Abstract 020: C-reactive Protein As A Moderator And Insulin Resistance As A Mediator For The Association Between Endothelin-1 And Type 2 Diabetes Progression Among African Americans In The Jackson Heart Study

Abstract

Objective: Little is known about the moderation and mediation factors among the association between endothelin-1 (ET-1) level and type 2 diabetes progression in African Americans. We explored the role of high sensitivity C-reactive protein (hsCRP) as a moderator and homeostatic model assessment of insulin resistance (HOMA-IR) as a mediator for the association between ET-1 level and type 2 diabetes progression among African Americans enrolled in the Jackson Heart Study (JHS). Methods: We included 1,692 participants free of prediabetes and diabetes at baseline, who attended Exam 1 of the JHS in 2000-2004 and Exam 3 in 2009-2013, and with measured ET-1 level at Exam 1. Incident prediabetes and diabetes were ascertained at Exam 3. We used a sequential regression model procedure. Zou’s modified Poisson multivariable models were used to calculate risk ratios (RR) and 95% confidence intervals (CI) for prediabetes and diabetes. Effect modification was assessed in the multivariable adjusted model. Valeri and VanderWeele’s mediation analysis approach was utilized to evaluate mediation. Results: A higher log-transformed ET-1 level was detected when comparing non-diabetes versus prediabetes and diabetes participants (p-value for trend = 0.03). Compared to quartile 1 (<0.9 pg/mL) of ET-1, quartile 2 (0.9-1.2 pg/mL) of ET-1 was significantly associated with higher risk of prediabetes (RR=1.19 [95% CI 1.02, 1.38]) and diabetes (RR=1.19 [95% CI 1.02, 1.40]). This association only remained significant for diabetes in the multivariable adjusted model (RR=1.20 [95% CI 1.02, 1.40]) and was not attenuated after adjusted for hsCRP (RR=1.20 [95% CI 1.03, 1.40]), HOMA-IR (RR=1.20 [95% CI 1.02, 1.40]), and both hsCRP and HOMA-IR (RR=1.20 [95% CI 1.03, 1.40]) in quartile 2 of ET-1.The risk of elevated ET-1 level on diabetes was higher in participants with increased hsCRP level in the multivariable adjusted model (RR=1.06 [95% CI 1.02, 1.09]), and further adjusted for HOMA-IR (RR=1.06 [95% CI 1.02, 1.09]. The indirect effect of ET-1 on prediabetes through HOMA-IR is 0.96 (P<0.01), but not found for hsCRP (p=0.26). The total effect of ET-1 on prediabetes mediated by HOMA-IR is 47%. No such mediation effect of HOMA-IR was found among diabetes participants. Conclusions: African Americans with higher ET-1 levels have a higher risk of prediabetes and diabetes. Additionally, the risk of diabetes is elevated among those African Americans with increased hsCRP levels. The mediation analysis result supports that ET-1 is involved in the stage of glucose metabolism imbalances leading to diabetes progression.