Publications by authors named "Sonsoles Morcillo"

48 Publications

Impact of Tumor Methylation Level and Neoadjuvant Treatment and Its Association with Colorectal Cancer Survival.

J Pers Med 2020 Nov 11;10(4). Epub 2020 Nov 11.

Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, 29016 Malaga, Spain.

Recent studies suggest that long-interspersed nucleotide element-1 () hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect methylation. Thus, the aim of this study was to assess the prognostic value of tumor methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor methylation, as well as pathological and oncological variables. We also studied the association between methylation and pathological features, and finally, we assessed the overall and disease-free survival of methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area ( < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated tumors than those with normal methylation ( = 0.004 and 0.0049, respectively). Indeed, was hypermethylated more in the treated patients than in the non-treated patients ( < 0.05). The present study showed that tumor hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.
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http://dx.doi.org/10.3390/jpm10040219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712476PMC
November 2020

Relationship between environmental temperature and the diagnosis and treatment of gestational diabetes mellitus: An observational retrospective study.

Sci Total Environ 2020 Nov 16;744:140994. Epub 2020 Jul 16.

Department of Endocrinology and Nutrition, Virgen de la Victoria Universitary Hospital, Malaga, Spain.

Introduction: Environmental temperature has been described to affect plasma glucose levels after oral glucose tolerance testing (OGTT).

Aims: We evaluated the relationship between seasons and environmental temperature and gestational diabetes mellitus (GDM) diagnosis and treatment.

Methods: We analyzed data from 2374 women retrospectively. GDM was diagnosed in 473 patients by a 100-g OGTT. OGTT results and needing of insulin therapy were evaluated in relation to seasons and environmental temperature (mean temperature and temperature change) the day of the OGTT and the preceding 14 and 28 days.

Results: We found significant seasonal differences in the percentage of GDM: 24.4% in summer vs. 15.6% in autumn (p < 0.01). The odds ratio (OR) for being diagnosed with GDM was 1.78 in summer relative to autumn, after controlling for age. A higher mean temperature the day of the OGTT and the preceding 14 and 28 days increased the risk of being diagnosed with GDM the months in which temperature was rising (March-August) but not the months in which temperature was decreasing (September-February). We observed a negative correlation between temperature and fasting glucose and a positive correlation with post-load glucose. Neither the season nor the environmental temperature affected the risk of requiring insulin therapy.

Conclusions: There is a higher prevalence of GDM diagnosis at warmer seasons and at rising temperatures the 2-4 weeks prior to the OGTT. The impact of temperature is different between fasting and post-load glucose.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140994DOI Listing
November 2020

Association between variation of circulating 25-OH vitamin D and methylation of secreted frizzled-related protein 2 in colorectal cancer.

Clin Epigenetics 2020 06 9;12(1):83. Epub 2020 Jun 9.

Deparment of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA) and University of Malaga, Malaga, Spain.

Backgrounds: Colorectal cancer (CRC) results from the accumulation of epigenetic and genetic changes in colon cells during neoplasic transformation, which the activation of Wingless (Wnt) signaling pathway is a common mechanism for CRC initiation. The Wnt pathway is mainly regulated by Wnt antagonists, as secreted frizzled-related protein (SFRP) family. Indeed, SFRP2 is proposed as a noninvasive biomarker for CRC diagnosis. Vitamin D also antagonizes Wnt signaling in colon cancers cells. Several studies showed that vitamin D was able to alter DNA methylation, although this mechanism is not yet clear. Therefore, the aim of this study was to find an association between circulating 25-OH vitamin D (30th percentile of vitamin D) and the SFRP2 methylation.

Methods: A total of 67 CRC patients were included in the study. These patients were subdivided into two groups based on their 30th percentile vitamin D (20 patients were below, and 47 participants were above the 30th percentile of vitamin D). We investigated the SFRP2 methylation in peripheral blood mononuclear cells (PBMCs), visceral adipose tissue (VAT), CRC tumor tissue, and adjacent tumor-free area. We also determined the relationship between SFRP2 methylation and methylation of carcinogenic and adipogenic genes. Finally, we tested the effect of vitamin D on the SFRP2 methylation in human colorectal carcinoma cell lines 116 (HCT116) and studied the association of neoadjuvant therapy under the 30th percentile vitamin D with SFRP2 promoter methylation.

Results: SFRP2 methylation in tumor area was decreased in patients who had higher levels of vitamin D. SFRP2 promoter methylation was positively correlated in tumor area with insulin and homeostasis model assessment of insulin resistance (HOMA-IR) but negatively correlated with HDL-c. SFRP2 methylation was also correlated with T cell lymphoma invasion and metastasis 1 (TIAM1) methylation in tumor area and CCAAT/enhancer-binding protein alpha (C/EBPα) in VAT. Treatment with vitamin D did not affect SFRP2 methylation in HCT116 cell line. Finally, neoadjuvant treatment was correlated with higher circulating 25-OH vitamin D and SFRP2 methylation under linear regression model.

Conclusion: Our results showed that higher circulating vitamin D is associated with low SFRP2 promoter methylation. Therefore, our results could suggest that vitamin D may have an epigenetic effect on DNA methylation. Finally, higher vitamin D could contribute to an improvement response to neoadjuvant treatment.
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http://dx.doi.org/10.1186/s13148-020-00875-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285750PMC
June 2020

Association between the rs3813627 Single Nucleotide Polymorphism and HDL and APOA1 Levels Through BMI.

Biomedicines 2020 Feb 27;8(3). Epub 2020 Feb 27.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain.

