eplerenone and Insulin-Resistance

Key components of the metabolic syndrome (MetS), ie, obesity and insulin resistance, are associated with increased aldosterone production and mineralocorticoid receptor (MR) activation. Both MetS and hyperaldosteronism are proinflammatory and pro-oxidative states associated with cardiovascular disease. This review discusses emerging data that MR activation may contribute to abnormalities seen in MetS. In view of these data, MR antagonists may be beneficial in MetS, not only by controlling hypertension but also by reversing inflammation, oxidative stress, and defective insulin signaling at the cellular-molecular level. Clinical trials have demonstrated benefits of MR antagonists in heart failure, hypertension, and diabetic nephropathy, but additional trials are needed to demonstrate the clinical significance of MR blockade in MetS.

Topics: Aldosterone; Antihypertensive Agents; Eplerenone; Humans; Hypertension; Inflammation; Insulin Resistance; Lipid Metabolism; Lipids; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Obesity; Signal Transduction; Spironolactone

HIV-infected individuals demonstrate increased renin-angiotensin-aldosterone system activation in association with visceral adiposity, insulin resistance, and inflammation. A physiologically based treatment approach targeting mineralocorticoid receptor (MR) blockade may improve metabolic and inflammatory indices in HIV.. To investigate effects of eplerenone on insulin sensitivity, inflammatory indices, and other metabolic parameters in HIV.. Six-month, double-blind, randomized, placebo-controlled trial.. Academic clinical research center.. HIV-infected individuals with increased waist circumference and abnormal glucose homeostasis.. Eplerenone 50 mg or placebo daily.. The primary end point was change in insulin sensitivity measured by the euglycemic-hyperinsulinemic clamp technique. Secondary end points included change in body composition and inflammatory markers.. Forty-six individuals were randomized to eplerenone (n = 25) vs placebo (n = 21). Eplerenone did not improve insulin sensitivity [0.48 (-1.28 to 1.48) vs 0.43 (-1.95 to 2.55) mg/min/μIU/mL insulin; P = 0.71, eplerenone vs placebo] when measured by the gold standard euglycemic-hyperinsulinemic clamp technique. Intramyocellular lipids (P = 0.04), monocyte chemoattractant protein-1 (P = 0.04), and high-density lipoprotein (P = 0.04) improved among those randomized to eplerenone vs placebo. Trends toward decreases in interleukin-6 (P = 0.10) and high-sensitivity C-reactive protein (P = 0.10) were also seen with eplerenone vs placebo. Plasma renin activity and aldosterone levels increased in the eplerenone vs placebo-treated group, demonstrating expected physiology. MR antagonism with eplerenone was well tolerated among the HIV population, with no considerable changes in blood pressure or potassium.. MR blockade may improve selected metabolic and inflammatory indices in HIV-infected individuals. Further studies are necessary to understand the clinical potential of MR antagonism in HIV.

Topics: Adiposity; Adult; Aged; Blood Pressure; Double-Blind Method; Eplerenone; Female; Glucose Clamp Technique; HIV Infections; Humans; Inflammation; Insulin Resistance; Lipids; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Treatment Outcome

Mineralocorticoid receptor antagonists (MRAs) decrease morbidity and mortality in patients with heart failure (HF). However, spironolactone, a non-selective MRA, has been shown to exert a harmful effect on glucose homeostasis. The objective of this multicenter, randomized, controlled, double-blind trial was to compare the effects of spironolactone to those of the selective MRA eplerenone on glucose homeostasis among 62 HF patients with glucose intolerance or type II diabetes. Trial registration number:NCT01586442.

Topics: Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Eplerenone; Female; Glucose Intolerance; Glycated Hemoglobin; Heart Failure; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Prospective Studies; Spironolactone; Stroke Volume

