- Open Access
The involvement of aldosterone on vascular insulin resistance: implications in obesity and type 2 diabetes
© Bruder-Nascimento et al.; licensee BioMed Central Ltd. 2014
Received: 23 June 2014
Accepted: 2 August 2014
Published: 24 August 2014
Aldosterone, a mineralocorticoid hormone produced at the adrenal glands, controls corporal hydroelectrolytic balance and, consequently, has a key role in blood pressure adjustments. Aldosterone also has direct effects in many organs, including the vasculature, leading to many cellular events that influence proliferation, migration, inflammation, redox balance and apoptosis.
Aldosterone effects depend on its binding to mineralocorticoid receptors (MR). Aldosterone binding to MR triggers two pathways, the genomic pathway and the non-genomic pathway. In the vasculature e.g., activation of the non-genomic pathway by aldosterone induces rapid effects that involve activation of kinases, phosphatases, transcriptional factors and NAD(P)H oxidases.
Aldosterone also plays a crucial role on systemic and vascular insulin resistance, i.e. the inability of a tissue to respond to insulin. Insulin has a critical role on cell function and vascular insulin resistance is considered an early contributor to vascular damage. Accordingly, aldosterone impairs insulin receptor (IR) signaling by altering the phosphatidylinositol 3-kinase (PI3K)/nitric oxide (NO) pathway and by inducing oxidative stress and crosstalk between the IR and the insulin-like growth factor-1 receptor (IGF-1R).
This mini-review focuses on the relationship between aldosterone and vascular insulin resistance. Evidence indicating MR antagonists as therapeutic tools to minimize vascular injury associated with obesity and diabetes type 2 is also discussed.
For a long time, aldosterone was simply considered a hormone that regulates renal function and corporal hydroelectrolytic balance/plasma osmolality and, consequently, extracellular volume and blood pressure [1, 2]. However, aldosterone influences the function of many other organs including the brain, the heart, and the vasculature [1, 3].
Aldosterone is mainly synthesized by the adrenal glands, at the glomerular zone. Aldosterone binds to mineralocorticoid receptors (MR), a cytoplasmic receptor that operates as a transcription factor regulating gene and protein expression, the so-called genomic pathway. Furthermore, aldosterone rapidly activates many other signaling pathways, or non-genomic pathways, which are not sensitive to translation or transcription inhibitors [4, 5]. These quick events are described as being associated to the classic MR or to a membrane aldosterone receptor, the G protein-coupled receptor 30 (GPR30) . MR are expressed not only in the kidneys, but also in extrarenal tissues, such as adipocytes, cardiomyocytes, macrophages, endothelial cells (EC) and vascular smooth muscle cells (VSMC) [7–9]. In these cells, aldosterone activates inflammatory, proliferative and migratory processes, as discussed below [7, 10, 11].
In the vasculature, aldosterone activates several signaling proteins including mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 and c-Jun N-terminal kinase (JNK) [12–14], Rho kinase , transcriptional factors like the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) , adhesion molecules including vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), and the non-receptor tyrosine kinase protein c-Src , which then trigger other signaling pathways. c-Src, for example, activates the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxes) through p47phox phosphorylation, leading to the generation of reactive oxygen species (ROS)  and to further activation of redox-sensitive proteins [7, 17, 18].
Due to its many effects in the cardiovascular system, aldosterone plays a critical role in cardiovascular diseases (CVD) as well as in metabolic diseases including insulin resistance, diabetes type 2 (DM2) and obesity [1, 19]. Accordingly, epidemiological studies demonstrate a positive relationship between increased aldosterone levels and enhanced rates of CVD [20, 21] and metabolic diseases [1, 19, 22–30].
Angiotensin II (Ang II), the most powerful biologically active product of the Renin-Angiotensin-Aldosterone system (RAAS), stimulates aldosterone secretion and cell growth in adrenocortical cells . The RAAS plays a major role in the genesis and progression of CVD, including arterial hypertension, myocardial infarction and stroke. Of importance, aldosterone contributes along with Ang II to the adverse actions of the RAAS in CVD . Accordingly, treatment of patients with cardiovascular risk like diabetic patients, with antagonists of the Ang II type 1 receptor (AT1) or with inhibitors of the Angiotensin Converting Enzyme (ACE) importantly reduce cardiovascular risks [33, 34]. In addition, MR antagonists, such as eplerenone and spironolactone, also have beneficial effects in patients with CVD, as discussed below [35, 36].
Clinical trials, as the Randomized Aldactone Evaluation Study (RALES), have shown that daily treatment with 25 mg of spironolactone substantially reduces the risk of both morbidity and death among patients with severe heart failure. In addition, after eight weeks of treatment, if the patient showed signs or symptoms of progression of heart failure, the dose of spironolactone could be increased to 50 mg without evidence of hyperkalemia .
In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) clinical trial, patients were randomly assigned to eplerenone (25 mg per day initially, until to a maximum of 50 mg per day) or placebo. The addition of eplerenone to optimal medical therapy reduced morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure . In hypertensive patients, eplerenone treatment, compared with an atenolol regimen, reduced proinflammatory mediators, such as macrophage chemoattractant protein 1 (MCP-1), osteopontin, basic fibroblast growth factor (bFGF), and inteleukin-8 (IL-8), as well as stiffness of subcutaneous small resistance arteries . An important finding in clinical studies with MR antagonists is that reduction of cardiovascular risks does not depend on blood pressure changes [39, 40].
