Ana Alonso

University of Oviedo, Oviedo, Asturias, Spain

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Publications (44)126.77 Total impact

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    ABSTRACT: Menopause leads to a decrease in estrogen production that increases central insulin resistance, contributing to the development of neurodegenerative diseases. We have evaluated the influence of aging and estradiol or genistein treatments on some key stages of the insulin signaling pathway in the cerebral cortex. Young and aged female Wistar rats were ovariectomized and treated acutely with 17β-estradiol (1.4μg/kg body weight), two doses of genistein (10 or 40mg/kg body weight), or vehicle. The cortical expression of several key insulin signaling pathway components was analyzed by western blotting. Our results showed an age-related deterioration in the interactions between the regulatory subunit of phosphatidylinositol 3-kinase (p85α) and the activated form of insulin receptor substrate 1 (p-IRS1tyr612), as well as between p85α and the 46kDa isoform of the estrogen receptor α (ERα46). Moreover, aging also decreased the translocation of glucose transporter-4 (GLUT4) to the plasma membrane. 17β-estradiol but not genistein reduced the negative impact of aging on central insulin sensitivity by favoring this GLUT4 translocation, and therefore could be neuroprotective against the associated neurodegenerative diseases. However, protein kinase B (Akt) activation by genistein suggests other possible mechanisms are involved in the neuroprotective effects of this phytoestrogen during the aging process.
    Experimental gerontology. 07/2014;
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    Dataset: 2012 AJNR
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    ABSTRACT: Metabolic reprogramming strategies focus on the normalization of metabolism of cancer cells and constitute promising targets for cancer treatment. Here we demonstrate that the glucose transporter 4 (GLUT4) has a prominent role in basal glucose uptake in MCF7 and MDA-MB-231 breast cancer cells. We show that shRNA-mediated down-regulation of GLUT4 diminishes glucose uptake and induces metabolic reprogramming by reallocating metabolic flux to oxidative phosphorylation. This reallocation is reflected on an increased activity of the mitochondrial oxidation of pyruvate and lower lactate release. Altogether, GLUT4 inhibition compromises cell proliferation and critically affects cell viability under hypoxic conditions, providing proof-of-principle for the feasibility of using pharmacological approaches to inhibit GLUT4 in order to induce metabolic reprogramming in vivo in breast cancer models. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 06/2014; · 4.22 Impact Factor
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    ABSTRACT: The objective of this study was to assess the association between severe disc degeneration (DD) and low back pain (LBP). A case-control study was conducted with 304 subjects, aged 35-50, recruited in routine clinical practice across six hospitals; 240 cases (chronic LBP patients with a median pain duration of 46 months) and 64 controls (asymptomatic subjects without any lifetime history of significant LBP). The following variables were assessed once, using previously validated methods: gender, age, body mass index (BMI), lifetime smoking exposure, degree of physical activity, severity of LBP, disability, and findings on magnetic resonance (MRI) (disc degeneration, Modic changes (MC), disc protrusion/hernia, annular tears, spinal stenosis, and spondylolisthesis). Radiologists who interpreted MRI were blinded to the subjects' characteristics. A multivariate logistic regression model assessed the association between severe DD and chronic LBP, adjusting for gender, age, BMI, physical activity, MC, disc protrusion/hernia, and spinal stenosis. Severe DD at ≥1 level was found in 46.9 % of the controls and 65.8 % of the cases. Crude odds ratio (95 % CI), for suffering chronic LBP when having severe DD, was 2.06 (1.05; 4.06). After adjusting for "MC" and "disc protrusion/hernia," it was 1.81 (0.81; 4.05). The association between severe DD and LBP ceases to be significant when adjusted for MC and disc protrusion/hernia. These results do not support that DD as a major cause of chronic LBP.