The prevalence of metabolic syndrome is especially high in older adults. Metabolic syndrome is associated with impaired vascular endothelial function, insulin resistance, and increased risk for cardiovascular disease but the underlying mechanisms are not fully elucidated. Plasma aldosterone is independently associated with metabolic syndrome and is linked to endothelial dysfunction and insulin resistance. Thus, we hypothesized that mineralocorticoid receptor (MR) blockade would improve flow-mediated dilation and insulin resistance in older adults with metabolic syndrome.. To test this hypothesis, we conducted a balanced, randomized, double-blind, placebo-controlled, crossover study using selective MR blockade (eplerenone; 100 mg/day) for 1 month with 1 month washout in older adults with metabolic syndrome (62.6 ± 3.2 yrs; mean ± standard error). We evaluated brachial artery flow-mediated dilation (ultrasonography), oxidative stress (oxidized low-density lipoproteins and F2-isoprostanes) and insulin resistance (homeostatic model assessment).. In response to MR blockade, flow-mediated dilation (5.37 ± 0.85 vs. 5.98 ± 1.29%; placebo vs. eplerenone; P = 0.4), oxidized low-density lipoproteins (51.6 ± 11.5 vs. 56.1 ± 10.9 U/L; P = 0.6), and F2-isoprostanes (0.07 ± 0.02 vs. 0.06 ± 0.01 pg/mL; P = 0.3) did not improve. Insulin resistance also did not change following MR blockade (1.04 ± 0.26 vs. 1.38 ± 0.50; P = 0.6). However, MR blockade resulted in a large reduction (10 mmHg) in systolic blood pressure (140 ± 6 vs. 130 ± 6 mmHg; P = 0.02), with no significant change in diastolic blood pressure (81 ± 3 vs. 75 ± 2 mmHg; P = 0.2).. Our data do not support a contributing role for MRs in endothelial dysfunction and insulin resistance in older adults with metabolic syndrome. However, our findings suggest MR activation is an important contributor to systolic hypertension in this patient group.

Topics: Aged; Brachial Artery; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Eplerenone; Humans; Insulin Resistance; Metabolic Syndrome; Middle Aged; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Placebos; Regional Blood Flow; Spironolactone; Ultrasonography; Vasodilation

Topics: Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Eplerenone; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid

Extensive research has explored the role of aldosterone in insulin resistance. Recent evidence suggests that the mineralocorticoid receptor (MR) mediates aldosterone-induced dysregulation of cytokines, and most of this research has focused on adjustments in fat tissue and adipocytes. However, the direct effect of MR blockade on insulin resistance in cardiomyocytes remains largely unknown. In the present study, we investigated whether MR blockade improves insulin-sensitizing factors in insulin-resistant rats and attenuates the dysregulation of the aldosterone-related transport of adiponectin and glucose in cardiomyocytes and examined the underlying mechanisms.. The effects of aldosterone, MR inhibitors (e.g., eplerenone), a peroxisome proliferator-activated receptor (PPAR) α agonist, and a p38 mitogen-activated protein kinase (MAPK) inhibitor on adiponectin and glucose transport were studied at the mRNA and protein levels in vitro and in vivo.. Our data revealed that aldosterone reduced the expression of adiponectin and inhibited the transport of glucose in cardiomyocytes and that MR blockade reversed these affects. In vivo, MR blockade improved insulin-sensitive parameters and increased adiponectin expression in the myocardia of high-fat diet rats. Furthermore, aldosterone promoted p38MAPK expression but negatively affected PPARα expression, and the downregulation of adiponectin by aldosterone was reversed by MR blockade, a PPARα agonist, and a p38 MAPK inhibitor.. The above results suggested that aldosterone promoted insulin resistance in the heart and that this effect could be partly reversed by MR blockade through signal transduction in the P38 MAPK pathway and PPARα.

Topics: Adiponectin; Aldosterone; Animals; Animals, Newborn; Biological Transport; Eplerenone; Gene Expression Regulation; Glucose; Glucose Clamp Technique; Insulin; Insulin Resistance; Male; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; PPAR alpha; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; RNA, Messenger; Signal Transduction; Spironolactone

