure, or ≥40% eGFR decline), and hard microvascular or macrovascular events (hard microvascular events, cardiovascular events (myocardial infarction, stroke, or arterial interventions), or cardiovascular mortality), using Cox models. All models were adjusted for sex, baseline age, diabetes duration, systolic blood pressure, HbA1c, body mass index, total cholesterol, smoking, and statin treatment. 

RESULTS: The full cohort investigated consisted of 487 participants. Mean (SD) follow-up was 4.8 (2.9, 5.7) years. Baseline biothesiometry was available in 202 participants, comprising the cross-sectional cohort. Eight metabolites were significantly associated with presence of DR, DKD, and DSPN, and six with additive microvascular burden severity. In the full cohort longitudinal analysis, higher levels of 3,4-dihydroxybutanoic acid (DHBA), 2,4-DHBA, ribonic acid, glycine, and ribitol were associated with development of events in both crude and adjusted models. Adding 3,4-DHBA, ribonic acid, and glycine to a traditional risk factor model improved the discrimination of hard microvascular events. 

CONCLUSIONS: While prospective studies directly assessing the predictive ability of these markers are needed, our results strengthen the role of clinical metabolomics in relation to risk assessment of diabetic complications in chronic type 1 diabetes.

TidsskriftBMJ Open Diabetes Research & Care
Udgave nummer2
Antal sider8
StatusUdgivet - 11 apr. 2024

Bibliografisk note

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© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use.


  • Kidney Disease
  • Microvascular Disease
  • Neuropathy
  • Retinopathy

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