The interaction between obesity and genetic traits on high density lipoprotein (HDL) levels has been extensively studied. The variance of serum HDL has a strong genetic heritability, although the studied variant only explains a small part of this variation. The goal of this study was to investigate the associations between the apolipoprotein type 2 ( rs3813627 single nucleotide polymorphism (SNP) and anthropometric and biochemical variables, though body mass index (BMI). This study included 153 subjects (91 overweight/obese (BMI³25 kg/m) and 62 non-obese individuals (BMI < 25 kg/m)). The rs3813627 SNP was selected and genotyped. Genotype analysis was performed to analyze the associations between SNPs and anthropometric and biochemical variables through BMI. The rs3813627 TT genotype was associated with low HDL levels in comparison with the rs3813627 GG and GT genotype in overweight/obese individuals, but not in the non-obese subjects ( < 0.05). The same trend was observed in the apolipoprotein type 1 (APOA1) protein levels ( < 0.05). Correlation analysis revealed a negative correlation between HDL and APOA1 levels and rs3813627 SNP under recessive model ( < 0.05). The odds ratio for low HDL levels was 3.76 and 3.94 for low APOA1 levels. The mediation analysis of rs3813627 SNP through BMI showed a full mediation on HDL and partial mediation on APOA1 levels ( < 0.05). Bioinformatic analysis showed that rs3813627 lies in the promoter and overlaps motifs for several bound transcription factors. : On the basis of these data, the rs3813627 SNP is associated with low HDL and APOA1 levels susceptibility, and this effect was mediated by an increased BMI.
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http://dx.doi.org/10.3390/biomedicines8030044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148512PMC
February 2020

The Expression/Methylation Profile of Adipogenic and Inflammatory Transcription Factors in Adipose Tissue Are Linked to Obesity-Related Colorectal Cancer.

Cancers (Basel) 2019 Oct 24;11(11). Epub 2019 Oct 24.

Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, University of Malaga (IBIMA), 29010 Málaga, Spain.

Obesity is well accepted as crucial risk factor that plays a critical role in the initiation and progression of colorectal cancer (CRC). More specifically, visceral adipose tissue (VAT) in people with obesity could produce chronic inflammation and an altered profile expression of key transcription factors that promote a favorable microenvironment to colorectal carcinogenesis. For this, the aim of this study was to explore the relationship between adipogenic and inflammatory transcription factors in VAT from nonobese, obese, and/or CRC patients. To test this idea, we studied the expression and methylation of CCAAT-enhancer binding protein type alpha (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in VAT from non-obese control, non-obese CRC subjects, overweight/obese control, and overweight/obese CRC patients and their correlation with anthropometric and biochemical variables. We found decreased expression of C/EBP-α in overweight/obese CRC patients in comparison with overweight/obese control subjects. PGC-1α and NF-κB were overexpressed in CRC patients independently of the BMI. NF-κB promoter was hypomethylated in overweight/obese CRC patients when compared to overweight/obese control individuals. In addition, multiple significant correlations between expression, methylation, and biochemical parameters were found. Finally, linear regression analysis showed that the expression of C/EBP-α and NF-κB and that NF-κB methylation were associated with CRC and able to explain up to 55% of CRC variability. Our results suggest that visceral adipose tissue may be a key factor in tumor development and inflammatory state. We propose C/EBP-α, PGC-1α and NF-κB to be interesting candidates as potential biomarkers in adipose tissue for CRC patients.
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http://dx.doi.org/10.3390/cancers11111629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893417PMC
October 2019

Novel DNA Methylation Profile Following Neoadjuvant Therapy in Colorectal Cancer Patients with Different Grades of BMI.

J Clin Med 2019 Jul 17;8(7). Epub 2019 Jul 17.

Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, University of Malaga (IBIMA), 29010 Málaga, Spain.

The relationship between body weight and different cancers is now well-recognized and among such cancers, colorectal cancer (CRC) is reported most frequently. Our group recently published findings, through an epigenome-wide association study, suggesting that body mass index (BMI) could act as a relevant risk factor in the CRC. In addition, aberrant methylation is one of the major mechanisms for Wnt signaling activation in CRC. Conversely, neoadjuvant chemo-radiotherapy appears to alter the rectal cancer epigenome. This study was aimed to evaluate the effect of obesity, measured by BMI, on the methylation of in tumor samples of patients with CRC. Non-treated CRC patients and CRC patients treated with pre-operative neoadjuvant therapy from 2011 to 2013 were included and classified by BMI < 25.0 kg/m and BMI > 25.0 kg/m. DNA methylation in tumor samples was measured by pyrosequencing. Our findings suggest a possible interaction between methylation levels and BMI in CRC tumor samples. The correlation of hypomethylation with an elevated BMI was stronger within the non-treated CRC patient group than within the treated CRC patient group. We have successfully demonstrated that the beneficial association of tumor hypomethylation is dependent on patient BMI in non-treated CRC, suggesting a possible tumor suppressor role for in overweight and obese patients. Additional studies of clinical pathologies would be necessary to strengthen these preliminary results.
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http://dx.doi.org/10.3390/jcm8071041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678889PMC
July 2019

Association between serum 25-hydroxyvitamin D and global DNA methylation in visceral adipose tissue from colorectal cancer patients.

BMC Cancer 2019 Jan 21;19(1):93. Epub 2019 Jan 21.

Unidad de Gestión Clínica Endocrinología y Nutrición. Instituto de Investigación Biomédica de Málaga (IBIMA), Complejo Hospitalario de Málaga (Virgen de la Victoria) Málaga (Spain). CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Málaga, Spain.

Background: Visceral adipose tissue (VAT) has been identified as the essential fat depot for pathogenetic theories that associateobesity and colon cancer. LINE-1 hypomethylation has been mostly detected in tumor colon tissue, but less is known about the epigenetic pattern in surrounding tissues. The aim was to analyze for the first time the potential relationship between serum vitamin D, obesity and global methylation (LINE-1) in the visceral adipose tissue (VAT) from patients with and without colorectal cancer.

Methods: A total of 55 patients with colorectal cancer and 35 control subjects participated in the study. LINE-1 DNA methylation in VAT was measured by pyrosequencing. Serum 25(OH)D levels were determined by ELISA.

Results: Cancer patients had lower levels of LINE-1 methylation in VAT compared with the control group. In the subjects with colorectal cancer, LINE-1 DNA methylation levels were associated positively with vitamin D levels (r = 0,463; p < 0.001) and negatively with BMI (r = - 0.334, p = 0.01) and HOMA insulin resistance index (r = - 0.348, p = 0.01). Serum vitamin D was the main variable explaining the LINE-1% variance in the cancer group (β = 0.460, p < 0.001). In a multivariate analysis, subjects with higher LINE-1 methylation values had lower risk of developing colorectal cancer (OR = 0.53; IC95% =0.28-0.99) compared with the control group.