    Neuroradiology 11/2013; · 2.70 Impact Factor
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    ABSTRACT: Estrogens are not only critical for sexual differentiation it is well-known for the role of 17β-estradiol (E2) in the adult brain modulating memory, learning, mood and acts as a neuroprotector. E2 exerts its actions through two classical receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). The distribution of both receptors changes from one brain area to another, E2 being able to modulate their expression. Among the classical features of aging in humans, we find cognitive impairment, dementia, memory loss, etc. As estrogen levels change with age, especially in females, it is important to know the effects of low E2 levels on ERα distribution; results from previous studies are controversial regarding this issue. In the present work, we have studied the effects of long-term E2 depletion as well as the ones of E2 treatment on ERα brain distribution of ovariectomized rats along aging in the diencephalon and in the telencephalon. We have found that ovariectomy causes downregulation and affects subcellular localization of ERα expression during aging, meanwhile prolonged estrogen treatment produces upregulation and overexpression of the receptor levels. Our results support the idea of the region-specific neuroprotection mechanisms mediated by estradiol.
    Age 06/2013; 35:821-837. · 6.28 Impact Factor
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    ABSTRACT: Aging is associated with decreased insulin sensitivity and impaired cerebral glucose homeostasis. These changes increase neural sensitivity to metabolic damage contributing to cognitive decline, being the decrease in plasma estrogen following menopause one of the main factors involved in aged females. Phytoestrogens as genistein are structurally similar to 17β-estradiol, bind to estrogen receptors, and can evoke both estrogenic and anti-estrogenic effects. Estrogens and phytoestrogens have neuroprotective potential, but the physiological mechanisms are not fully understood. Young and aged female Wistar rats were ovariectomized and treated acutely with 17β-estradiol (1.4μg/kg body weight), genistein (10 or 40mg/kg body weight), or vehicle. Cortical expression of glucose transporter-3 (GLUT-3) and -4 (GLUT-4), cytochrome c oxidase (CO), estrogen receptor-α (ERα) and -β (ERβ) was measured by Western blotting. There was an age-related decline in GLUT-4, CO and ERβ levels. Both drugs, estradiol and genistein, were able to reverse GLUT-3 downregulation in the cortex following late ovariectomy. However, genistein was the only treatment able to restore completely GLUT-4 levels in aged rats. In contrast, estradiol was more potent than genistein at increasing CO, a marker of cerebral oxidative metabolism. As regards ER levels, estradiol increased the ERα67 quantity diminished by late ovariectomy, while genistein did the same with the other ERα isoform, ERα46, highlighting drug-specific differences in expression changes for both isoforms. On the other hand, no treatment-related differences were found regarding ERβ levels. Therefore, genistein like estradiol could be suitable treatments against cortical metabolic dysfunction caused by aging. These treatments may hold promise as neuroprotective strategies against diabetes and age-related neurodegenerative diseases.
    Experimental gerontology 02/2013; · 3.34 Impact Factor
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    Article: Reply.
    American Journal of Neuroradiology 01/2013; 34(1):E9. · 3.17 Impact Factor
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    Spine 06/2012; 37(13):1184. · 2.16 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Data on the association between vertebral endplate changes and low back pain are contradictory. This study was designed to assess whether this association exists among Southern European subjects. MATERIALS AND METHODS: Patients in this study serving as cases were 35-50 years of age with low back pain lasting >90 days, for whom a lumbar MR imaging had been prescribed. Controls were subjects 35-50 years of age, having a cranial MR imaging for headache with normal findings, and no history of clinically relevant LBP. Two hundred forty cases and 64 controls were recruited consecutively in the radiology services across 6 cities in Spain. Imaging findings and subject characteristics were gathered through previously validated instruments. Radiologists who interpreted MRI were blinded to the subject characteristics. A multivariate logistic regression model was developed to assess the association of vertebral endplate changes with LBP, adjusting for sex, age, body mass index, lifetime exposure to smoking, physical activity, disk degeneration, and the interaction between disk degeneration and vertebral endplate changes. RESULTS: Vertebral endplate changes were found in 80.4% of the cases and in 87.5% of the controls. In the regression model, disk degeneration was the only variable showing a confounding effect. Results showed that after adjusting for disk degeneration, the presence of vertebral endplate changes is associated with the absence of chronic LBP (OR for LBP: 0.31; 95% CI, 0.10-0.95). CONCLUSIONS: In Southern European subjects, vertebral endplate changes are not associated with chronic LBP.
