Plasma epoxyeicosatrienoic acids and dihydroxyeicosatrieonic acids, insulin, glucose and risk of diabetes: The strong heart study

EBioMedicine. 2021 Apr;66:103279. doi: 10.1016/j.ebiom.2021.103279. Epub 2021 Mar 19.


Background: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid with multiple biological functions. Rodent experiments suggest EETs play a role in insulin sensitivity and diabetes, but evidence in humans is limited. To address this knowledge gap, we conducted a case-cohort study in the Strong Heart Family Study, a prospective cohort among American Indians.

Methods: We measured 4 EET species and 4 species of corresponding downstream metabolites, dihydroxyeicosatrieonic acids (DHETs), in plasma samples from 1161 participants, including 310 with type 2 diabetes. We estimated the associations of total (esterified and free) EETs and DHETs with incident diabetes risk, adjusting for known risk factors. We also examined cross-sectional associations with plasma fasting insulin and glucose in the case-cohort and in 271 participants without diabetes from the older Strong Heart Study cohort, and meta-analyzed the results from the 2 cohorts.

Findings: We observed no significant association of total EET or DHET levels with incident diabetes. In addition, plasma EETs were not associated with plasma insulin or plasma glucose. However, higher plasma 14,15-DHET was associated with lower plasma insulin and lower plasma glucose.

Interpretation: In this first prospective study of EETs and diabetes, we found no evidence for a role of total plasma EETs in diabetes. The novel associations of 14,15-DHET with insulin and glucose warrant replication and exploration of possible mechanisms.

Funding: US National Institutes of Health.

Keywords: Diabetes; Dihydroxyeicosatrieonic acids; Epidemiology; Epoxyeicosatrienoic acids; Glucose; Insulin.

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives
  • 8,11,14-Eicosatrienoic Acid / blood*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood*
  • Blood Glucose*
  • Case-Control Studies
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / etiology*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Disease Susceptibility
  • Female
  • Glucose / metabolism
  • Humans
  • Insulin / blood*
  • Male
  • Middle Aged
  • Risk Assessment
  • Risk Factors
  • Young Adult


  • Biomarkers
  • Blood Glucose
  • Insulin
  • 8,11,14-Eicosatrienoic Acid
  • Glucose