Conclusions: We showed for the first time an association between LINE-1 DNA methylation in VAT and vitamin D levels in subjects with colorectal cancer, highlighting the importance of VAT from cancer patients, which could be modified epigenetically compared to healthy subjects.
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http://dx.doi.org/10.1186/s12885-018-5226-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341579PMC
January 2019

Altered Adipose Tissue DNA Methylation Status in Metabolic Syndrome: Relationships Between Global DNA Methylation and Specific Methylation at Adipogenic, Lipid Metabolism and Inflammatory Candidate Genes and Metabolic Variables.

J Clin Med 2019 Jan 13;8(1). Epub 2019 Jan 13.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain.

Metabolic syndrome (MetS) has been postulated to increase the risk for type 2 diabetes, cardiovascular disease and cancer. Adipose tissue (AT) plays an important role in metabolic homeostasis, and AT dysfunction has an active role in metabolic diseases. MetS is closely related to lifestyle and environmental factors. Epigenetics has emerged as an interesting landscape to evaluate the possible interconnection between AT and metabolic disease, since it can be modulated by environmental factors and metabolic status. The aim of this study was to determine whether MetS has an impact on the global DNA methylation pattern and the DNA methylation of several genes related to adipogenesis (PPARG, PPARA), lipid metabolism (RXRA, SREBF2, SREBF1, SCD, LPL, LXRb), and inflammation (LRP1 C3, LEP and TNF) in visceral adipose tissue. LPL and TNF DNA methylation values were significantly different in the control-case comparisons, with higher and lower methylation respectively in the MetS group. Negative correlations were found between global DNA methylation (measured by LINE-1 methylation levels) and the metabolic deterioration and glucose levels. There were associations among variables of MetS, BMI, and HOMA-IR with DNA methylation at several CpG positions for the studied genes. In particular, there was a strong positive association between serum triglyceride levels (TG) with PPARA and LPL methylation levels. TNF methylation was negatively associated with the metabolic worsening and could be an important factor in preventing MetS occurrence according to logistic regression analysis. Therefore, global DNA methylation and methylation at specific genes related to adipogenesis, lipid metabolism and inflammation are related to the etiology of MetS and might explain in part some of the features associated to metabolic disorders.
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http://dx.doi.org/10.3390/jcm8010087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352101PMC
January 2019

Decreased blood pressure is related to changes in NF-kB promoter methylation levels after bariatric surgery.

Surg Obes Relat Dis 2018 Sep 23;14(9):1327-1334. Epub 2018 Jun 23.

Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Clínico Virgen de la Victoria, Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Málaga, Spain.

Background: Obesity is characterized by a chronic, low-grade inflammation, and bariatric surgery is proposed as an effective treatment for reducing the obesity-related co-morbidities. Epigenetic modifications could be involved in the metabolic improvement after surgery.

Objective: The main aim of this study was to evaluate whether DNA methylation pattern from genes related to inflammation and insulin response is associated with the metabolic improvement after bariatric surgery in morbidly obese patients and if these changes depend on the surgical procedure.

Setting: University hospital, Spain.

Methods: We studied 60 severely obese patients; 31 underwent Roux-en-Y gastric bypass and 29 underwent laparoscopic sleeve gastrectomy. All patients were examined before and at 6 months after bariatric surgery. DNA methylation profile of genes related to the inflammatory response and insulin sensitivity was measured by pyrosequencing.

Results: The promoter methylation levels of the NFKB1 gene were increased significantly after surgery (2.16 ± .9 versus 2.8 ± 1.03). The decrease in blood pressure, both systolic and diastolic, after surgery was significantly associated with the changes in the promoter methylation levels of the NFKB1 gene (β = -.513, P = .003 and β = -.543, P = .004, respectively). A decrease in inflammation status, measured by high sensitivity C-reactive protein values, was associated with changes in SLC19A1 methylation levels.

Conclusion: Our study shows for the first time an association between NFKB1 methylation levels and blood pressure after bariatric surgery, highlighting the possible function of this gene in the regulation of arterial pressure. Regarding SLC19A1, this gene could position as a potential target linking inflammation and insulin resistance.
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http://dx.doi.org/10.1016/j.soard.2018.06.011DOI Listing
September 2018

Adipose tissue inflammation and expression and methylation in colorectal cancer.

Clin Epigenetics 2018 25;10:60. Epub 2018 Apr 25.

11Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.

Background: Lack of vitamin D (VD) has been associated with colorectal cancer (CRC). VD has anti-inflammatory effects and regulates several cellular pathways by means of its receptor, including epigenetic modifications. Adipose tissue dysfunction has been related to low-grade inflammation, which is related to diseases like cancer. The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D (25(OH)D), adipose tissue gene expression of VD receptor (VDR), pro-inflammatory markers, and the epigenetic factor DNA methyltransferase 3a (DNMT3A) as well as VDR promoter methylation in CRC.

Methods: Blood and visceral adipose tissue from 57 CRC and 50 healthy control subjects were collected. CRC subjects had lower serum 25(OH)D levels and higher VDR gene expression, and these were negatively correlated in the CRC group.

Results: Adipose tissue , , and gene expression were higher in the CRC subjects than in the control subjects. 25(OH)D correlated negatively with and CRP. In turn, CRP correlated positively with , , , and gene expression as well as that correlated positively with and . mRNA was negatively correlated with serum 25(OH)D and positively correlated with DNA methylation. DNA methylation at position 4 had lower levels in the CRC group. Global methylation at dinucleotide 3 was lower in the CRC group.

Conclusion: Our results suggest that adipose tissue may be a key factor in CRC development. The low 25(OH)D levels and high adipose tissue expression in CRC may, at least in part, mediate this relationship by modifying adipose tissue DNA methylation and promoting inflammation.
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http://dx.doi.org/10.1186/s13148-018-0493-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921388PMC
May 2019

Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis.

Int J Obes (Lond) 2019 01 1;43(1):176-188. Epub 2018 May 1.

CIBERobn Fisiopatologia de la Nutricion y Obesidad (CB06/03), Madrid, Spain.

Background: Obesity was established as a relevant modifiable risk factor in the onset and progression of colorectal cancer (CRC). This relationship could be mediated by an epigenetic regulation.

Objectives: The current work aimed to explore the effects of excess body weight on the DNA methylation profile of CRC using a genome-wide DNA methylation approach and to identify an epigenetic signature of obesity-related CRC.

