Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas

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Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas

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Gonzalez-Rodriguez A.,Institute of Biomedicine Alberto Sols CSIC UAM | Gonzalez-Rodriguez A.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Mas-Gutierrez J.A.,Rey Juan Carlos University | Mirasierra M.,Institute of Biomedicine Alberto Sols CSIC UAM | And 14 more authors.
Aging Cell | Year: 2012

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16months in PTP1B -/- mice maintained on mixed genetic background (C57Bl/6J×129Sv/J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16months, these parameters did not change with aging in PTP1B -/- mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1α were observed only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B -/- animals. Leanness in 16-month-old PTP1B -/- mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16-month-old control mice; however, studies with the hyperinsulinemic-euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.


Insenser M.,University of Alcalá | Insenser M.,Instituto Ramon Y Cajal Of Investigacion Sanitaria Irycis | Insenser M.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Montes-Nieto R.,University of Alcalá | And 8 more authors.
Molecular and Cellular Endocrinology | Year: 2013

Polycystic ovary syndrome (PCOS) is considered a complex multifactorial disorder resulting from the interaction of genetic, environmental, and lifestyle influences. Nontargeted proteomics and metabolomics have been used in the past years with the aim of identifying molecules potentially involved in the pathophysiology of this frequent disorder. The biomolecules identified so far participate in many metabolic pathways, including energy metabolism (glucose and lipid metabolism), protein metabolic processes and protein folding, cytoskeleton structure, immune response, inflammation and iron metabolism, fibrinolysis and thrombosis, oxidative stress and intracellular calcium metabolism. These molecules provide key information about molecular functions altered in PCOS and raise questions concerning their precise role in the pathogenesis of this syndrome. The biomolecules identified by nontargeted proteomic and metabolomic approaches should be considered as candidates in future studies aiming to define specific molecular phenotypes of PCOS. © 2013 Elsevier Ireland Ltd.


Calderon B.,Hospital Universitario Ramon y Cajal | Gomez-Martin J.M.,Hospital Universitario Ramon y Cajal | Vega-Pinero B.,Hospital Universitario Ramon y Cajal | Martin-Hidalgo A.,Hospital Universitario Ramon y Cajal | And 8 more authors.
Andrology | Year: 2016

To study the prevalence of male obesity-secondary hypogonadism (MOSH) in patients with moderate to severe obesity, we performed a prospective prevalence study including 100 male patients with moderate to severe obesity at a university tertiary hospital. Total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations among others were assayed in all patients. Serum-free testosterone (FT) concentration was calculated from TT and SHBG levels. Semen analysis was conducted in 31 patients. We found a prevalence of 45% (95% CI: 35-55%) when considering decreased TT and/or FT concentrations. Serum concentrations of TT were correlated negatively with glucose (r = -0.328, p < 0.001) and insulin resistance (r = -0.261, p = 0.011). The same occurred with FT and glucose (r = -0.340, p < 0.001) and insulin resistance (r = -0.246, p = 0.016). Sixty-two percent (95% CI: 39-85%) of the patients with seminogram also presented abnormal results in semen analysis. The frequencies of low TT or low FT values were similar in patients with abnormal or normal semen analysis (p = 0.646 and p = 0.346, respectively). Ejaculate volume inversely correlated with BMI (ρ = -0.400, p = 0.029) and with excess body weight (ρ = -0.464, p = 0.010). Our data show the prevalence of MOSH in patients with moderate to severe obesity is high. Low circulating testosterone is associated with insulin resistance and low ejaculate volume with higher BMI and excess body weight. Semen analysis must be performed in these patients when considering fertility whether or not presenting low circulating testosterone. © 2016 American Society of Andrology and European Academy of Andrology.


San-Millan J.L.,University of Alcalá | Escobar-Morreale H.F.,University of Alcalá | Escobar-Morreale H.F.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas
Clinical Endocrinology | Year: 2010

Objective To study the association of polymorphisms in the genes encoding peroxisome proliferator-activated receptors (PPARs) with the polycystic ovary syndrome (PCOS). Design Case-control study and meta-analysis of published evidence. Patients One hundred and sixty-one polycystic ovary syndrome patients and 113 non-hyperandrogenic women. Measurements Genotyping for PPAR-γ coactivator-1 gene (PPARGC1A) Gly482Ser, PPAR-α Leu162Val, PPAR-δ rs2267668A/G, PPAR-δ -87T/C, PPAR-γ2 Pro12Ala and PPAR-γ2 -681C/G variants and systematic review of the literature using the Entrez-PubMed search engine, followed by meta-analysis whenever possible. Results Polycystic ovary syndrome patients carried the Gly482Ser variant in PPARGC1A more frequently than controls (72% vs. 58%, χ2=5·54 P = 0·019), whereas carriers of the PPAR-α Leu162Val, PPAR-δ rs2267668A/G, PPAR-δ -87T/C, PPAR-γ2 Pro12Ala and PPAR-γ2 -681C/G variants were distributed similarly among both groups. The interaction between the PPARGC1A Gly482Ser and PPAR-δ -87T/C variants was also associated with PCOS (OR = 1·24, 95% CI 1·05-1·50, P = 0·008). The systematic review identified 31 studies addressing associations between PPARs variants and PCOS; meta-analysis was possible for nine studies focusing on the PPAR-γ2 Pro12Ala variant. Although the individual studies did not reveal any statistically significant association, meta-analysis uncovered that carrying the PPAR-γ2 Pro12Ala variant was associated with a reduced probability of having PCOS (OR = 0·77, 95% CI 0·61-0·96, P = 0·025), and that this association may be mediated by an effect on insulin sensitivity. Conclusions Common polymorphisms in the PPARGC1A, PPAR-δ and PPAR-γ2 loci are associated with PCOS. © 2010 Blackwell Publishing Ltd.