Aldosterone has also been implicated in the development of insulin resistance. One interesting study published by Catena et al.  showed that patients with tumoral and idiopathic aldosteronism present insulin resistance, and that both surgical treatment and treatment with aldosterone antagonists rapidly and persistently restore sensitivity to insulin. A positive association between increased plasma aldosterone concentrations with plasma glucose, insulin, C-peptides, and HOMA (Homeostasis Model Assessment, which estimates steady state β cell function and insulin sensitivity) has also been reported in a population of patients with essential hypertension .
A positive correlation between fasting insulin and plasma and urinary aldosterone levels was demonstrated in patients with class II–IV heart failure included in the ALOFT (Aliskiren Observation of Heart Failure Treatment) study. In addition, early-morning fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and insulin/glucose ratio (IGR) were higher in patients with aldosterone escape and high urinary aldosterone excretion, when compared to the healthy population . Furthermore, in experimental models of obesity (ob/ob and db/db mice), eplerenone treatment also reduced the high levels of glucose, HOMA-IR, and plasma triglyceride concentration, and increased adiponectin levels .
In cultured adipocytes, basal and insulin-stimulated glucose uptake is decreased by high aldosterone concentrations, an effect prevented by RU486, an antagonist of glucocorticoid receptors. Surprisingly, eplerenone did not abolish these effects, indicating that aldosterone has MR-independent effects . In addition, a strong relationship between genetic variants of the CYP11B2 gene, which encodes for aldosterone synthase, and glucose plasma levels has been reported .
The relationship between obesity, insulin resistance and aldosterone secretion
Recently, Briones and colleagues showed that aldosterone is also produced by the perivascular adipose tissue (PVAT) . Their study showed that adipocytes express aldosterone synthase and produce aldosterone in an Ang II/AT1/calcineurin/nuclear factor of activated T-cells (NFAT)-dependent manner. Interestingly, adipocyte-derived aldosterone regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner, respectively. These findings indicate that adipocytes may represent an important source of aldosterone as well as the putative link between aldosterone and vascular dysfunction in metabolic diseases, such as diabetes mellitus and obesity. Goodfriend and colleagues have previously suggested that aldosterone can be released by visceral fat in obese male and female voluntaries . These authors also found that certain fatty acids stimulate aldosterone production in vitro by rat adrenal cells incubated with rat hepatocytes, but not in adrenal cells alone, suggesting that fatty acids from visceral adipocytes induce hepatic formation of an adrenal secretagogue .
Leptin plays a crucial role on body fat gain. Leptin increases energy expenditure and induces satiety . Obese and insulin-resistant patients exhibit higher leptin plasma levels than control subjects, i.e. they become leptin-resistant, exhibiting a loss of leptin effects. There is a controversy regarding the effects of leptin on aldosterone release. For example, renin and aldosterone levels do not change after treatment of rats with leptin . In addition, leptin infusion leads to natriuresis and diuresis  and stimulation of primary adrenal cell cultures with leptin inhibits adrenocortical steroid production .
On the other hand, increased plasma renin activity is observed in rats chronically treated with leptin . Furthermore, Belin de Chantemelle and colleagues showed that plasma aldosterone levels are increased in obese mice and further increase with sustained leptin infusion, and the chronic α1-adrenergic receptor antagonism with prazosin blunted obesity-induced increased aldosterone levels and also abolished leptin-stimulated aldosterone secretion in obese mice . These data indicate that obesity-associated increased renin activity and leptin-stimulated aldosterone production may result from increased sympathetic activity. These results also suggest that leptin may influence aldosterone secretion and perhaps participate in obesity- and type 2 diabetes-associated insulin resistance. Accordingly, aldosterone would be an interesting target to minimize insulin resistance- and/or obesity-associated deleterious effects.
Reinforcing this suggestion, aldosterone has been shown to inhibit insulin effects in the vasculature, i.e. aldosterone induces vascular insulin resistance . Although still unclear, some potential mechanisms for aldosterone-induced insulin-resistance are already described, including desensitization of proteins involved in insulin effects, such as Insulin Receptor Substrate (IRS)-1, Phosphatidylinositide 3-Kinase (PI3K), Akt and nitric oxide synthase (NOS). Oxidative stress, possibly mediated by increased NAD(P)H-oxidase activity, as well as hybridization of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) are also candidate mechanisms [1, 2, 19].
The relationship between aldosterone and vascular insulin resistance is discussed in detail in the next section. Evidence suggesting the MR antagonists as therapeutic tool to minimize vascular injury associated with obesity and diabetes type 2 is also discussed.
Pancreatic β-cell dysfunction plays an important role in the pathogenesis of DM1 and DM2. Insulin is a peptide hormone composed of 51 amino acids that is synthesized, packaged, and secreted in pancreatic β cells. It was the first protein whose primary structure was elucidated. This feat was accomplished by Fred Sanger and led to a Nobel Prize [54, 55].
