Inhibition by aldosterone of insulin receptor mRNA levels and insulin binding in U-937 human promonocytic cells

Campión, Javier; Maestro, Beatríz; Mata, F.; Dávila, Norma; Carranza, M. C.; Calle, C.

doi:10.1016/s0960-0760(99)00117-x

Cited by 27 publications

(19 citation statements)

References 41 publications

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“…11 In the ®rst part of the present work, we demonstrate that the detected inhibition by aldosterone was accompanied by impaired insulin action in terms of both glucose transport and DNA synthesis in these cells under the same conditions of dose and time. We observed that while aldosterone had no effects on basal glucose transport or on basal thymidine incorporation into DNA, cell responsiveness re¯ected by the maximal response to insulin was decreased by 23% for glucose transport and by 31% for thymidine incorporation, after the aldosterone treatment.…”

Section: Discussionsupporting

confidence: 54%

“…10 In addition, our laboratory recently demonstrated an in vitro aldosterone inhibition of the two major species of the human IR mRNA (11 and 8.5 kb in size) present in U-937 promonocytic cells in a dose-and timedependent manner. 11 RNA stability and protein turnover were both unaltered, suggesting an effect on transcription. Aldosterone also decreased the IR number but not the af®nity of this receptor, which suggests a possible failure in the insulin responsiveness of the cells.…”

Section: Introductionmentioning

confidence: 99%

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Aldosterone impairs insulin responsiveness in U‐937 human promonocytic cells via the downregulation of its own receptor

Campión

Maestro

Molero

et al. 2002

Cell Biochemistry & Function

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In an earlier study, we have reported an inhibition of insulin receptor (IR) mRNA levels and insulin binding by aldosterone in U-937 human promonocytic cells. In the present extension of our studies, we demonstrate that this inhibition by aldosterone had no effects on basal glucose transport or on basal thymidine incorporation into DNA, while the cell responsiveness reflected by the maximal response to insulin was decreased by 23% for glucose transport and by 31% for DNA synthesis after the aldosterone treatment. We also prove that this inhibition of the insulin response by aldosterone is mediated by a downregulation of the levels of mineralocorticoid receptors (MRs) (50% decrease) and their mRNA (50% decrease). In addition, the mineralocorticoid antagonist spironolactone reversed the decrease in MR mRNA levels elicited by aldosterone, which suggests the involvement of this receptor in the process.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Aldosterone impairs insulin responsiveness in U‐937 human promonocytic cells via the downregulation of its own receptor

Campión

Maestro

Molero

et al. 2002

Cell Biochemistry & Function

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“…Indeed, diabetes is associated with both hyperkalemia and hypoaldosteronism (31,32), and glucose infusions decreased plasma aldosterone (33,34) and potassium levels (34,35) in nondiabetic individuals. Furthermore, there is evidence that aldosterone can affect insulin receptor mRNA levels, at least in cultured cells (36), and aldosterone levels have been correlated with insulin resistance (37). Finally, aldosterone induces the expression of the serum glucocorticoid-inducible kinase gene, whose expression level also responds to changes in glucose and insulin levels (38,39), suggesting yet another potential connection between aldosterone and glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in aldosterone synthase predicts plasma glucose levels