Plasma aldosterone is elevated in type 2 diabetes and obesity in experimental and clinical studies and can act to inhibit both glucose-stimulated insulin secretion by the β-cell and insulin signaling. Currently mineralocorticoid receptor antagonism is the best characterized treatment to ameliorate aldosterone-mediated effects. A second alternative is inhibition of aldosterone synthase, an approach with protective effects on end-organ damage in heart or kidney in animal models. The effect of aldosterone synthase inhibition on metabolic parameters in type 2 diabetes is not known. Therefore, male Zucker diabetic fatty (ZDF) rats were treated for 11 weeks with the aldosterone synthase inhibitor FAD286, beginning at 7 weeks of age. Results were compared with the mineralocorticoid receptor antagonist eplerenone. Plasma aldosterone was abolished by FAD286 and elevated more than 9-fold by eplerenone. The area under the curve calculated from an oral glucose tolerance test (OGTT) was lower and overall insulin response during OGTT was increased by FAD286. In contrast, eplerenone elevated blood glucose levels and blunted insulin secretion during the OGTT. Fasting glucose was lowered and fasting insulin was increased by FAD286 in the prediabetic state. Glycated hemoglobin was lowered by FAD286, whereas eplerenone showed no effect. We conclude that aldosterone synthase inhibition, in contrast to mineralocorticoid receptor antagonism, has the potential for beneficial effects on metabolic parameters in type 2 diabetes.

Topics: Adrenal Glands; Aldosterone; Animals; Blood Glucose; Body Weight; Cytochrome P-450 CYP11B2; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Eplerenone; Fadrozole; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Mineralocorticoid Receptor Antagonists; Organ Size; Potassium; Random Allocation; Rats, Zucker; Sodium; Spironolactone; Triglycerides

Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene.. In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele.. Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency.

Topics: Adipose Tissue; Adolescent; Adult; Aged; Aldehyde Reductase; Aldosterone; Animals; Blood Glucose; Caveolin 1; Cholesterol; Dyslipidemias; Eplerenone; Female; Gene Frequency; Glucose; Homeostasis; Humans; Hypertriglyceridemia; Insulin; Insulin Resistance; Lipid Metabolism; Lipoproteins, HDL; Liver; Male; Mice; Mice, Knockout; Middle Aged; Mineralocorticoid Receptor Antagonists; NADPH Oxidase 4; Polymorphism, Single Nucleotide; Receptors, Mineralocorticoid; Resistin; Retinol-Binding Proteins, Plasma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Spironolactone; Triglycerides; Young Adult

Obesity, diabetes, fatty liver, and hypertension are major determinants of the metabolic syndrome. The effects of aldosterone and mineralocorticoid receptor blockers on fatty liver are largely unknown. The aim of the present study was to evaluate the relationships between aldosterone and the development of fatty liver.. In our experiments, we performed adrenalectomy (ADX) or administered 100 mg/kg/day eplerenone, a specific mineralocorticoid receptor blocker, to male C57BL/6 mice fed with a 60% fat diet for 20 weeks.. High-fat diet led to metabolic syndrome as indicated by increased body weight, elevated systolic blood pressure, impaired glucose tolerance, elevated insulin levels, and development of fatty liver. A marked reduction of aldosterone by ADX or blockade of aldosterone interaction with its receptor by eplerenone, which increased serum aldosterone considerably, resulted in reduced blood pressure, and reduced serum insulin and levels of triglycerides. However, differential effects were found on reduction of blood glucose to normal levels, which was observed only in ADX. Neither ADX nor eplerenone affected fatty liver formation or body weight. In cultured hepatocytes, triglyceride loading induced by high glucose, oleic acid or very low density lipoprotein was not affected by aldosterone, spironolactone or eplerenone.. Our results suggest that whereas aldosterone might be involved in some of the diet-induced insulin and glucose metabolic effects, it played no role in the development of fatty liver.

Topics: Adrenalectomy; Aldosterone; Animals; Blood Glucose; Blood Pressure; Cells, Cultured; Cholesterol; Diet, High-Fat; Disease Models, Animal; Eplerenone; Fatty Liver; Hepatocytes; Insulin; Insulin Resistance; Lipoproteins, VLDL; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Oleic Acid; Spironolactone; Triglycerides; Weight Gain

Mineralocorticoid Receptor (MR) activation is involved in blood pressure regulation and the pathogenesis of cardiovascular diseases, such as cardiac fibrosis, vascular inflammation and arterial aging. Recent investigations suggest a role for MR activation in metabolic dysregulation.. To test the effect of MR blockade on basal and postprandial glucose and lipid levels after a meal high in fat and glucose in healthy males.. A prospective, self-controlled study was performed in 13 healthy adult males aged 18-45years. Blood was drawn before, 2h, and 4h after a high fat/high glucose meal (50g fat, 75g glucose), followed by low-dose eplerenone treatment (50mg daily) for 14days. Subjects returned for a second high fat/high glucose meal after the medication period. Basal and postprandial blood glucose and lipid levels were compared before and after eplerenone treatment.. Eplerenone treatment affected neither basal nor postprandial glucose and lipid levels in our study population.. Our results suggest that low-dose, non-blood pressure-affecting, MR blockade does not alter postprandial lipid and glucose homeostasis in healthy adult subjects.

