Renin-Angiotensin-Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

Joshua J Joseph, Justin B Echouffo Tcheugui, Valery S Effoe, Willa A Hsueh, Matthew A Allison, Sherita H Golden, Joshua J Joseph, Justin B Echouffo Tcheugui, Valery S Effoe, Willa A Hsueh, Matthew A Allison, Sherita H Golden

Abstract

Background Mechanistic studies suggest that aldosterone impairs glucose metabolism. We investigated the cross-sectional associations of aldosterone and plasma renin activity with fasting plasma glucose, insulin resistance ( IR ), β-cell function, and longitudinal association with incident diabetes mellitus among adults in MESA (the multiethnic study of atherosclerosis) prospective cohort study. Methods and Results Homeostatic model assessment of IR ( HOMA 2- IR ) and HOMA 2-β were used to estimate IR and β-cell function, respectively. Incident diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL or anti-diabetic medication use at follow-up. Linear regression was used to examine cross-sectional associations of aldosterone with fasting plasma glucose, HOMA 2- IR and HOMA 2-β; Cox regression was used to estimate hazard ratios ( HR ) for incident diabetes mellitus with multivariable adjustment. There were 116 cases of incident diabetes mellitus over 10.5 years among 1570 adults (44% non-Hispanic white, 13% Chinese American, 19% Black, 24% Hispanic American, mean age 64±10 years, 51% female). A 100% increase in log-aldosterone was associated with a 2.6 mg/dL higher fasting plasma glucose, 15% higher HOMA 2- IR and 6% higher HOMA 2-β ( P<0.01). A 1- SD increase in log-aldosterone was associated with a 44% higher risk of incident diabetes mellitus ( P<0.01) with the greatest increase of 142% ( P<0.01) observed in Chinese Americans ( P for interaction=0.09 versus other ethnicities). Similar cross-sectional findings for log-plasma renin activity existed, but log-plasma renin activity was not associated with incident diabetes mellitus after full adjustment. Conclusions Aldosterone is associated with glucose homeostasis and diabetes mellitus risk with graded associations among Chinese Americans and blacks, suggesting that pleiotropic effects of aldosterone may represent a modifiable mechanism in diabetes mellitus pathogenesis with potential racial/ethnic variation.

Keywords: aldosterone; race and ethnicity; renin angiotensin system; type 2 diabetes mellitus.

Figures

Figure 1
Figure 1
Race/ethnicity‐specific associations of aldosterone with incident diabetes mellitus. The cubic spline regressions estimate the hazard ratio of incident diabetes mellitus, according to concentrations of aldosterone (picograms per milliliter, pg/mL) examined as a continuous variable up to the 99th percentile with 3 knots placed at the 25th, 50th, and 75th percentiles. Splines are adjusted for age, sex, study site, education, current alcohol use, physical activity, estimated glomerular filtration rate, systolic blood pressure, and waist circumference. Below each spline is the histogram of the distribution of aldosterone concentration among participants with detectable aldosterone (n=1548).

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