    American Journal of Neuroradiology 04/2012; 33(8):1519-1524. · 3.17 Impact Factor
  • Spine 04/2012; · 2.16 Impact Factor
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    Radiology 04/2012; 263(1):310-1. · 6.34 Impact Factor
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    ABSTRACT: To determine the involvement of physiological doses of oestradiol on brain lipid composition, we have analysed the lipid class and fatty acid composition of phospholipids in the brain from pregnant and 17β-oestradiol-treated rats. Rats were randomly divided into three groups: ovariectomised control (OVX + VEH), ovariectomised oestradiol-treated (OVX + E(2) ) and pregnant (PREG) rats. Rats from the OVX + E(2) group were injected daily with different doses of 17β-oestradiol mimicking the plasma levels observed during pregnancy. Analyses of brain lipid class composition showed that physiological doses of oestradiol increased cholesterol levels of the OVX + E(2) group compared to the OVX + VEH group. It was also found that cholesterol levels in the PREG group were significantly lower than in the OVX + VEH and OVX + E(2) groups, indicating the involvement of gestational hormones other than oestradiol in the regulation of brain cholesterol during pregnancy. Brains from pregnant rats also exhibited reduced levels of plasmalogens and saturated fatty acids compared to the ovariectomised groups, especially in the second half of pregnancy. Interestingly, analyses of fatty acid composition of phospholipids revealed that physiological doses of oestradiol increased brain docosahexaenoic acid (DHA; 22:6 n-3) levels. Moreover, DHA levels in pregnant rats were similar to those observed in the OVX + E(2) group at all stages, suggesting that oestradiol is the main hormone in the regulation of brain DHA levels during pregnancy. Liver appears to be the major source for n-3 and n-6 long chain polyunsaturated fatty acids (LCPUFAs) DHA and arachidonic acid, which are released and transported to the maternal brain and the developing foetus under the influence of oestrogens. We also observed that the largest depots of n-3 and n-6 LCPUFA precursors (linolenic acid and linoleic acid, respectively) occur in adipose tissue triglycerides, which, in turn are significantly increased during pregnancy. Our observations are in accordance with an oestradiol-induced increased bioavailability of brain DHA in pregnant rats. We hypothesise that the reduction of maternal brain DHA observed at the end of pregnancy is a result of the very high demand DHA of foetal brain, which overcomes the maximal maternal (and likely foetal) capacity for de novo DHA synthesis in the liver and brain.
    Journal of Neuroendocrinology 02/2012; 24(2):292-309. · 3.33 Impact Factor
  • Ana Alonso, Celestino Gonzalez
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    ABSTRACT: Postmenopausal women have an elevated risk of developing a neurodegenerative disease. These clinical observation supported by basic research, suggest that estrogens are neuroprotective. Insulin resistance represents an independent factor in the etiology of age-associated disease and metabolic syndrome should be considered as a contributing factor to the higher post-menopausal vulnerability to neurological disorders. Elucidating the relationship between insulin resistance associated with aging in females, and the cross-talk between estradiol, insulin, and insulin-like growth factor (IGF-1) signaling pathways, will lead to a more complete understanding of the mechanism underlying estradiol-mediated neuroprotection. In past decades, estrogen replacement therapy (ERT) was commonly used as a palliative therapy during menopause, but the mid-term and long-term effects of estrogen as possible promoters of breast cancer and the increased risk of coronary illness or stroke, has limited current usage. A deeper understanding of the molecular mechanisms common to all forms of neurodegenerative diseases may hasten the development of protective strategies against chronic age-related deterioration and acute illness, ultimately providing a better quality of life for the elderly.
    Frontiers in bioscience (Elite edition) 01/2012; 4:607-19.