Insulin is synthetized in the pancreatic β cells as preproinsulin and then processed to proinsulin, whose structure is stabilized by three disulfide bonds. In the Golgi apparatus insulin is sorted into secretory vesicles, where it is converted to insulin and C-peptide. These peptides are stored in organized mature secretory vesicles/granules, awaiting their regulated on-demand discharge into the bloodstream [56–58]. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. In these cases aerobic glycolysis and mitochondrial oxidation produce metabolic signals, including a rise in the ATP to ADP concentration ratio. This closes ATP-dependent potassium (K+-ATP) channels, leading to depolarization of the plasma membrane, which causes calcium (Ca2+) influx that stimulates insulin exocytosis [56–58]. β cells are especially adapted to support these processes in the face of varying demands. However, high-level stimulation of insulin synthesis, such as in diabetes, may lead to β cells damage or death [56–58].
Insulin receptors are composed of two extracellular α-subunits that are each linked to a β-subunit and to each other by disulfide bonds. Reduction of the bonds that link the α-subunits produces a α-β monomer that binds insulin with reduced affinity and is devoid of insulin-stimulated tyrosine kinase activity [58–60]. Reconstitution of such hetero-dimers into hetero-tetramers restores both high affinity insulin binding and insulin-stimulated kinase activity [58–60].
The main effects of insulin in the organism include glucose uptake in muscle and adipose tissues, glycolysis, glycogen synthesis, protein synthesis and uptake of ions, including K+. Otherwise, insulin blocks glucogenesis, glycogenolysis, lipolysis and proteolysis [56–58]. Insulin also contributes to nutrient and hormone delivery to skeletal muscle by increasing blood flow and recruiting capillaries . Insulin-induced vasodilatation and capillaries recruitment in skeletal muscle seem to depend on NO, since a nitric oxide inhibitor, L-NG-Nitroarginine Methyl Ester (L-NAME), inhibits the microvascular effects of insulin . In addition to promote endothelium-dependent vasodilation and NO release, insulin also stimulates production of vasoconstrictors agents, such as endothelin-1 (ET-1), mediated by Ras/MAPKs signaling [63, 64]. Although there are controversies on insulin effects, it is suggested that insulin-induced NO production limits the contractile, proliferative, and inflammatory actions of insulin-stimulated growth factor production [65, 66].
Aldosterone may impair insulin-signaling pathway in skeletal muscle by different mechanisms: by reducing NO bioavailability and Akt activity, by increasing the sources and production of ROS and insulin-like growth factor-1 (IGF-1) signaling pathway. These mechanisms are detailed in the next section, but with emphasis on the role of aldosterone on vascular insulin resistance.
In the vasculature, insulin directly promotes vasodilation through changes in Ca+2 sensitivity and Ca+2 handling mechanisms in VSMC, and indirectly through activation of PI3K/inducible NO synthase (iNOS)/cyclic guanosine monophosphate signaling, and phosphorylation of Akt or PKB in the endothelial cells [67, 68]. Thus, insulin induces vasodilation mediated by IRS/PI3K signaling both in VSMC and EC.
Resistance to insulin signaling is a cardiovascular risk factor that underlies the pathophysiology of the metabolic syndrome. Although insulin in compensatory hyperinsulinemia has adverse mitogenic and proinflammmatory effects, at normal physiologic concentrations, preserved sensitivity to insulin signaling has a protective effect in the vasculature .
Insulin resistance is characterized by the inability of a tissue to respond to insulin, which will impair the input of glucose into the cell as well as the sensitivity of IRS/PI3K/NO signaling pathway [64, 68]. Vascular insulin resistance is considered an early contributor to vascular damage . Under insulin resistance conditions, the antioxidant, anti-inflammatory, anti-atherogenic properties of insulin, as well as its ability to induce PI3K/NO-dependent vasodilation are attenuated, prevailing its deleterious effects [30, 64, 68, 70, 71].
The role of aldosterone on vascular insulin resistance
There is growing interest in the role of aldosterone and its receptors in the pathogenesis of insulin resistance . As already discussed, evidence points that aldosterone plays an important role on the metabolic syndrome [1, 19]. Elevated levels of aldosterone are present in obese and insulin-resistant patients and rodent models [23–25], leading to proliferation, inflammation, oxidative stress, contributing to impaired insulin signaling, decreasing glucose transport, inducing vascular dysfunction and cardiovascular abnormalities [26–30, 70, 71].
In 3T3-L1 adipocytes, aldosterone blocks insulin-induced glucose uptake and induces degradation of IRS-1 and 2, an effect that depends on ROS generation; in human adipocytes aldosterone also impairs insulin sensitivity, implying that aldosterone induces insulin resistance in the adipose and vascular tissues [70, 71].
Aldosterone exerts negative effects on structural and functional integrity of the pancreatic β-cell by favoring inflammatory and oxidative stress conditions, which lead to decreased insulin release and actions, including actions in the vasculature .