Topics: Adolescent; Adult; Blood Glucose; Blood Pressure; Cholesterol; Eplerenone; Glucose; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Postprandial Period; Prospective Studies; Receptors, Mineralocorticoid; Regression Analysis; Spironolactone; Young Adult

We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs). Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor.. Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by (3)H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and α-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 μg/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes.. Aldosterone induces vascular remodeling through IGF1R- and hybrid receptor-dependent vascular insulin resistance. Mineralocorticoid receptor blockade may attenuate angiopathy in hypertensive patients with hyperinsulinemia.

Topics: Aldosterone; Animals; Aorta, Thoracic; Blood Pressure; Cells, Cultured; Chimera; Eplerenone; Glucose; Hypertrophy; Insulin; Insulin Resistance; Male; Models, Animal; Muscle, Smooth, Vascular; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1; Receptor, Insulin; Spironolactone; Up-Regulation

Primary aldosteronism (PA) patients display an increased incidence of insulin resistance. Herein we demonstrate the decreased gene expression of lipid metabolism genes PCK1, PLIN, ADIPOQ and PPARG in the visceral adipose tissue (VAT) of PA patients compared to age-, sex- and BMI-matched controls. In VAT, the expression of PCK1, PLIN, ADIPOQ and PPARG was inversely correlated with aldosterone levels; furthermore, PLIN and ADIPOQ gene expression was correlated with potassium levels. Therefore, raised aldosterone and low potassium may contribute to the reduced expression of these genes in PA patients. Finally, incubation of primary cultures of human adipocytes with aldosterone resulted in a decrease in the expression of PCK1, PLIN and ADIPOQ and this effect was blocked by eplerenone. Therefore, the characteristic aldosterone excess of PA patients may mediate the down-regulation of PCK1, PLIN and ADIPOQ in VAT that in turn may contribute to the insulin resistance observed in PA patients.

Topics: Adipocytes; Adiponectin; Adult; Aged; Aldosterone; Carrier Proteins; Cells, Cultured; Down-Regulation; Eplerenone; Female; Gene Expression; Humans; Hyperaldosteronism; Insulin Resistance; Intra-Abdominal Fat; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Perilipin-1; Phosphoenolpyruvate Carboxykinase (GTP); Phosphoproteins; Potassium; PPAR gamma; Spironolactone

In obesity, chronic low-grade inflammation and overproduction of reactive oxygen species (ROS) in fat contribute to the development of metabolic syndrome. Suppression of inflammation and ROS production in fat may attenuate the metabolic syndrome. Activation of mineralocorticoid receptor (MR) promotes inflammation in heart, kidney, and vasculature via ROS generation. However, the significance of MR in fat remains elusive. Here we investigated whether MR blockade attenuates obesity-related insulin resistance and improves adipocyte dysfunction.. Obese ob/ob and db/db mice were treated with eplerenone, a MR antagonist, for 3 weeks. 3T3-L1 adipocytes were treated with aldosterone or H2O2, with and without eplerenone or MR-siRNA. High levels of MR mRNA were detected in adipose tissue of obese ob/ob and db/db mice. Eplerenone treatment significantly reduced insulin resistance, suppressed macrophage infiltration and ROS production in adipose tissues, and corrected the mRNA levels of obesity-related genes in obese mice. In 3T3-L1 adipocytes, aldosterone and H2O2 increased intracellular ROS levels and MR blockade inhibited such increases. H2O2 and aldosterone resulted in dysregulation of mRNAs of various genes related to ROS and cytokines, whereas MR blockade corrected such changes.. MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Eplerenone; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Obesity; Reactive Oxygen Species; Receptors, Mineralocorticoid; RNA, Messenger; RNA, Small Interfering; Spironolactone