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    ABSTRACT: Objective To investigate the effect of a soy isoflavone extract over insulin sensitivity and plasma leptin levels. Methods Eighty postmenopausal women were randomly assigned to participate for 24 months either to a physical exercise and Mediterranean diet program (Control group: CG) or this intervention plus a daily oral intake of a soy isoflavone extract (Soy isoflavone group: SIG). Anthropometry, body composition analysis, blood biochemistry, menopausal symptoms and health-related quality of life were assessed at baseline and every 6 months. Results Sixty-five women completed the protocol with no differences found among groups at baseline in age and time since the menopause. At month 24, body mass index (BMI) was lower in the SIG as compared to the CG. Fat mass, glucose, insulin, HOMA-IR, tumor necrosis factor-α (TNF-α), Kupperman Index and Cervantes Scale values significantly decreased in the SIG as compared to baseline and to CG values. Kupperman scores and serum TNF-α levels significantly decreased in both studied groups. No changes in plasma leptin levels were observed after 24 months within and between groups. When analysis was stratified according to BMI values, changes in the aforementioned parameters displayed a similar trend; however, the impact over glucose, insulin and HOMA-IR values was more evident among obese women assigned to the SIG. Conclusion Diet, physical exercise and a daily oral intake of soy isoflavones exerted a beneficial effect on the homeostatic model in postmenopausal women which was not related to significant changes in plasma leptin levels, despite a decrease in TNF-α, fat mass and Kupperman values.
    Climacteric 12/2011; · 1.96 Impact Factor
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    ABSTRACT: : Finding variables that predict decline or stability in persons with amnestic mild cognitive impairment (aMCI) is an important step in identifying subjects in prodromal stages of dementia. This study tests a clinical observation suggesting that aMCI cases with better-preserved recognition skills, despite similar delayed recall deficits, are more likely to remain functionally stable. : A cohort of 210 cases with aMCI, diagnosed with standardized criteria that had been followed up for 48 ± 12 months (range: 36-100), were divided into two groups according to their initial recognition memory discrimination index (DI) on the Hopkins Verbal Learning Test (DI ≥ or <8). We compared the two groups according to demographic and neuropsychological variables, cerebral small vessel disease, and outcome (progression to dementia versus stability as aMCI). : Thirty-seven percent progressed to dementia. In the group with the higher DI scores (n = 107), only 21.5% of the cases converted, compared with 52.4% of lower scorers (n = 103; Fisher's test: p < 0.0001). Progression to dementia occurred significantly later in cases with higher DI (50 ± 17 versus 26 ± 11 months in cases with impaired DI, Mann-Whitney test, U statistic = 1092.5, p < 0.0001). The group with lower DI showed a threefold-increased rate of progression to dementia. A multivariate regression model revealed DI, delayed recall, age, and family history of dementia as the strongest predictors of dementia, in this order. : The aMCI patients with better-preserved recognition at baseline have a more benign prognosis. Detection of these cases may aid in isolating other aMCI cases that are already in prodromal stages of AD and in selecting more homogeneous groups for clinical trials.
    The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 09/2011; 20(10):827-35. · 3.35 Impact Factor
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    ABSTRACT: Conflicting reports exist regarding the prevalence of Modic changes among low back pain (LBP) patients and factors associated with their existence. To assess the prevalence of Modic changes and other findings on lumbar magnetic resonance imaging (MRI) among Spanish adult chronic LBP patients and the patient characteristics and radiological findings associated with Modic changes. A cross-sectional imaging study among chronic LBP patients. Four hundred eighty-seven patients (263 women and 224 men) undergoing lumbar spine MRI examination for chronic LBP. Gender, age, body mass index (BMI), lifetime smoking exposure, degree of physical activity, and image features (disc degeneration, type and extension of Modic changes, disc contour, annular tears, spinal stenosis, and spondylolisthesis). Ten radiologists from six hospitals across six cities in Spain consecutively recruited adult patients in whom lumbar MRI had been prescribed for LBP lasting ≥3 months. Patients' characteristics and imaging findings were assessed through previously validated instruments. A multivariate logistic regression model was developed to assess the features associated with Modic changes. Modic changes were found in 81% of the patients. The most common was Type II (51.3%), affecting only the end plate. Variables associated with Type I changes were disc contour abnormalities, spondylolisthesis, and disc degeneration. The same variables were associated with a higher risk of Type II or any type of Modic changes, as well as being male, and having a higher BMI. Modic changes are found in 81% (95% confidence interval, 77-85) of adult Spanish patients in whom an MRI is prescribed for chronic LBP. Modic changes are more likely to be found in males with a high BMI, who also show disc contour abnormalities, spondylolisthesis, or disc degeneration.