A model of dietary salt restriction, associated with increased aldosterone production, exhibits impaired insulin-induced vasodilation, as well as increased systemic insulin resistance , indicating that even mild elevations in plasma aldosterone produce significant effects on vascular insulin sensitivity and may influence cardiovascular outcomes . Furthermore, rats infused with aldosterone also develop systemic and vascular insulin resistance, effects that might be related to increased levels of insulin-like growth factor-1 receptor (IGF-1R) and to hybridization of IGF-1R and IR . Since these effects are prevented by a MR antagonist and tempol, an antioxidant agent, a role for MR receptor and ROS generation, probably from NAD(P)H oxidase source, has been suggested [70, 71]. Compared with IR, IGF-1R is more abundant in VSMCs, and expression of IGF-1R is increased in aortas of diabetic animals. Furthermore, subunits of IR and IGF-1R easily build hybrid receptors that have higher affinity for IGF-1 than for insulin. IGF-1 induces hypertrophic changes and insulin resistance via IGF-1R in the vasculature. Although the affinity of IGF-1R for insulin is lower compared with IGF-1, high concentrations of insulin, which are often observed in patients and animal models with insulin resistance, may affect intracellular signaling pathways dependent on IGF-1R or hybrid receptors [74–78].
Signaling mechanisms by which insulin regulates endothelial NO production have been substantially clarified. Insulin receptor phosphorylation of IRS-1, which binds and activates PI3K, leads to activation of 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which in turn phosphorylates and activates Akt. Akt directly phosphorylates eNOS at Ser1177, resulting in increased eNOS activity and NO production. Endothelium-derived NO diffuses into adjacent vascular smooth muscle, where it evokes vasorelaxation [65, 79–81].
Aldosterone can affect insulin-induced eNOS activation at different points. Aldosterone increases IGF-1R, which is an important negative regulator of insulin sensitivity in the endothelium. This has been confirmed by deletion of IGF-1R, which culminates in increase in NO bioavailability . In addition, aldosterone increases ROS production , which attenuates insulin signaling by impairing NOS activity and reducing NO bioavailability. Accordingly, superoxide anion (-O2) interacts with NO, forming peroxynitrite (-ONOO), which has less ability than NO to induce relaxation. Also, the overproduction of ROS leads to oxidation of tetrahydrobiopterin (BH4), which is an essential cofactor for eNOS. The reduction of BH4 converts eNOS to a -O2- producing enzyme, leading to reduced NO release and enhanced oxidative stress . This phenomenon impairs insulin signaling and insulin-induced vascular relaxation. Aldosterone also leads to proteosomal degradation of IRS-1, increasing IGF-1 signaling, which attenuates insulin-induced Akt phosphorylation and NOS activation, and decreases glucose uptake in VSMC [30, 70, 71, 84, 85].
Sherajee and colleagues determined the effects of insulin on Akt phosphorylation in aortas from control rats and rats treated with aldosterone plus salt. Incubation with insulin for 30 minutes increased Akt phosphorylation in aortas from the control group, but was significantly less in aortas from rats treated with aldosterone plus salt, indicating that insulin effects are attenuated by aldosterone actions on Akt signaling. Decreased Akt phosphorylation leads to decreased NOS activity and, consequently, to reduced NO bioavailability. Treatment with spironolactone and tempol recovered Akt phosphorylation, reinforcing the involvement of ROS on aldosterone-induced impairment of insulin signaling [70, 71, 86].
Although MR signaling has been discussed as the primary responsible in outcomes related to diabetes and obesity, it is important to recognize that others mediators, including cytokines, also contribute to vascular insulin resistance. Thus, aldosterone and MR binding, synergistically, converge to effects from others pathways .
This study was funded by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico - 142739/2011-1) and FAPESP (Fundação de Amparo a Pesquisa do Estado de São Paulo - 2010/52214-6 and 2011/01785-6).
- Nguyen Dinh Cat A, Jaisser F: Extrarenal effects of aldosterone. Curr Opin Nephrol Hypertens. 2012, 21 (suppl2): 147-156.View ArticlePubMedGoogle Scholar
- Namsolleck P, Unger T: Aldosterone synthase inhibitors in cardiovascular and renal diseases. Nephrol Dial Transplant. 2014, 29 (suppl1): i62-i68.View ArticlePubMedGoogle Scholar