Methods: Fifty-six CRC-diagnosed patients (50 years) were included in the study and categorized according to their body mass index (BMI) as non-obese (BMI ≤ 25 kg/m) or overweight/obese (BMI > 25 kg/m). Data from Infinium 450k array-based methylomes of 28 CRC tumor samples were coupled with information on BMI categories. Additionally, DNA methylation results were validated in 28 CRC tumor samples.

Results: The analysis revealed statistically significant differences at 299 CpG sites, and they were mostly characterized as changes towards CpG hypermethylation occurring in the obese group. The 152 identified genes were involved in inflammatory and metabolic functional processes. Among these genes, novel genes were identified as epigenetically regulated in CRC depending on adiposity. ZNF397OS and ZNF543 represented the top scoring associated events that were further validated in an independent cohort and exhibited strong correlation with BMI and excellent and statistically significant efficiency in the discrimination of obese from non-obese CRC patients (area under the curve >0.80; p < 0.05).

Conclusions: The present study identifies a potential epigenome mark of obesity-related CRC that could be useful for precision medicine in the management of this disease taking into account adiposity as a relevant risk factor.
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http://dx.doi.org/10.1038/s41366-018-0065-6DOI Listing
January 2019

The Effect of Metabolic and Bariatric Surgery on DNA Methylation Patterns.

Curr Atheroscler Rep 2017 Aug 30;19(10):40. Epub 2017 Aug 30.

Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Clínico Virgen de la Victoria, Málaga, Spain.

Purpose Of Review: Metabolic and bariatric surgery (MBS) is considered to be the most effective treatment for obesity. Not only due to the significant weight reduction but also because of the many health benefits associated with it. In the last 5 years, several studies have suggested that epigenetic modifications could be involved in the mechanisms underlying the response to bariatric surgery. In this review, we will compile the different studies (2012-2017) concerning the effect of this surgical procedure on DNA methylation patterns (the most studied epigenetic marker) and its association with metabolic improvement. This is an emerging area, and currently, there are not many studies in the literature. The aim is to show what has been done so far and what the future direction in this emerging area might be.

Recent Findings: Recent findings have shown how metabolic and bariatric surgery modifies the DNA methylation profile of the specific genes associated with the pathophysiology of the disease. The studies were performed in morbidly obese subjects, mainly in women, with the aim of reducing weight and improving the obesity-associated comorbidities. DNA methylation has been measured both in specific tissue and in peripheral blood samples. In general, studies about site-specific DNA methylation have shown a change in the methylation profile after surgery, whereas the studies analyzing global DNA methylation are not so conclusive. Summing up, metabolic and bariatric surgery can modify the DNA methylation profile of different genes and contributes to the metabolic health benefits that are often seen after metabolic and bariatric surgery. Although there are still many issues to be resolved, the capacity to revert the DNA methylation profile of specific sites opens a window for searching for target markers to treat obesity-related comorbidities.
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http://dx.doi.org/10.1007/s11883-017-0676-8DOI Listing
August 2017

Changes in SCD gene DNA methylation after bariatric surgery in morbidly obese patients are associated with free fatty acids.

Sci Rep 2017 04 10;7:46292. Epub 2017 Apr 10.

CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Málaga, Spain.

Stearoyl CoA Desaturase-1 (SCD) is considered as playing an important role in the explanation of obesity. The aim of this study was to evaluate whether the DNA methylation SCD gene promoter is associated with the metabolic improvement in morbidly obese patients after bariatric surgery. The study included 120 subjects with morbid obesity who underwent a laparoscopic Roux-en Y gastric by-pass (RYGB) and a control group of 30 obese subjects with a similar body mass index (BMI) to that found in morbidly obese subjects six months after RYGB. Fasting blood samples were obtained before and at six months after RYGB. DNA methylation was measured by pyrosequencing technology. DNA methylation levels of the SCD gene promoter were lower in morbidly obese subjects before bariatric surgery but increased after RYGB to levels similar to those found in the control group. Changes of DNA methylation SCD gene were associated with the changes of free fatty acids levels (r = -0.442, p = 0.006) and HOMA-IR (r = -0.249, p = 0.035) after surgery. RYGB produces an increase in the low SCD methylation promoter levels found in morbidly obese subjects. This change of SCD methylation levels is associated with changes in FFA and HOMA-IR.
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http://dx.doi.org/10.1038/srep46292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385880PMC
April 2017

The role of vitamin D and VDR in carcinogenesis: Through epidemiology and basic sciences.

J Steroid Biochem Mol Biol 2017 03 30;167:203-218. Epub 2016 Nov 30.

Unidad de Gestiòn Clìnica y Endocrinologìa y Nutriciòn, Instituto de Investigaciòn Biomèdica de Màlaga (IBIMA),Complejo Hospitalario de Màlaga (Virgen de la Victoria), Universidad de Màlaga, 29010 Malaga, Spain; CIBER Pathophysiology of Obesity and Nutrition (CB06/03),Instituto Salud Carlos III, 28029 Madrid, Spain. Electronic address:

In the last two decades vitamin D (VD) research has demonstrated new extraskeletal actions of this pre-hormone, suggesting a protective role of this secosteroid in the onset, progression and prognosis of several chronic noncommunicable diseases, such as cardiovascular disease, diabetes mellitus or cancer. Regarding carcinogenesis, both preclinical and epidemiological evidence available show oncoprotective actions of VD and its receptor, the VDR. However, in late neoplastic stages the VD system (VDS) seems to be less functional, which appears to be due to an epigenetic silencing of the system. In preclinical experimental studies, VD presents oncoprotective actions through modulation of inflammation, cell proliferation, cell differentiation, angiogenesis, invasive and metastatic potential, apoptosis, miRNA expression regulation and modulation of the Hedgehog signalling pathway. Moreover, epidemiological evidence points towards an oncoprotective role of vitamin D and VDR in colorectal cancer. This association is more controversial with breast, ovarian and prostate cancers, although with a few adverse effects. Nonetheless, we should consider other factors to determine the benefit of increased serum concentration of VD. Much of the epidemiological evidence is still inconclusive, and we will have to wait for new, better-designed ongoing RCTs and their results to discern the real effect of vitamin D in cancer risk reduction and therapy. The objective of this literature review is to offer an up-to-date analysis of the role of the VD and VDR, in the onset, progression and prognosis of all types of cancer. We further discuss the available literature and suggest new hypotheses and future challenges in the field of VD research.
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http://dx.doi.org/10.1016/j.jsbmb.2016.11.020DOI Listing
March 2017

Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.