Ranade

Risch

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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The mineralocorticoid hormone, aldosterone, is known to play a role in sodium homeostasis. We serendipitously found, however, highly significant association between single-nucleotide polymorphisms in the aldosterone synthase gene and plasma glucose levels in a large population of Chinese and Japanese origin. Two polymorphisms-one in the putative promoter (T-344C) and another resulting in a lysine͞arginine substitution at amino acid 173, which are in complete linkage disequilibrium in this population-were associated with fasting plasma glucose levels (P ‫؍‬ 0.000017) and those 60 (P ‫؍‬ 0.017) and 120 (P ‫؍‬ 0.0019) min after an oral glucose challenge. A C͞T variant in intron 1, between these polymorphisms, was not associated with glucose levels. Arg-173 and -344C homozygotes were most likely to be diabetic [odds ratio 2.51; 95% confidence interval (C.I.) 1.39 -3.92; P ‫؍‬ 0.0015] and have impaired fasting glucose levels (odds ratio 3.53; 95% C.I. 2.02-5.5; P ‫؍‬ 0.0000036). These results suggest a new role for aldosterone in glucose homeostasis.H ypertension affects 15-50% of the adult population and is one of the major risk factors for stroke, myocardial infarction, and renal disease. Despite intense effort, our understanding of heritable factors in the etiology of hypertension is rather poor. Twin, adoption, and epidemiologic studies indicate that variation in blood pressure (BP) is genetically determined to some extent (1-3). Insulin resistance, defined as the sluggish uptake of glucose by peripheral tissue in the presence of normal or elevated levels of insulin, is frequently associated with hypertension (4). One of the goals of the Stanford, Asia, and Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) study is to identify predisposing genes for essential hypertension and insulin resistance.To maximize our chances of finding susceptibility genes for these diseases, we took several steps. First, in an attempt to reduce genetic heterogeneity, we focused on a relatively homogeneous population of Chinese and Japanese descent. Second, we sampled subjects from tails of the systolic or diastolic BP distributions-the affected hypertensives were recruited from the upper 20% of the distribution, whereas the unaffected ''low-normotensive'' individuals had BP readings in the lower 30% of the distribution (5). Third, because recent theoretical work suggests that association studies might be adequately powerful to detect susceptibility loci that have a modest effect on the phenotype (6), we began candidate gene studies by testing specific variants in genes that might, for biological reasons, be expected to be involved in BP regulation or glucose homeostasis for association with hypertension or insulin resistance.The mineralocorticoid hormone, aldosterone, by determining the amount of sodium and water reabsorbed by the kidney, plays a key role in regulating BP (7). Indeed, mutations in the aldosterone synthase gene or in the receptor for the hormone can cause Mendelian forms of hypertension and hypotension ...

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“…13 Another study 14 demonstrated that aldosterone suppresses the expression of glucose transporters in avian animal colonic cells, whereas in human promonocytes aldosterone promotes down-regulation of the insulin receptor as well as reduced subcutaneous adipose tissue insulin receptor expression by approximately 54%. 15 Clinical studies have confirmed insulin resistance, evaluated through Homeostatic Model Assessment (HOMA), as well as impaired insulin-stimulated glucose utilization (measured by euglycaemic hyperinsulinaemic clamp) in PA patients but not in essential hypertensive individuals. 16 However, a study by Shamiss, also using clamp techniques, found increased insulin sensitivity in patients with PA, which adds to previous observations that pharmacologic treatment does not consistently result in improved glucose tolerance.…”

Section: Aldosterone Insulin Resistance and Adipose Tissue Raasmentioning

confidence: 99%

Role of aldosterone and angiotensin II in insulin resistance: an update

Lastra-Lastra

Sowers

Restrepo-Erazo

et al. 2009

Clinical Endocrinology

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SummaryThe role of the Renin-Angiotensin-Aldosterone system (RAAS) on the development of insulin resistance and cardiovascular disease is an area of growing interest. Most of the deleterious actions of the RAAS on insulin sensitivity appear to be mediated through activation of the Angiotensin II (Ang II) Receptor type 1 (AT 1 R) and increased production of mineralocorticoids. The underlying mechanisms leading to impaired insulin sensitivity remain to be fully elucidated, but involve increased production of reactive oxygen species and oxidative stress. Both experimental and clinical studies also implicate aldosterone in the development of insulin resistance, hypertension, endothelial dysfunction, cardiovascular tissue fibrosis, remodelling, inflammation and oxidative stress. There is abundant evidence linking aldosterone, through non-genomic actions, to defective intracellular insulin signalling, impaired glucose homeostasis and systemic insulin resistance not only in skeletal muscle and liver but also in cardiovascular tissue. Blockade of the different components of the RAAS, in particular Ang II and AT 1 R, results in attenuation of insulin resistance, glucose homeostasis, as well as decreased cardiovascular disease morbidity and mortality. These beneficial effects go beyond to those expected with isolated control of hypertension. This review focuses on the role of Ang II and aldosterone in the pathogenesis of insulin resistance, as well as in clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and cardiovascular disease.

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Inhibition by aldosterone of insulin receptor mRNA levels and insulin binding in U-937 human promonocytic cells

Cited by 27 publications

References 41 publications

Aldosterone impairs insulin responsiveness in U‐937 human promonocytic cells via the downregulation of its own receptor

Aldosterone impairs insulin responsiveness in U‐937 human promonocytic cells via the downregulation of its own receptor

Genetic variation in aldosterone synthase predicts plasma glucose levels

Role of aldosterone and angiotensin II in insulin resistance: an update

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