- Geerling JC, Loewy AD: Aldosterone in the brain. Am J Physiol Renal Physiol. 2009, 297 (suppl3): F559-F576.PubMed CentralView ArticlePubMedGoogle Scholar
- Fuller PJ, Young MJ: Mechanisms of mineralocorticoid action. Hypertension. 2005, 46 (6): 1227-1235. 10.1161/01.HYP.0000193502.77417.17.View ArticlePubMedGoogle Scholar
- Viengchareun S, Le Menuet D, Martinerie L, Munier M, Tallec LP, Lombès M: The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology. Nucl Recept Signal. 2007, 30 (5): e012-Google Scholar
- Gros R, Ding Q, Sklar LA, Prossnitz EE, Arterburn JB, Chorazyczewski J, Feldman RD: GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone. Hypertension. 2011, 57: 442-451. 10.1161/HYPERTENSIONAHA.110.161653.View ArticlePubMedGoogle Scholar
- Callera GE, Yogi A, Briones AM, Montezano AC, He Y, Tostes RC, Schiffrin EL, Touyz RM: Vascular proinflammatory responses by aldosterone are mediated via c-Src trafficking to cholesterol-rich microdomains: role of PDGFR. Cardiovasc Res. 2011, 1 (suppl 4): 720-731.View ArticleGoogle Scholar
- Bienvenu LA, Reichelt ME, Delbridge LM, Young MJ: Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte. Clin Sci (Lond). 2013, 125 (9): 409-421. 10.1042/CS20130050.View ArticleGoogle Scholar
- Briones AM, Nguyen Dinh Cat A, Callera GE, Yogi A, Burger D, He Y, Corrêa JW, Gagnon AM, Gomez-Sanchez CE, Gomez-Sanchez EP, Sorisky A, Ooi TC, Ruzicka M, Burns KD, Touyz RM: Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction. Hypertension. 2012, 59 (5): 1069-1078. 10.1161/HYPERTENSIONAHA.111.190223.View ArticlePubMedGoogle Scholar
- Pruthi D, McCurley A, Aronovitz M, Galayda C, Karumanchi SA, Jaffe IZ: Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors. Arterioscler Thromb Vasc Biol. 2014, 34 (2): 355-364. 10.1161/ATVBAHA.113.302854.PubMed CentralView ArticlePubMedGoogle Scholar
- Miyata K, Hitomi H, Guo P, Zhang GX, Kimura S, Kiyomoto H, Hosomi N, Kagami S, Kohno M, Nishiyama A: Possible involvement of Rho-kinase in aldosterone-induced vascular smooth muscle cell remodeling. Hypertens Res. 2008, 31 (7): 1407-1413. 10.1291/hypres.31.1407.View ArticlePubMedGoogle Scholar
- Mazak I, Fiebeler A, Muller DN, Park JK, Shagdarsuren E, Lindschau C, Dechend R, Viedt C, Pilz B, Haller H, Luft FC: Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation. 2004, 8 (suppl 22): 2792-2800.View ArticleGoogle Scholar
- Ishizawa K, Izawa Y, Ito H, Miki C, Miyata K, Fujita Y, Kanematsu Y, Tsuchiya K, Tamaki T, Nishiyama A, Yoshizumi M: Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension. 2005, 46 (4): 1046-1052. 10.1161/01.HYP.0000172622.51973.f5.View ArticlePubMedGoogle Scholar
- Fu GX, Xu CC, Zhong Y, Zhu DL, Gao PJ: Aldosterone-induced osteopontin expression in vascular smooth muscle cells involves MR, ERK, and p38 MAPK. Endocrine. 2012, 42 (3): 676-683. 10.1007/s12020-012-9675-2.View ArticlePubMedGoogle Scholar
- Lemarié CA, Simeone SM, Nikonova A, Ebrahimian T, Deschênes ME, Coffman TM, Paradis P, Schiffrin EL: Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors. Circ Res. 2009, 23 (suppl. 9): 852-859.View ArticleGoogle Scholar
- Callera GE, Touyz RM, Tostes RC, Yogi A, He Y, Malkinson S, Schiffrin EL: Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension. 2005, 45 (4): 773-779. 10.1161/01.HYP.0000154365.30593.d3.View ArticlePubMedGoogle Scholar
- Mii S, Khalil RA, Morgan KG, Ware JA, Kent KC: Mitogen-activated protein kinase and proliferation of human vascular smooth muscle cells. Am J Physiol. 1996, 270: H142-H150.PubMedGoogle Scholar
- Bruder-Nascimento T, Chinnasamy P, Riascos-Bernal DF, Cau SB, Callera GE, Touyz RM, Tostes RC, Sibinga NE: Angiotensin II induces Fat1 expression/activation and vascular smooth muscle cell migration via Nox1-dependent reactive oxygen species generation. J Mol Cell Cardiol. 2014, 66: 18-26.PubMed CentralView ArticlePubMedGoogle Scholar
- Briet M, Schiffrin EL: The role of aldosterone in the metabolic syndrome. Curr Hypertens Rep. 2011, 3: 163-172.View ArticleGoogle Scholar
- Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005, 45: 1243-1248. 10.1016/j.jacc.2005.01.015.View ArticlePubMedGoogle Scholar
- Ivanes F, Susen S, Mouquet F, Pigny P, Cuilleret F, Sautière K, Collet JP, Beygui F, Hennache B, Ennezat PV, Juthier F, Richard F, Dallongeville J, Hillaert MA, Doevendans PA, Jude B, Bertrand M, Montalescot G, Van Belle E: Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure. Eur Heart J. 2012, 33: 191-202. 10.1093/eurheartj/ehr176.View ArticlePubMedGoogle Scholar
- Lastra-Lastra G, Sowers JR, Restrepo-Erazo K, Manrique-Acevedo C, Lastra-González G: Role of aldosterone and angiotensin II in insulin resistance: an update. Clin Endocrinol (Oxf). 2009, 71: 1-6. 10.1111/j.1365-2265.2008.03498.x.View ArticleGoogle Scholar