Diabetes 2016 10 14;65(10):3200-11. Epub 2016 Jul 14.

Cardiovascular Health Research Unit, University of Washington, Seattle, WA Department of Biostatistics, University of Washington, Seattle, WA.

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
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http://dx.doi.org/10.2337/db16-0199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033262PMC
October 2016

Methylation patterns of Vegfb promoter are associated with gene and protein expression levels: the effects of dietary fatty acids.

Eur J Nutr 2017 Mar 26;56(2):715-726. Epub 2015 Dec 26.

UGC Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, Málaga, Spain.

Purpose: We have investigated the epigenetic regulation by dietary fatty acids of Vegfb levels in rats' white adipose tissue and 3T3-L1 cells.

Methods: A group of rats were assigned to three diets, each one with a different composition of saturated, monounsaturated and polyunsaturated fatty acids. Samples of white adipose tissues were taken for the methylation and expression studies. Additionally, 3T3-L1 cells were treated with palmitic, oleic, and linoleic fatty acids. After treatment, cells were harvested and genetic material was extracted for the analysis of Vegfb levels.

Results: We report evidence of changes in the methylation levels of the CpG island at the Vegfb promoter and in the Vegfb expression levels in vivo and in vitro by dietary fatty acid, with the main contribution of the linoleic fatty acid. Vegfb promoter methylation levels were closely related to the Vegfb gene expression.

Conclusion: According to our results, the regulation of Vegfb gene expression by dietary fatty acids may be mediated, at least in part, by epigenetic modifications on Vegfb promoter methylation. Considering the deep association between angiogenesis and tissue growth, we suggest the nutriepigenetic regulation of Vegfb as a key target in the control of the adipose tissue expansion.
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http://dx.doi.org/10.1007/s00394-015-1115-7DOI Listing
March 2017

The nutrigenetic influence of the interaction between dietary vitamin E and TXN and COMT gene polymorphisms on waist circumference: a case control study.

J Transl Med 2015 Sep 2;13:286. Epub 2015 Sep 2.

Genotyping and Genetic Diagnosis Unit, Fundación de Investigación del Hospital Clínico de Valencia-INCLIVA, Av. Blasco Ibañez 17, 46010, Valencia, Spain.

Background: Abdominal obesity (AO) is a common modifiable risk factor for certain non-communicable diseases associated with enhanced oxidative stress (OS). The objective of this work was to investigate whether the interaction between antioxidant vitamin intake and OS-related polymorphisms modulates gene-associated anthropometry in a Spanish population.

Methods: A total of 246 subjects with AO, and 492 age and gender matched non-AO subjects were included in the study. Anthropometric, biochemical, and OS parameters, and antioxidant dietary intake data were assessed using validated procedures. DNA from white blood cells was isolated and the genotype of seven polymorphisms from genes involved in OS (pro-oxidant and antioxidant) were analyzed using the SNPlex system. The effects of the c.-793T > C polymorphism on promoter activity and thus thioredoxin (TXN) activity were examined using reporter assays.

Results: The AO group had higher 8-Oxo-2'-deoxyguanosine levels and took in less vitamin A and vitamin E compared to the non-AO group. Logistic regression analysis revealed that the rs2301241 polymorphism in TXN and rs740603 in catechol-O-methyltransferase (COMT) were associated with waist circumference (WC) and AO. Moreover, these polymorphisms were more strongly associated with variations in WC in subjects with low vitamin E intakes. A promoter assay revealed that the T to C conversion at c.-793 (rs2301241) induced a more than two fold increase in reporter gene expression.

Conclusions: WC is associated both with dietary vitamin E intake and genetic variants of TXN and COMT suggesting that existence of a complex nutrigenetic pathway that involves regulation of AO.
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http://dx.doi.org/10.1186/s12967-015-0652-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557824PMC
September 2015

Polymorphisms in endothelin system genes, arsenic levels and obesity risk.

PLoS One 2015 23;10(3):e0118471. Epub 2015 Mar 23.

Genotyping and Genetic Diagnosis Unit, Hospital Clínico Research Foundation (INCLIVA), Valencia, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.

Background/objectives: Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity.

Subjects/methods: We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex.

Results: We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53).

Conclusions: Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118471PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370725PMC
February 2016

Type 2 diabetes mellitus in relation to global LINE-1 DNA methylation in peripheral blood: a cohort study.

Epigenetics 2014 Oct;9(10):1322-8

a UGCI de Endocrinología y Nutrición ; Instituto de Investigación Biomédica de Málaga (IBIMA) ; Hospital Regional Universitario ; Malaga , Spain.

In the last years, epigenetic processes have emerged as a promising area of complex diseases research. DNA methylation measured in Long Interspersed Nucleotide Element 1 (LINE-1) sequences has been considered a surrogate marker for global genome methylation. New findings have suggested the potential involvement of epigenetic mechanisms in Type 2 diabetes (T2DM) as a crucial interface between the effects of genetic predisposition and environmental influences. Our study evaluated whether global DNA methylation predicted increased risk from T2DM or other carbohydrate metabolism disorders in a cohort study. We used a prospective cohort intervention study and a control group. We collected phenotypic, anthropometric, biochemical, and nutritional information from all subjects. Global LINE-1 DNA methylation was quantified by pyrosequencing technology. Subjects that did not improve their carbohydrate metabolism status showed lower levels of global LINE-1 DNA methylation (63.9 ± 1.7 vs. 64.7 ± 2.4) and they practiced less intense physical activity (5.8% vs. 21.5%). Logistic regression analyses showed a significant association between LINE-1 DNA methylation and metabolic status after adjustment for sex, age, BMI, and physical activity. Our study showed that lower LINE-1 DNA methylation levels were associated with a higher risk metabolic status worsening, independent of other classic risk factors. This finding highlights the potential role for epigenetic biomarkers as predictors of T2DM risk or other related metabolic disorders.
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http://dx.doi.org/10.4161/15592294.2014.969617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622014PMC
October 2014

Night-time sleep duration and the incidence of obesity and type 2 diabetes. Findings from the prospective Pizarra study.

