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

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.

FIGURE 1

Associations between serum endotrophin and incidence of complications estimated by Cox proportional-hazards models. Hazard ratios (HRs) with 95% confidence intervals (CIs) are listed per doubling of serum endotrophin for the primary (A) and secondary (B) endpoints. HRs are reported as unadjusted and adjusted for the conventional risk factors sex, baseline age, BMI, LDL-cholesterol, current smoking, HbA1c, systolic blood pressure, eGFR, and UAE (except for analyses on albuminuria progression). For each outcome, participants previously diagnosed with the outcome were excluded.