- Hollenberg NK, Stevanovic R, Agarwal A, Lansang MC, Price DA, Laffel LM, Williams GH, Fisher ND: Plasma aldosterone concentration in the patient with diabetes mellitus. Kidney Int. 2004, 65 (4): 1435-1439. 10.1111/j.1523-1755.2004.00524.x.View ArticlePubMedGoogle Scholar
- Lamounier-Zepter V, Rotthoff T, Ansurudeen I, Kopprasch S, Scherbaum WA, Ehrhart-Bornstein M, Bornstein SR: Increased aldosterone/renin quotient in obese hypertensive women: a novel role for low-density lipoproteins?. Horm Metab Res. 2006, 38 (7): 471-475. 10.1055/s-2006-948137.View ArticlePubMedGoogle Scholar
- Fredersdorf S, Endemann DH, Luchner A, Heitzmann D, Ulucan C, Birner C, Schmid P, Stoelcker B, Resch M, Muders F, Riegger GA, Weil J: Increased aldosterone levels in a model of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2009, 117 (1): 15-20. 10.1055/s-2008-1073128.View ArticlePubMedGoogle Scholar
- Giugliano D, Ceriello A, Paolisso G: Oxidative stress and diabetic vascular complications. Diabetes Care. 1996, 19 (3): 257-267. 10.2337/diacare.19.3.257.View ArticlePubMedGoogle Scholar
- Feener EP, King GL: Vascular dysfunction in diabetes mellitus. Lancet. 1997, 350 (1): SI9-SI13.View ArticlePubMedGoogle Scholar
- Creager MA, Lüscher TF, Cosentino F, Beckman JA: Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation. 2003, 23 (suppl. 12): 1527-1532.View ArticleGoogle Scholar
- Hartge MM, Unger T, Kintscher U: The endothelium and vascular inflammation in diabetes. Diab Vasc Dis Res. 2007, 4 (2): 84-88.View ArticlePubMedGoogle Scholar
- Hitomi H, Kiyomoto H, Nishiyama A, Hara T, Moriwaki K, Kaifu K, Ihara G, Fujita Y, Ugawa T, Kohno M: Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. Hypertension. 2007, 50: 750-755. 10.1161/HYPERTENSIONAHA.107.093955.View ArticlePubMedGoogle Scholar
- Tanabe A, Naruse M, Arai K, Naruse K, Yoshimoto T, Seki T, Imaki T, Kobayashi M, Miyazaki H, Demura H: Angiotensin II stimulates both aldosterone secretion and DNA synthesis via type 1 but not type 2 receptors in bovine adrenocortical cells. J Endocrinol Invest. 1998, 21 (10): 668-672. 10.1007/BF03350796.View ArticlePubMedGoogle Scholar
- Wong WT, Tian XY, Xu A, Ng CF, Lee HK, Chen ZY, Au CL, Yao X, Huang Y: Angiotensin II type 1 receptor-dependent oxidative stress mediates endothelial dysfunction in type 2 diabetic mice. Antioxid Redox Signal. 2010, 15 (suppl. 6): 757-768.View ArticleGoogle Scholar
- Mavrakanas TA, Gariani K, Martin PY: Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review. Eur J Intern Med. 2014, 25 (2): 173-176. 10.1016/j.ejim.2013.11.007.View ArticlePubMedGoogle Scholar
- Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000, 355: 253-259.View ArticleGoogle Scholar
- Eschalier R1, McMurray JJ, Swedberg K, van Veldhuisen DJ, Krum H, Pocock SJ, Shi H, Vincent J, Rossignol P, Zannad F, Pitt B: Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol. 2013, 22 (suppl. 17): 1585-1593.View ArticleGoogle Scholar
- Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, Randomized Aldactone Evaluation Study Investigators: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999, 341: 709-717. 10.1056/NEJM199909023411001.View ArticlePubMedGoogle Scholar
- Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003, 348: 1309-1321. 10.1056/NEJMoa030207.View ArticlePubMedGoogle Scholar
- Berg AH, Scherer PE: Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005, 96: 939-949. 10.1161/01.RES.0000163635.62927.34.View ArticlePubMedGoogle Scholar
- McCurley A, Jaffe IZ: Mineralocorticoid receptors in vascular function and disease. Mol Cell Endocrinol. 2012, 350: 256-265. 10.1016/j.mce.2011.06.014.PubMed CentralView ArticlePubMedGoogle Scholar
- Bender SB, McGraw AP, Jaffe IZ, Sowers JR: Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease?. Diabetes. 2013, 62 (suppl2): 313-319.PubMed CentralView ArticlePubMedGoogle Scholar
- 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: 3457-3463. 10.1210/jc.2006-0736.View ArticlePubMedGoogle Scholar
- Colussi G, Catena C, Lapenna R, Nadalini E, Chiuch A, Sechi LA: Insulin resistance and hyperinsulinemia are related to plasma aldosterone levels in hypertensive patients. Diabetes Care. 2007, 30: 2349-2354. 10.2337/dc07-0525.View ArticlePubMedGoogle Scholar
- Tsorlalis IK, Lewsey JD, Latini R, Maggioni AP, Solomon S, Pitt B, Connell JM, McMurray JJ: Aldosterone status associated with insulin resistance in patients with heart failure data from the ALOFT study. Heart. 2007, 95: 1920-1924.Google Scholar