Sleep Med 2014 Nov 11;15(11):1398-404. Epub 2014 Aug 11.

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain; UGCI de Endocrinología y Nutrición, Hospital Regional Universitario, Málaga, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.

Background: Several recent studies have related short sleep duration with different health problems, though the results related with the risk of obesity and type 2 diabetes (T2D) are far from conclusive. The aim of this study was to investigate the association between night-time sleep duration and the incidence of obesity and T2D in a prospective study with a follow-up of 11 years.

Material And Methods: The study comprised 1145 people evaluated in 1997-1998 and re-evaluated after 6 years and 11 years. At the three study points, subjects without known diabetes mellitus (KDM) were given an oral glucose tolerance test (OGTT). Anthropometric and biochemical variables were measured. The subjects were asked about their number of hours of night-time sleep.

Results: After adjustment, the OR of becoming obese was significantly higher in subjects who slept ≤ 7 hours per night, at both the 6-year follow-up (OR = 1.99; 95% CI = 1.12-3.55) and the 11-year follow-up (OR = 2.73; 95% CI = 1.47-5.04). The incidence of T2D at the 6-year follow-up in subjects without T2D at baseline was higher in those who slept ≤ 7 hours per night (OR = 1.96; 95% CI = 1.10-3.50). However, this association was not independent of obesity, weight gain or abnormal glucose regulation at baseline. At the 11-year follow-up however there was no association between night-time sleep duration and the incidence of T2D.

Conclusions: The incidence of obesity over the 11-year follow-up increased in subjects with fewer hours of night-time sleep. The incidence of T2D according to the hours of night-time sleep depended on obesity and the carbohydrate metabolism phenotype.
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http://dx.doi.org/10.1016/j.sleep.2014.06.014DOI Listing
November 2014

Methylation levels of the SCD1 gene promoter and LINE-1 repeat region are associated with weight change: an intervention study.

Mol Nutr Food Res 2014 Jul 15;58(7):1528-36. Epub 2014 May 15.

UGCI de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Malaga, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.

Scope: Epigenetic processes may be affected by environmental factors. DNA methylation measured in LINE-1 elements (LINE-1, long interspersed nucleotide element-1) correlates with LINE-1 DNA methylation. Variations in stearoyl CoA desaturase (SCD) activity (a key enzyme in the fatty acid metabolism) may be involved in various processes that can lead to diseases such as obesity. We evaluated whether changes in diet after a nutritional intervention would be associated with changes in LINE-1 DNA methylation and/or specific methylation of SCD1 gene promoter.

Methods And Results:

Design: Prospective cohort intervention study with a control group. We recorded phenotypic, anthropometric, biochemical, and nutritional information at baseline and 1 year later. DNA methylation was quantified by pyrosequencing. LINE-1 DNA methylation and SCD1 gene promoter methylation levels were similar at the beginning of the study in both populations, whereas after a year these levels were higher in the control group (p < 0.001). In the intervention group, those subjects who lost weight showed higher levels of SCD1 gene promoter methylation after the intervention. Subjects with lower adherence to a Mediterranean diet experienced larger changes in LINE-1 methylation.

Conclusion: DNA methylation levels were associated with weight change and with adherence to a Mediterranean diet.
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http://dx.doi.org/10.1002/mnfr.201400079DOI Listing
July 2014

Modifications of the homeostasis model assessment of insulin resistance index with age.

Acta Diabetol 2014 Dec 1;51(6):917-25. Epub 2014 Apr 1.

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.

The aim of the study was to analyze the association between aging and insulin resistance estimated by the homeostasis model assessment of insulin resistance (HOMA-IR). This work involved two studies: (1) the [email protected] study is a cross-sectional study including 4,948 subjects, comprising a representative sample of the adult Spanish population; (2) the Pizarra study is a population-based cohort study undertaken in Pizarra (Spain), in which 1,051 subjects were evaluated at baseline and 714 completed the 6-year follow-up study. Study variables included a clinical and demographic structured survey, a lifestyle survey, a physical examination, and an oral glucose tolerance test in subjects without diabetes. In the [email protected] study overall, an increase occurred in blood glucose until the age of 50, after which it remained stable (data adjusted for gender, body mass index, abnormal glucose regulation [AGR]). The HOMA-IR increased significantly with age (p = 0.01), due to a higher prevalence of obesity (p < 0.0001) and AGR (p < 0.001). In non-obese subjects without AGR, HOMA-IR values were not modified with age (p = 0.30), but they were with body mass index (p < 0.001). In the Pizarra study, the HOMA-IR was significantly lower after 6-year follow-up in the whole study population. Subjects with a HOMA-IR level higher than the 75th percentile at baseline were more likely to develop diabetes (OR 2.2, 95 % CI 1.2-3.9; p = 0.007) than subjects with a lower HOMA-IR. We concluded that age per se did not increase HOMA-IR levels, changes that might be related to higher rates of obesity and AGR in older subjects. The HOMA-IR was associated with an increased risk of developing type 2 diabetes 6 years later.
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http://dx.doi.org/10.1007/s00592-013-0523-5DOI Listing
December 2014

Impact of obesity-related genes in Spanish population.

BMC Genet 2013 Nov 23;14:111. Epub 2013 Nov 23.

Hypertension Clinic, Hospital Clínico Universitario and INCLIVA, University of Valencia, Valencia 46010, Spain.

Background: The objective was to investigate the association between BMI and single nucleotide polymorphisms previously identified of obesity-related genes in two Spanish populations. Forty SNPs in 23 obesity-related genes were evaluated in a rural population characterized by a high prevalence of obesity (869 subjects, mean age 46 yr, 62% women, 36% obese) and in an urban population (1425 subjects, mean age 54 yr, 50% women, 19% obese). Genotyping was assessed by using SNPlex and PLINK for the association analysis.

Results: Polymorphisms of the FTO were significantly associated with BMI, in the rural population (beta 0.87, p-value <0.001). None of the other SNPs showed significant association after Bonferroni correction in the two populations or in the pooled analysis. A weighted genetic risk score (wGRS) was constructed using the risk alleles of the Tag-SNPs with a positive Beta parameter in both populations. From the first to the fifth quintile of the score, the BMI increased 0.45 kg/m2 in Hortega and 2.0 kg/m2 in Pizarra. Overall, the obesity predictive value was low (less than 1%).