    The spine journal: official journal of the North American Spine Society 05/2011; 11(5):402-11. · 2.90 Impact Factor
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    ABSTRACT: Evaluate the effect of diet, physical exercise, and a daily oral intake of a soy isoflavones extract (Fisiogen(®)) contained 200 mg of Glycine max, which corresponded to 80 mg of isoflavone (60.8 mg of genistein, 16 mg of daidzein and 3.2 mg of glicitein) on leptin and other adipokines plasma levels in healthy obese postmenopausal women. A multicentric randomized longitudinal prospective cohort study was conducted in a sample of 87 healthy obese postmenopausal women. Patients were randomly assigned to a 1200 kcal diet and exercise group (control group) or a group of 1200 kcal diet, exercise, and daily oral intake of daily oral intake of a soy isoflavones extract (Fisiogen(®)) contained 200 mg of Glycine max, which corresponded to 80 mg of isoflavone (60.8 mg of genistein, 16 mg of daidzein and 3.2 mg of glicitein) (soy isoflavones group) along 6 months. Main outcome measures were: anthropometric measures, body composition, leptin, adiponectin, TNF-alpha, homocysteine, C-reactive protein, glucose, insulin, lipid profile and oestradiol serum levels, Kupperman index and Cervantes Scale. Mean serum leptin and TNF-alpha levels declined after 6 months in both groups of the study, but only women in the soy isoflavones group showed a significant increase of mean serum levels of adiponectin. Diet, physical exercise and daily oral intake of a soy isoflavones extract (Fisiogen(®)) contained 200 mg of Glycine max, which corresponded to 80 mg of isoflavone (60.8 mg of genistein, 16 mg of daidzein and 3.2 mg of glicitein) have a beneficial effect on serum leptin, adiponectin and TNF-α in healthy obese postmenopausal women after 6 months of treatment.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 02/2011; 18(4):245-50. · 2.97 Impact Factor
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    ABSTRACT: Bifidobacterium animalis subsp. lactis IPLA R1 and Bifidobacterium longum IPLA E44 strains were tested for their safety and ability to modulate the intestinal microbiota in vivo. Chemically simulated gastrointestinal digestion showed considerably lower survival of E44 than R1 strain, the first microorganism also being more sensitive to refrigerated storage in 10% skimmed milk at 4°C. Harmful glycosidic activities were absent, or at low levels, in the strains R1 and E44. Both strains were sensitive to most antibiotics and resistant to aminoglycosides, a common feature in bifidobacteria. Similar to several other bifidobacteria strains, B. animalis subsp. lactis IPLA R1 displayed a moderate resistance against tetracycline which correlated with the presence of tet(W) gene in its genome. The general parameters indicating well-being status, as well as translocation to different organs and histological examination of the gut tissues, revealed no changes induced by the administration of bifidobacteria to rats. Twelve-week-old male Wistar rats were distributed into three groups, eight rats in each. Two groups were administered daily over 10⁸cfu of the corresponding strain suspended in 10% skimmed milk for 24 days, whereas rats in the placebo group received skimmed milk without microorganisms added. The microbiota and short chain fatty acids (SCFA) were monitored in faeces at different time points during treatment and in caecum content at the end of the assay. Quantitative PCR (qPCR) showed that faecal and caecal Bifidobacterium levels were higher in bifidobacteria-fed rats than in the placebo rats at the end of the intervention, whereas total anaerobic plate counts did not show significant differences. Quantification of B. animalis and B. longum by qPCR showed that, independent of the microorganism administered, treatment with bifidobacteria resulted in higher levels of B. animalis in the caecum. PCR-DGGE analysis of microbial populations revealed a higher diversity of bands in caecum content of rats fed B. animalis IPLA R1 than in the placebo group and rats fed B. longum IPLA E44. Remarkably, although no variations in the proportion of acetate, propionate and butyrate were found, at the end of the assay the total SCFA concentration in the faeces of rats fed bifidobacteria was significantly higher and those in caecum content significantly lower, than that of the placebo group. This suggests a displacement of the SCFA production to parts of the colon beyond the caecum in rats receiving bifidobacteria. Therefore, the oral administration of B. animalis IPLA R1 and B. longum E44 can be considered safe, these microorganisms having the ability to modulate the intestinal microbiota of rats by influencing SCFA and the bifidobacterial population levels.