- Hirata A, Maeda N, Hiuge A, Hibuse T, Fujita K, Okada T, Kihara S, Funahashi T, Shimomura I: Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice. Cardiovasc Res. 2009, 84: 164-172. 10.1093/cvr/cvp191.View ArticlePubMedGoogle Scholar
- Wada T, Ohshima S, Fujisawa E, Koya D, Tsuneki H, Sasaoka T: Aldosterone inhibits insulin-induced glucose uptake by degradation of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen species-mediated pathway in 3 T3-L1 adipocytes. Endocrinology. 2009, 150: 1662-1669. 10.1210/en.2008-1018.View ArticlePubMedGoogle Scholar
- Ranade K, Wu KD, Risch N, Olivier M, Pei D, Hsiao CF, Chuang LM, Ho LT, Jorgenson E, Pesich R, Chen YD, Dzau V, Lin A, Olshen RA, Curb D, Cox DR, Botstein D: Genetic variation in aldosterone synthase predicts plasma glucose levels. Proc Natl Acad Sci U S A. 2001, 98: 13219-13224. 10.1073/pnas.221467098.PubMed CentralView ArticlePubMedGoogle Scholar
- Sanger F, Thompson EO: The amino-acid sequence in the glycyl chain of insulin: I: the identification of lower peptides from partial hydrolysates. Biochem J. 1953, 53 (suppl3): 353-366.PubMed CentralView ArticlePubMedGoogle Scholar
- Goodfriend TL, Egan BM, Kelley DE: Plasma aldosterone, plasma lipoproteins, obesity and insulin resistance in humans. Prostaglandins Leukot Essent Fatty Acids. 1999, 60 (suppl5-6): 401-405.View ArticlePubMedGoogle Scholar
- Goodfriend TL, Ball DL, Elliott ME, Morrison AR, Evenson MA: Fatty acids are potential endogenous regulators of aldosterone secretion. Endocrinology. 1991, 128 (5): 2511-2519. 10.1210/endo-128-5-2511.View ArticlePubMedGoogle Scholar
- Jéquier E: Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002, 967: 379-388.View ArticlePubMedGoogle Scholar
- Shek EW, Brands MW, Hall JE: Chronic leptin infusion increases arterial pressure. Hypertension. 1998, 31 (pt 2): 409-414.View ArticlePubMedGoogle Scholar
- Jackson EK, Li P: Human leptin has natriuretic activity in the rat. Am J Physiol. 1997, 272 (pt 2): F333-F338.PubMedGoogle Scholar
- Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA: Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes. 1997, 46: 1235-1238. 10.2337/diab.46.7.1235.View ArticlePubMedGoogle Scholar
- Bornstein SR, Torpy DJ: Leptin and the renin-angiotensin-aldosterone system. Hypertension. 1998, 32: 376-377. 10.1161/01.HYP.32.2.376.View ArticlePubMedGoogle Scholar
- Belin de Chantemèle EJ, Mintz JD, Rainey WE, Stepp DW: Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice. Hypertension. 2011, 58 (suppl2): 271-279.PubMed CentralView ArticlePubMedGoogle Scholar
- Sanger F, Thompson EO: The amino-acid sequence in the glycyl chain of insulin. II: the investigation of peptides from enzymi hydrolysates. Biochem J. 1953, 53 (suppl3): 366-374.PubMed CentralView ArticlePubMedGoogle Scholar
- De Meyts P: Insulin and its receptor: structure, function and evolution. Bioessays. 2004, 26 (suppl12): 1351-1362.View ArticlePubMedGoogle Scholar
- Fu Z, Gilbert ER, Liu D: Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev. 2013, 1 (suppl1): 25-53.View ArticleGoogle Scholar
- Pittman I, Philipson L, Steiner D, (last edition: 2009 by Dhemy Padilla): Insulin biosynthesis, secretion, structure, and structure-activity relationships.http://diabetesmanager.pbworks.com/w/page/17680216/Insulin%20Biosynthesis,%20Secretion,%20Structure,%20and%20StructureActivity%20Relationships#INSULINBIOGENESISANDMECHANISMOFRELEASE,
- Blundell T, Dodson G, Hodgkin D, Mercola D: Insulin: the structure in the crystal and its reflection in chemistry and biology. Adv Protein Chem. 1972, 1972 (26): 279-402.View ArticleGoogle Scholar
- Clark MG, Wallis MG, Barrett EJ, Vincent MA, Richards SM, Clerk LH, Rattigan S: Capillary recruitment and its role in metabolic regulation: a focus on insulin action in skeletal muscle. Am J Physiol. 2003, 284: E241-E258.Google Scholar
- Vincent MA, Barrett EJ, Lindner JR, Clark MG, Rattigan S: Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol. 2003, 285: E123-E129.Google Scholar
- Baker EN1, Blundell TL, Cutfield JF, Cutfield SM, Dodson EJ, Dodson GG, Hodgkin DM, Hubbard RE, Isaacs NW, Reynolds CD, Sakabe K, Sakabe N, Vijayan NM: The structure of 2Zn pig insulin at 1.5 A° resolution. Phil Trans R Soc Lond B. 1988, 19: 369-456.View ArticleGoogle Scholar
- Hartell NA, Archer HE, Bailey CJ: Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochem Pharmacol. 2005, 1 (suppl5): 781-790.View ArticleGoogle Scholar
- Kim JA1, Montagnani M, Koh KK, Quon MJ: Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006, 113: 1888-1904. 10.1161/CIRCULATIONAHA.105.563213.View ArticlePubMedGoogle Scholar
- Moncada S: Nitric oxide. J Hypertens. 1994, 12: S35-S39.Google Scholar