Conclusion: The risk associated with polymorphisms is low and the overall effect on BMI or obesity prediction is minimal. A weighted genetic risk score based on genes mainly acting through central nervous system mechanisms was associated with BMI but it yields minimal clinical prediction for the obesity risk in the general population.
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http://dx.doi.org/10.1186/1471-2156-14-111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222487PMC
November 2013

[Relationship between vitamin D deficiency and metabolic syndrome].

Med Clin (Barc) 2014 Jun 9;142(11):473-7. Epub 2013 Nov 9.

Servicio de Endocrinología y Nutrición, Hospital Regional Carlos Haya, Málaga, España; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Málaga, España.

Background And Objective: Vitamin D deficiency and metabolic syndrome are 2 very common health problems in the Spanish population. It has been suggested that patients with metabolic syndrome may be vitamin D deficient more often than subjects without it and that low vitamin D levels may predispose to metabolic syndrome development. However, the results of prospective and intervention studies have been different and such relationship remains unclear. We assessed the relationship between 25-hydroxyvitamin D levels and the prevalence and incidence of metabolic syndrome.

Patients And Methods: We undertook a population-based cohort study in Spain. At baseline (1996-1998), 1,226 subjects were evaluated. Follow-up visits were performed in 2002-2004 and 2005-2007.At baseline and follow-up, participants underwent an interview and a standardized clinical examination with an oral glucose tolerance test in those subjects without known diabetes. At the second visit, 25-hydroxyvitamin D levels and intact parathyroid hormone levels were measured.

Results: The prevalence of metabolic syndrome at the second and third visit was 29.4 and 42.5%, respectively. Mean levels of 25-hydroxyvitamin D were lower in subjects with metabolic syndrome: 21.7 (6.21) vs 23.35 (6.29) ng/ml, P<.001.The prevalence of vitamin D deficiency (25-hydroxyvitamin D<20 ng/ml) at the second evaluation was 34.7%, with significant differences between subjects with and without metabolic syndrome(34.6 vs 26.5%, P<.01). Men with vitamin D deficiency had more frequently hypertension and metabolic syndrome than men with normal levels. Women with vitamin D deficiency had more frequently hyperglycemia, hypertension, increased waist circumference and hypertriglyceridemia. In a prospective study, 25-hydroxyvitamin D values<20 ng/ml were not significantly associated with an increased risk of developing metabolic syndrome in the next 5 years (odds ratio 0,99, 95% confidence interval 0.57-1.7, P=.97) after adjusting by sex and age.

Conclusions: Vitamin D deficiency is associated with an increased prevalence but not with an increased incidence of metabolic syndrome.
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http://dx.doi.org/10.1016/j.medcli.2013.05.049DOI Listing
June 2014

Polymorphisms in the SCD1 gene are associated with indices of stearoyl CoA desaturase activity and obesity: a prospective study.

Mol Nutr Food Res 2013 Dec 12;57(12):2177-84. Epub 2013 Aug 12.

Endocrinology and Nutrition Service, Hospital Carlos Haya, Instituto de Investigación Biomédica (IBIMA), Malaga, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) of the Instituto de Salud Carlos III, Barcelona, Spain.

Scope: The serum fatty acid (FA) composition is influenced by dietary fat and the endogenous production of FAs. Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme catalyzing the synthesis of MUFAs from saturated FAs. Variations in SCD1 activity have been associated with obesity, diabetes, or inflammation. We evaluated the associations between genetic variation of the SCD1 gene, SCD1 activity, intake of oil, and obesity in a population-based prospective study in southern Spain.

Methods And Results: We collected phenotypic, metabolic, nutritional, and genetic information. The type of dietary fat was assessed from samples of cooking oil taken from the participants' kitchens and analyzed by GC. A total of nine single nucleotide polymorphisms (SNPs) of the SCD1 gene were analyzed by SNPlex technology. We found a significant association between SCD1 genetic variation and enzyme activity in four of nine polymorphisms studied. An interaction between rs10883463 and olive oil intake on the [18:1/18:0] desaturase index was found (p = 0.009). We also showed that genetic variations in the SCD1 gene were associated with obesity.

Conclusion: Our results show a relationship between genetic variation of the SCD1 gene, enzyme activity, and the risk of obesity, an association that is not independent of the type of oil consumed.
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http://dx.doi.org/10.1002/mnfr.201300208DOI Listing
December 2013

Metabolically healthy but obese, a matter of time? Findings from the prospective Pizarra study.

J Clin Endocrinol Metab 2013 Jun 4;98(6):2318-25. Epub 2013 Apr 4.

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, 29029 Madrid, Spain.

Background: Prospective longitudinal studies evaluating the relevance of "Metabolically Healthy but Obese" (MHO) phenotype at risk for type 2 diabetes mellitus (T2D) and cardiovascular diseases are few and results are contradictory.

Methods: As a representative of the general population, 1051 individuals were evaluated in 1997-1998 and re-evaluated after 6 years and 11 years. Subjects without known T2D were given an oral glucose tolerance test. Anthropometric and biochemical variables were measured. Four sets of criteria were considered to define MHO subjects besides body mass index ≥30 kg/m(2): A: Homeostatic Model of Assessment-Insulin Resistance Index (HOMA-IR) <90th percentile; B: HOMA-IR <90th percentile, high-density lipoprotein cholesterol >40 mg/dL in men and high-density lipoprotein cholesterol >50 mg/dL in women, triglycerides <150 mg/dL, fasting glucose <110 mg/dL, and blood pressure ≤140/90 mm Hg; C: HOMA-IR <90th percentile, triglycerides <150 mg/dL, fasting glucose <110 mg/dL, and blood pressure ≤140/90 mm Hg; D: HOMA-IR <90th percentile, triglycerides <150 mg/dL, and fasting glucose <110 mg/dL. Subjects with T2D at baseline were excluded from the calculations of incidence of T2D.

Results: The baseline prevalence of MHO phenotype varied between 3.0% and 16.9%, depending on the set of criteria chosen. Metabolically nonhealthy obese subjects were at highest risk for becoming diabetic after 11 years of follow-up (odds ratio = 8.20; 95% confidence interval = 2.72-24.72; P < .0001). In MHO subjects the risk for becoming diabetic was lower than in metabolically nonhealthy obese subjects, but this risk remained significant (odds ratio = 3.13; 95% confidence interval = 1.07-9.17; P = .02). In subjects who lost weight during the study, the association between MHO phenotype and T2D incidence disappeared, even after adjusting for HOMA-IR.