    International journal of food microbiology 11/2010; 144(3):342-51. · 3.01 Impact Factor
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    ABSTRACT: Aging is characterized by decline in metabolic function and insulin resistance, and both seem to be in the basis of neurodegenerative diseases and cognitive dysfunction. Estrogens prevent age-related changes, and phytoestrogens influence learning and memory. Our hypothesis was that estradiol and genistein, using rapid-action mechanisms, are able to modify insulin sensitivity, process of learning, and spatial memory. Young and aged ovariectomized rats received acute treatment with estradiol or genistein. Aged animals were more insulin-resistant than young. In each age, estradiol and genistein-treated animals were less insulin-resistant than the others, except in the case of young animals treated with high doses of genistein. In aged rats, no differences between groups were found in spatial memory test, showing a poor performance in the water maze task. However, young females treated with estradiol or high doses of genistein performed well in spatial memory task like the control group. Only rats treated with high doses of genistein showed an optimal spatial memory similar to the control group. Conversely, acute treatment with high doses of phytoestrogens improved spatial memory consolidation only in young rats, supporting the critical period hypothesis for the beneficial effects of estrogens on memory. Therefore, genistein treatment seems to be suitable treatment in aged rats in order to prevent insulin resistance but not memory decline associated with aging. Acute genistein treatment is not effective to restore insulin resistance associated to the early loss of ovarian function, although it can be useful to improve memory deficits in this condition.
    Age 05/2010; 32(4):421-34. · 6.28 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate whether a standard dose of 40 mg of soy isoflavones prescribed in routine clinical practice for treatment of menopausal symptoms has some influence on glucose homeostasis in postmenopausal women with insulin resistance (IR). A total of 116 postmenopausal women with IR were randomly assigned to a group of Mediterranean diet and physical exercise (control group) or a group of Mediterranean diet, physical exercise, and daily oral ingestion of 40 mg of soy isoflavones (soy isoflavones group). Anthropometric measures, Kupperman Index values, Cervantes Scale score, and blood samples for glucose, insulin, lipid profile, creatinine, uric acid, homocysteine, folic acid, vitamin B12, selenium, and estradiol were determined at baseline and at intervals of 6, 12, 18, and 24 months. Mean homeostasis model assessment of IR (HOMA-IR) values remained unchanged from the baseline in the control group but steadily decreased in the soy isoflavones group at 6 months (P = 0.042). There were no statistically significant differences between both groups in mean HOMA-IR scores at baseline, but statistically significantly lower values were found in the soy isoflavones group at 6 months (P = 0.009), 12 months (P = 0.011), 18 months (P = 0.018), and 24 months (P = 0.012). Changes in HOMA-IR values were also clearly related to body mass index (P < 0.001), abdominal circumference (P < 0.001), and treatment (P = 0.044) when a linear regression analysis was carried out. Daily intake of 40 mg of soy isoflavones together with a Mediterranean diet and exercise reduced IR in postmenopausal women who had IR in the first place. It was significantly better than lifestyle changes alone. If corroborated, this may be a useful intervention for these women.
    Menopause (New York, N.Y.) 03/2010; 17(2):372-8. · 3.08 Impact Factor

Publication Stats

383 Citations
126.77 Total Impact Points

Institutions

  • 2000–2012
    • University of Oviedo
      • • Department of Functional Biology
      • • Department of Cell Biology and Morphology
      Oviedo, Asturias, Spain
  • 2011
    • Fundación Jiménez Díaz
      Madrid, Madrid, Spain
    • Instituto Valenciano de Oncologia
      Valenza, Valencia, Spain
  • 2008–2011
    • Hospital Universitario Central de Asturias
      Oviedo, Asturias, Spain