- Conti V, Russomanno G, Corbi G, Izzo V, Vecchione C, Filippelli A: Adrenoreceptors and nitric oxide in the cardiovascular system. Front Physiol. 2013, 6 (suppl4): 321-eCollectionGoogle Scholar
- Lee JH, Ragolia L: AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells. Am J Physiol Cell Physiol. 2006, 291 (suppl6): C1355-C1365.PubMed CentralView ArticlePubMedGoogle Scholar
- Sowers JR: Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol. 2004, 286: H1597-H1602. 10.1152/ajpheart.00026.2004.View ArticlePubMedGoogle Scholar
- Levine TB, Levine AB: Metabolic Syndrome and Cardiovascular Disease. 2006, Mishawaka, IN, USA: Saunders, Print, 1Google Scholar
- Sherajee SJ, Fujita Y, Rafiq K, Nakano D, Mori H, Masaki T, Hara T, Kohno M, Nishiyama A, Hitomi H: Aldosterone induces vascular insulin resistance by increasing insulin-like growth factor-1 receptor and hybrid receptor. Arterioscler Thromb Vasc Biol. 2012, 32 (suppl2): 257-263.View ArticlePubMedGoogle Scholar
- Urbanet R, Pilon C, Calcagno A, Peschechera A, Hubert EL, Giacchetti G, Gomez-Sanchez C, Mulatero P, Toffanin M, Sonino N, Zennaro MC, Giorgino F, Vettor R, Fallo F: Analysis of insulin sensitivity in adipose tissue of patients with primary aldosteronism. J Clin Endocrinol Metab. 2010, 95 (suppl8): 4037-4042.View ArticlePubMedGoogle Scholar
- Whaley-Connell A, Johnson MS, Sowers JR: Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis. 2010, 52 (suppl5): 401-409.PubMed CentralView ArticlePubMedGoogle Scholar
- Feldman RD, Schmidt ND: Moderate dietary salt restriction increases vascular and systemic insulin resistance. Am J Hypertens. 1999, 12: 643-647. 10.1016/S0895-7061(99)00016-3.View ArticlePubMedGoogle Scholar
- Moxham CP, Duronio V, Jacobs S: Insulin-like growth factor I receptor α-subunit heterogeneity: evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers. J Biol Chem. 1989, 264: 13238-13244.PubMedGoogle Scholar
- Schumacher R, Mosthaf L, Schlessinger J, Brandenburg D, Ullrich A: Insulin and insulin-like growth factor-1 binding specificity is determined by distinct regions of their cognate receptors. J Biol Chem. 1991, 266: 19288-19295.PubMedGoogle Scholar
- Frattali AL, Pessin JE: Relationship between β subunit ligand occupancy and α- subunit autophosphorylation in insulin/insulin-like growth factor-1 hybrid receptors. J Biol Chem. 1993, 268: 7393-7400.PubMedGoogle Scholar
- Arnqvist HJ: The role of IGF-system in vascular insulin resistance. Horm Metab Res. 2008, 40: 588-592. 10.1055/s-0028-1082325.View ArticlePubMedGoogle Scholar
- Zeng G, Quon MJ: Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest. 1996, 98: 894-898. 10.1172/JCI118871.PubMed CentralView ArticlePubMedGoogle Scholar
- Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ: Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000, 101: 1539-1545. 10.1161/01.CIR.101.13.1539.View ArticlePubMedGoogle Scholar
- Montagnani M, Chen H, Barr VA, Quon MJ: Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem. 2001, 276 (suppl32): 30392-30398.View ArticlePubMedGoogle Scholar
- Abbas A, Imrie H, Viswambharan H, Sukumar P, Rajwani A, Cubbon RM, Gage M, Smith J, Galloway S, Yuldeshava N, Kahn M, Xuan S, Grant PJ, Channon KM, Beech DJ, Wheatcroft SB, Kearney MT: The insulin-like growth factor-1 receptor is a negative regulator of nitric oxide bioavailability and insulin sensitivity in the endothelium. Diabetes. 2011, 60 (suppl8): 2169-2178.PubMed CentralView ArticlePubMedGoogle Scholar
- Masano T, Kawashima S, Toh R, Satomi-Kobayashi S, Shinohara M, Takaya T, Sasaki N, Takeda M, Tawa H, Yamashita T, Yokoyama M, Hirata K: Beneficial effects of exogenous tetrahydrobiopterin on left ventricular remodeling after myocardial infarction in rats: the possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthase. Circ J. 2008, 72 (suppl9): 1512-1519.View ArticlePubMedGoogle Scholar
- Engberding N, San Martín A, Martin-Garrido A, Koga M, Pounkova L, Lyons E, Lassègue B, Griendling KK: Insulin-like growth factor-1 receptor expression masks the antiinflammatory and glucose uptake capacity of insulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2009, 29: 408-415. 10.1161/ATVBAHA.108.181727.PubMed CentralView ArticlePubMedGoogle Scholar
- Cascella T, Radhakrishnan Y, Maile LA, Busby WH, Gollahon K, Colao A, Clemmons DR: Aldosterone enhances IGF-I-mediated signaling and biological function in vascular smooth muscle cells. Endocrinology. 2010, 151 (suppl12): 5851-5864.PubMed CentralView ArticlePubMedGoogle Scholar
- Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999, 10 (suppl6736): 601-605.Google Scholar
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