The predictive value of endothelin-1 and type 2 diabetes
Authors: Youssri T , Ohlsson M , Hamrefors V , Mellander O 
Published: November 2020

Abstract

Introduction
Endothelin 1 is a potent vasoconstrictor released from mainly vascular endothelial cells and to a lesser extent adipose, muscle and renal tissues. Its involvement in cardiovascular disease is well documented, with increasing ET-1 levels correlated to cardiovascular events. Less is however, known about its role in insulin resistance and type 2 diabetes.

Purpose
To test if ET-1 plasma levels predict the risk of developing type 2 diabetes independently of known risk factors.

Method
The Malmo Preventive project is a prospective single centre population-based study which recruited 33 346 inhabitants in Malmo, Sweden between 1974–1992. A follow up study was conducted between 2002 and 2006 on willing participants of which 18 240 accepted. Cardiovascular risk factors were documented along with blood plasma samples frozen to −80°C available for further analysis among approximately 5000 subjects. Record linkage with national and regional diagnoses and drug prescription registries was performed to identify all new onset type 2 diabetes cases in this cohort during a mean follow-up period of nine years. C-terminal proendothelin-1 (proET-1), a stable precursor to ET-1, levels were analysed by a double sandwich immunoassay (ThermoFisher) among 4536 individuals with complete data and without diabetes at baseline. The subjects were divided into quartiles based on proET-1 levels and hazard ratios (HR) for new onset diabetes were calculated by Cox Proportional Hazards Model adjusting for age, gender, smoking, hypertension, body mass index (BMI) and fasting glucose.

Results
There was a positive relationship between increasing proET-1 quartiles and age (p&lt;0.001), hypertension (p&lt;0.001), BMI (p&lt;0.001) and smoking (p&lt;0.001). There was no significant relationship between ET-1 quartiles and fasting glucose (p=0.08) and gender (p=0.21). In models adjusted for age, gender, smoking, hypertension, fasting glucose and BMI among non-diabetic subjects each 1 standard deviation increment of proET-1 conferred a hazard ratio (95% confidence interval) for new onset diabetes during follow up period of 1.12 (1.00–1.26) (p=0.05). The hazard ratio for incident diabetes in quartile 4 (Q4) vs quartile 1 (Q1) was 1.40 (1.03–1.92) (p=0.03). Of note, the predictive value of proET-1 was markedly higher among individuals without pre-diabetes (fasting glucose &lt;6.1) with a hazard ratio of 1.27 per standard deviation proET-1 (CI 1.09–1.49, p=0.02) and 2.18 (CI 1.41–3.36, p&lt;0.001) when comparing proET-1 Q4 vs Q1. There was no significant relationship between the risk of new onset diabetes and proET-1 levels among pre-diabetic individuals.

Conclusion
Raised proET-1 levels among non-diabetic individuals independently predict risk of new onset type 2 diabetes. The predictive value is driven by the part of the population without prediabetes, suggesting that proET-1 might identify individuals at “hidden high risk”, i.e. indivduals who do not get medical attention by having prediabetes.

Funding Acknowledgement
Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Knut & Alice Wallenberg Foundation Clinical Scholars and Göran Gustafsson Foundation