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From the University of Missouri, Columbia, Missouri, and the University of Miami School of Medicine and Harry S Truman and Miami Veterans Affairs Medical Center, Miami, Florida.
Acknowledgment: The authors thank Amanda Yarberry Behr, MA, CMI, for her excellent assistance with the artwork and Brenda Hunter for expert preparation of this manuscript.
Grant Support: By the National Institutes of Health (grant R01 HL73101-01A1 NIH/NHLBI) and the Department of Veterans Affairs (Merit Review) (Dr. Sowers); the Department of Veterans Affairs VISN-15, National Kidney Foundation, and the Missouri Kidney Program (Dr. Whaley-Connell) and the South Florida Veterans Affairs Foundation for Research and Education (Dr. Epstein).
Potential Financial Conflicts of Interest:Grants received: M. Epstein (Pfizer).
Requests for Single Reprints: Murray Epstein, MD, University of Miami School of Medicine, Nephrology Section, Veterans Affairs Medical Center, 1201 Northwest 16th Street, Miami, FL 33125; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Sowers: University of Missouri, D109 HSC, Columbia, MO 65212.
Dr. Whaley-Connell: University of Missouri, CE417, 5 Hospital Drive, Columbia, MO 65212.
Dr. Epstein: University of Miami School of Medicine, Nephrology Section, Veterans Affairs Medical Center, 1201 Northwest 16th Street, Miami, FL 33125.
The prevalence of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease is increasing in developed countries. Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. Emerging evidence supports a paradigm shift in our understanding of the reninâ€“angiotensinâ€“aldosterone system and in aldosterone's ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic Î²-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance.Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease.
High salt intake, obesity, inactivity, and other environmental factors interact to activate the renin–angiotensin–aldosterone system, with subsequent inflammation and oxidative stress that drive maladaptive tissue responses. ACE = angiotensin-converting enzyme; ACTH = adrenocorticotropic hormone; Aldo = aldosterone; Ang I = angiotensin I; Ang II = angiotensin II; ASCVD = atherosclerotic cardiovascular disease; AT1 = angiotensin type 1 receptor; AT2 = angiotensin type 2 receptor; CAD = coronary artery disease; CHF = congestive heart failure; CRH = corticotropin-releasing hormone; LVH = left ventricular hypertrophy; MR = mineralocorticoid receptor; SNS = sympathetic nervous system.
Aldosterone and angiotensin II mediate increases in inflammation and ROS that activate redox-sensitive serine kinases and contribute to impaired insulin metabolic signaling. Aldosterone and angiotensin II induce rapid maladaptive responses by stimulation of NADPH oxidase (step 1), thus generating ROS (step 2). An increase in ROS activates redox-sensitive serine kinase–signaling molecules (step 3) (5, 20–23). Reactive oxygen species–induced activation of these serine kinases induces phosphorylation of the serine moities of the IRS-1 docking protein (step 4). This serine phosphorylation of IRS-1 lessens its engagement with phosphatidylinositol 3-kinase (step 5), which leads to decreased activation of protein kinase B (step 6) and downstream metabolic effects, such as impaired glucose transport (step 7). AKT = protein kinase B; Aldo = aldosterone; AT = angiotensin; AT1R = angiotensin type 1 receptor; GLUT4 = glucose transport 4; IR = insulin receptor; MR = mineralocorticoid receptor; Mit = mitochondria; NADPH = nicotinamide ademine dinucleotide phosphate; P = phosphorus; PI3-K = phosphatidylinositol 3-kinase; R = renin; ROS = reactive oxygen species; Ser K = serine kinase; Tyr = tyrosine.
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The deleterious effect of aldosterone on the heart and kidneys is well established and Dr Sowers and colleagues nicely synthesized the supportive laboratory and clinical evidence (1). As the authors point out, laboratory data also provide grounds for a diabetogenic effect of aldosterone. However, clinical evidence linking aldosterone and glucose metabolism disorder still appears to be equivocal.
Primary aldosteronism (PA) is a natural model of sustained exposure to high levels of aldosterone. Hence, if aldosterone exerts a deleterious effect on glucose metabolism it should translate into an increased prevalence of glucose metabolism disorders in these patients. Several studies showing higher levels of fasting blood glucose and higher prevalence of the metabolic syndrome or diabetes in subjects with PA compared to essential hypertensive controls are cited by Dr Sowers, but other studies found no difference regarding these endpoints (2,3). All these reports were based on the assessment of few patients with PA (from 14 to 85).
We investigated the metabolic profile of a large group of patients with PA (4). We found no statistically significant differences in body- mass index, fasting blood glucose or hyperglycemia (diabetes or impaired fasting plasma glucose) between 460 cases with PA and 1363 controls with essential hypertension matched for age and sex. However, this evidence does not formally preclude a clinically patent metabolic effect of aldosterone in patients with PA: other unknown diabetogenic factors than aldosterone might be more prevalent in patients with essential hypertension and lead to a similar prevalence of glucose metabolism disorders in both groups.
But we also did not find differences between preoperative and postoperative levels of fasting plasma glucose in 61 patients with PA who underwent adrenalectomy (4). Furthermore, in case of a causal link, patients with the highest levels of aldosterone should have a higher prevalence of glucose metabolism disorders. Preliminary analyses do not show such dose "“ effect relationship in our patients with PA (5). Thus, it appears that neither an excessively high prevalence of glucose metabolism disorders in patients with PA, nor a causal influence of high aldosterone levels to explain it, can be considered as definitely established by now.
1. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med 2009;150:776-83
2. Matrozova J, Steichen O, Amar L, Zacharieva S, Jeunemaitre X, Plouin PF. Fasting plasma glucose and serum lipids in patients with primary aldsoteronism. A controlled cross-sectional study. Hypertension 2009;53:605-610.
3. Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi G, Novello M, Favret G, Melis A, Cavarape A, Sechi LA. Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab 2006;91:3457-63.
4. Widimsky J Jr, Strauch B, Sindelka G, Skrha J. Can primary hyperaldosteronism be considered as a specific form of diabetes mellitus? Physiol Res 2001;50:603-7.
5. Steichen O, Matrozova J, Zacharieva S, Jeunemaitre X, Amar L, Plouin PF. Glucose metabolism disorders in primary aldosteronism according to potassium and aldosterone levels [abstract]. J Hypertens 2009;27(Suppl 4):S291.
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