Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort

Alexandra Louise Møller; Ninna Hahn Tougaard; Daniel Guldager Kring Rasmussen; Federica Genovese; Pernille Falberg Rønn; Tine Willum Hansen; Morten Asser Karsdal; Peter Rossing

doi:10.3389/fmolb.2023.1229579

Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort

Front Mol Biosci. 2023 Sep 1:10:1229579. doi: 10.3389/fmolb.2023.1229579. eCollection 2023.

Authors

Alexandra Louise Møller^{1

2}, Ninna Hahn Tougaard³, Daniel Guldager Kring Rasmussen¹, Federica Genovese¹, Pernille Falberg Rønn³, Tine Willum Hansen³, Morten Asser Karsdal¹, Peter Rossing^{3

4}

Affiliations

¹ Nordic Bioscience, Herlev, Denmark.
² Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Steno Diabetes Center Copenhagen, Herlev, Denmark.
⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Abstract

Hyperglycemia triggers pathological pathways leading to fibrosis, where extracellular matrix (ECM) components are accumulated. We investigated the potential of endotrophin, a pro-fibrotic molecule generated during collagen type VI formation, as a risk marker for complications to type 1 diabetes. Endotrophin was measured in serum and urine from 1,468 persons with type 1 diabetes. Outcomes included a composite kidney endpoint, first major adverse cardiovascular event (MACE), all-cause mortality, progression of albuminuria, incident heart failure, and sight-threatening diabetic eye disease. Cox proportional hazards models adjusted for conventional risk factors were applied. A doubling of serum endotrophin was independently associated with the kidney endpoint (n = 30/1,462; hazard ratio 3.39 [95% CI: 1.98-5.82]), all-cause mortality (n = 93/1,468; 1.44 [1.03-2.0]), and progression of albuminuria (n = 80/1,359; 1.82 [1.32-2.52]), but not with first MACE, heart failure, or sight-threatening diabetic eye disease after adjustment. Urinary endotrophin was not associated with any outcome after adjustment. Serum endotrophin was a risk marker for mortality and kidney complications in type 1 diabetes. Biomarkers of ECM remodeling, such as serum endotrophin, may identify persons with active pro-fibrotic processes at risk for complications in diabetes and where antifibrotic agents may reduce this risk.

Keywords: biomarker; collagen; diabetes complications; endotrophin; extracellular matrix; fibrosis.

Grants and funding

The Innovation Fund Denmark provided research support (0172-00270B) but did not play any additional role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.