Abstract 460: Impaired Glucose Tolerance is Associated With an Exaggerated Renin-Angiotensin-Aldosterone System Response to Hydrochlorothiazide in Subjects With Metabolic Syndrome
Renin-angiotensin-aldosterone system (RAAS) activation worsens insulin resistance, and aldosterone impairs insulin secretion via a direct beta-cell effect in mice. To test the hypothesis that the endogenous RAAS contributes to impaired insulin secretion and contributes to impaired glucose tolerance in humans, we assessed glucose homeostasis in 37 subjects with metabolic syndrome (18 Female; 29 white/7 African American; age 45.6±1.8 years). After washout of anti-hypertensive medications, glucose tolerance was characterized as normal glucose tolerance (NGT, n=21), impaired glucose tolerance (IGT, n=11), or type 2 diabetes (T2DM, n=5). Baseline body mass index, body fat percentage, age, plasma renin activity (PRA) and aldosterone were similar among glucose tolerance groups.
We then provided hydrochlorothiazide 12.5mg daily for one month and conducted hyperglycemic clamps on a controlled diet (Na 160, K 80 mEq/d). Potassium was supplemented to similarly maintain serum K+ ≥3.8 (3.90±0.2 NGT, 3.82±0.2 IGT, and 3.86±0.2 mEq/L T2DM). During HCTZ, plasma aldosterone and PRA increased to a greater extent in subjects with IGT compared to NGT or T2DM groups (Figures a, b). Plasma aldosterone-renin ratio was similar among groups. Insulin sensitivity index was similar among groups (5.63±2.8 NGT, 7.27±5.4 IGT, and 4.13±3.7 in T2DM; P=0.29). The acute insulin response (AIR) to glucose was significantly impaired in IGT and T2DM subjects (figure c). The AIR correlated inversely with aldosterone (figure d) but not PRA.
HCTZ treatment activates the RAAS to a greater extent in subjects with IGT, and the aldosterone response specifically correlates with impaired insulin secretion.
- © 2012 by American Heart Association, Inc.