Murri M.,Obesity and Human Reproduction Research Group | Murri M.,University of Alcalá | Murri M.,Instituto Ramon Y Cajal Of Investigacion Sanitaria Irycis | Murri M.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | And 16 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: MicroRNAs (miRNAs) are small, noncoding RNA sequences that negatively regulate gene expression at the post-transcriptional level. miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 have been associated with metabolic disorders such as obesity and diabetes, which are also associated with polycystic ovary syndrome (PCOS). Objective: We aimed to evaluate the effects of sex, sex hormones, and PCOS and their interactions with obesity on the expression in the circulation of these miRNAs. Design: This was a case-control study. Settings: The setting was an academic hospital. Participants:Weincluded 12 controlwomen,12 patients with PCOS, and 12menselected as to have similar body mass index (BMI) and age. Six subjects per group had normal weight (BMI<25 kg/m2), and six subjects per group were obese (BMI ≥ 30 kg/m 2). Interventions: Blood samples were collected early in the morning after a 12-hour fast. Main Outcome Measures: We measured whole blood expression of miRNA-21, miRNA-27b, miRNA-103, and miRNA-155. Results: Obesity significantly reduced the expression of miRNA-21, miRNA-27b, and miRNA-103. However, there was a significant interaction between obesity and the group of subjects in the expression of miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 consisting of obesity reducing the expression of thesemiRNAsin controlwomanandmen,but tending to increase their expression in women with PCOS. These differences paralleled those observed in serum T concentrations. Conclusions: The present results suggest that miRNAs that play an important role in metabolic and immune system processes are influenced by obesity and circulating androgen concentrations. Copyright © 2013 by The Endocrine Society.


Ojeda-Ojeda M.,University of Alcalá | Ojeda-Ojeda M.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Martinez-Garcia M.A.,University of Alcalá | Martinez-Garcia M.A.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | And 6 more authors.
Journal of Reproductive Immunology | Year: 2016

Toll-like receptors (TLRs) are activated by inflammatory stimuli and influence endothelial functions, contributing to the pathogenesis of atherosclerosis. We investigate the influence of polymorphisms in the genes encoding toll-like receptor 2 (TLR2) and 4 (TLR4) and endothelial adhesion molecules on polycystic ovary syndrome (PCOS) and its interaction with obesity. Ten single nucleotide polymorphisms were genotyped in 305 women with PCOS and 166 non-hyperandrogenic control women. In obese women, TLR2 S450S and ICAM1 K469E polymorphisms differently influenced metabolic variables and PCOS, respectively. Irrespective of PCOS, variant alleles of TLR2 S450S increased triglycerides, fasting insulin levels, and insulin resistance in obese women. TLR2 S450S interacted with obesity and PCOS on androstenedione levels, mutant alleles were associated with increased androstenedione concentrations in all women, with the exception of obese patients with PCOS (P = 0.034). Regarding ICAM1 K469E, homozygosis for K469 alleles was more frequent in PCOS, but only in obese women (P = 0.014). K469 alleles were also related to increased body mass index (P = 0.017) and diastolic blood pressure (P = 0.034). Moreover, ICAM1 K469E interacted with obesity and PCOS on serum triglyceride levels (P = 0.019) and with PCOS on serum sex hormone-binding globulin concentrations (P = 0.006). In conclusion, TLR2 S450S and ICAM1 K469E polymorphisms may be associated with PCOS and metabolic comorbidities in obese women. © 2015 Elsevier Ireland Ltd.


Alvarez-Blasco F.,University of Alcalá | Alvarez-Blasco F.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Luque-Ramirez M.,University of Alcalá | Luque-Ramirez M.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | And 2 more authors.
Gynecological Endocrinology | Year: 2011

The polycystic ovary syndrome (PCOS) is a complex polygenic disorder in which environmental factors play an important modifying role. We aimed to find differences in diet and life-style that might contribute to the development of PCOS among overweight or obese premenopausal women. We compared diet composition and self-reported physical activity among 22 patients with PCOS and 59 women without androgen excess recruited from a total of 113 consecutive premenopausal women reporting for management of weight excess. After correcting for a difference in age between women with PCOS and controls, there were no overall statistical significant differences between them in the total caloric intake, in the intake of macro- and micro-nutrients, caffeine, fiber and alcohol, in the proportion of women exercising regularly, or in the number of hours of exercise per week. The proportion of fat in the diets of the overweight and obese women irrespective of PCOS was well-above current recommendations, yet this excessive fat intake occurred at the expense of monounsaturated fatty acids mostly. In conclusion, diet composition and physical activity were apparently not decisive for the development of PCOS among overweight and obese premenopausal women. © 2011 Informa UK, Ltd.


Insenser M.,University of Alcalá | Insenser M.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Montes-Nieto R.,University of Alcalá | Montes-Nieto R.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | And 10 more authors.
Molecular and Cellular Endocrinology | Year: 2012

Subcutaneous (SAT) and visceral adipose tissue (VAT) differ in biochemical and metabolic properties, especially when obesity is present. We submitted paired SAT and VAT samples from six morbidly obese patients and six non-obese persons to two-dimensional differential gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight mass spectrometry. Compared with non-obese subjects, obese patients presented with increased carboxylesterase-1, zinc finger protein 324A, annexin A5, ubiquitin carboxyl-terminal hydrolase, α-crystallin B chain, osteoglycin, retinal dehydrogenase-1 and 14-3-3 protein γ, and decreased transferrin, complement C3, fibrinogen γ chain, albumin, α1-antitrypsin and peroxiredoxin-6, irrespective of the adipose tissue depot studied. SAT and VAT differed in protein species of fibrinogen and osteoglycin, whereas adipose tissue depot and obesity interacted on the protein abundance of actin, α-actinin 1, one protein species of carboxylesterase-1, retinal dehydrogenase-1 and 14-3-3 protein γ Our nontargeted proteomic approach identified novel protein species that may be involved in the development of obesity in humans. © 2012 Elsevier Ireland Ltd.


Alpanes M.,University of Alcalá | Alpanes M.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Sanchon R.,University of Alcalá | Martinez-Garcia M.A.,University of Alcalá | And 4 more authors.
Clinical Endocrinology | Year: 2013

Objective The prevalence of asymptomatic hyperprolactinaemia has been widely studied in certain populations such as antipsychotic drugs users, infertile women or patients with primary hypothyroidism, but data on the prevalence of hyperprolactinaemia and macroprolactinaemia in the healthy population are very scarce in the literature. We aimed to obtain an unbiased estimation of the prevalence in premenopausal women of: (i) hyperprolactinaemia and (ii) its aetiology, including macroprolactinaemia and stress-related hyperprolactinaemia, while considering simultaneously the use of hormonal contraceptives. Design Prevalence survey. Subjects Three-hundred and ninety-three consecutive premenopausal women reporting spontaneously for blood donation. Measurements We performed an exhaustive clinical history and physical examination, establishing the presence of hirsutism, acne, alopecia, menstrual dysfunction and reproductive history. We also measured serum prolactin (PRL) (ruling out macroprolactinaemia when indicated), thyrotrophin, total testosterone, androstendione, sex hormone binding globulin and dehydroepiandrosterone sulphate concentrations. Results Serum PRL concentrations were increased in 16 of 393 women (4·1% prevalence, 95% CI: 2·1-6·0). The prevalence of macroprolactinaemia was 0·6% (95% CI: 0-1) in the total female blood donor population and was 12·5% (95% CI: 6-31) among hyperprolactinaemic patients. The remaining hyperprolactinaemic women had stress-related hyperprolactinaemia as the more likely aetiology. Finally, the frequency of hyperprolactinaemia was similar in users and nonusers of hormonal contraceptives (4·5% and 3·9% respectively, P = 0·209). Conclusions The prevalence of hyperprolactinaemia in healthy female blood donors is low and is not influenced by the use of hormonal contraceptives. Pathological causes are very rare with stress-related hyperprolactinaemia and macroprolactinaemia being the most frequent causes of hyperprolactinaemia in these women. © 2013 John Wiley & Sons Ltd.


Murri M.,University of Alcalá | Murri M.,Instituto Ramon Y Cajal Of Investigacion Sanitaria Irycis | Murri M.,Research Center Biomedica en Red Diabetes y Enfermedades Metabolicas Asociadas | Insenser M.,University of Alcalá | And 5 more authors.
Clinica Chimica Acta | Year: 2014

The association of androgen excess with abdominal adiposity, insulin resistance and metabolic derangements characterize many patients with PCOS. However, the mechanisms underlying these associations are not entirely understood, indicating the need for discovery of the origin of these metabolic alterations, and of new metabolic biomarkers for PCOS. This review summarizes the metabolites and metabolic pathways associated with PCOS according to recent metabolomic studies. PCOS-associated metabolites were involved mostly in carbohydrate, fat, and protein metabolism. Obesity, hyperinsulinemia and the intrinsic heterogeneity of PCOS are responsible of the metabolic variation observed in these women. Furthermore, treatment of PCOS seems to modify the levels of some metabolites. Hopefully, advances in the knowledge of metabolism will allow the detection of systemic imbalances in PCOS and will permit the identification of biomarkers that serve to predict the progression of the disease and its future complications. © 2013 Elsevier B.V.

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