Conclusions: The results suggest that MHO is a dynamic concept that should be taken into account over time. As a clinical entity, it may be questionable.
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http://dx.doi.org/10.1210/jc.2012-4253DOI Listing
June 2013

C-reactive protein and incidence of type 2 diabetes in the Pizarra study.

Eur J Clin Invest 2013 Feb 20;43(2):159-67. Epub 2012 Dec 20.

Department of Endocrinology and Nutrition, Hospital Universitario Carlos Haya, Málaga, Spain.

Aim: To determine the association between serum levels of high-sensitivity C-reactive protein (hs-CRP) and the incidence of type 2 diabetes in a prospective cohort from southern Spain (Pizarra study).

Materials And Methods: The study formed part of the Pizarra cohort study, a prospective study started in 1995 with a follow-up of 11 years. Anthropometric and metabolic variables were measured at baseline and at 6 years and 11 years of follow-up. All subjects underwent an oral glucose tolerance test. Serum levels of TNFα and its receptors, hs-CRP, IL-6, leptin, adiponectin and FABP4 were measured at 6 years of follow-up.

Results: After adjusting for age, sex and obesity, subjects with levels of hs-CRP> 2.9 mg/L in the second study (2003-4) had a higher risk of developing type 2 diabetes by the third study (2008-9) (OR = 7.97; 95% CI = 1.72-36.89; P = 0.008), and subjects with adiponectin levels > 13.2 mg/L had a lower risk of developing type 2 diabetes (OR = 0.23, P = 0.02). High values of hs-CRP and high values of adiponectin were associated positively (OR = 8.26; 95% CI = 1.84-37.19; P = 0.006) and negatively (OR = 0.17; 95% CI = 0.04-0.69; P = 0.01), respectively, with the risk of having HbA1c ≥ 6.5% at 11 years of follow-up.

Conclusions: Subjects with high serum hs-CRP levels and low serum adiponectin levels have a higher risk of developing type 2 diabetes within five years.
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http://dx.doi.org/10.1111/eci.12027DOI Listing
February 2013

Mediterranean diet and the Spanish paradox. A hypothesis.

Med Hypotheses 2013 Feb 8;80(2):150-5. Epub 2012 Dec 8.

Servicio de Endocrinología y Nutrición, Hospital Regional Universitario Carlos Haya, Málaga, Spain.

The Spanish paradox is a phenomenon observed in Spain and some other Mediterranean countries by which the cardiovascular morbidity and mortality levels are dissociated from their cardiovascular risk factors. The Mediterranean diet has been proposed as the main reason for this dissociation, but dietary changes themselves are not enough to explain this situation. It has been recently discovered that Stearoil-CoA desaturase (SCD) is involved in the dissociation between a favourable atherogenic metabolic profile and the risk for arteriosclerosis. We propose a hypothesis that attempts to clarify the Spanish paradox. This hypothesis contemplates the essential role of dietary olive oil and its interaction with different SCD genetic patterns. Confirmation of this hypothesis could provide the basis for the design of clinical and preventive strategies against cardiovascular morbidity and mortality, as well as certain metabolic risk factors.
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http://dx.doi.org/10.1016/j.mehy.2012.11.015DOI Listing
February 2013

White rice consumption and risk of type 2 diabetes.

Clin Nutr 2013 Jun 14;32(3):481-4. Epub 2012 Nov 14.

Endocrinology and Nutrition Department, Hospital Universitario Carlos Haya, Málaga, Spain.

Background & Aim: Recent studies suggest that white rice consumption increases risk of diabetes.

Aim: to assess the association between white rice intake and the incidence of diabetes in a population from Southern Spain.

Methods: A population-based cohort study was undertaken in Pizarra, Spain. At baseline and follow-up, participants underwent an interview and a standardized clinical examination which included an oral glucose tolerance test in those subjects without known diabetes. Incidence and odds ratio (OR) for diabetes were calculated. Multivariate analysis was performed using stepwise logistical regression.

Results: Thirty eight percent of subjects reported rice consumption 2-3 times a week, 58.5% once or less a week, and 3.6% no rice consumption. In subjects who reported rice intake 2-3 times a week, incidence of diabetes after 6 years follow-up was 12.0%, and in those who reported once or less a week, 20.2% (p = 0.04, non adjusted). Subjects who ate rice frequently had lower risk to develop diabetes 6 years later (OR = 0.43, p = 0.04; adjusted for age, sex, obesity, and presence of impaired fasting glucose and/or impaired glucose tolerance at baseline).

Conclusions: A negative association was found between white rice intake in the way it is consumed in Southern Spain, and the 6 years incidence of diabetes.
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http://dx.doi.org/10.1016/j.clnu.2012.11.008DOI Listing
June 2013

Factors determining weight gain in adults and relation with glucose tolerance.

Clin Endocrinol (Oxf) 2013 Jun 25;78(6):858-64. Epub 2013 Mar 25.

Department of Endocrinology and Nutrition, Hospital Universitario Carlos Haya, Málaga, Spain.

Objective: Modifications in lifestyle, diet and certain clinical events are major contributors for the high prevalence of obesity. The aim of this study was to assess factors associated with weight gain in a population of Spanish adults.

Design: The study was undertaken in two population-based cohorts from the north and the south of Spain (baseline and after 6 years). The Asturias Study, in the north, included 1034 persons aged 30-75 years, of whom 701 were reassessed. The Pizarra Study, in the south, included 1226 persons aged 18-65 years, of whom 783 were re-evaluated. Both studies involved a nutritional questionnaire, a physical examination and an oral glucose tolerance test (OGTT).

Results: During the follow-up, 32.3% of the participants lost weight, 34.5% gained fewer than 4 kg and 33.2% gained more than 4 kg. Weight gain was greater in persons younger than 50 years and in those with an initial body mass index below 30. Weight gain was associated with a greater incidence of type 2 diabetes mellitus (T2DM) and abnormal glucose tolerance, whereas weight loss in persons with these disorders was associated with a normal OGTT 6 years later. Persons who took less exercise and those who reported a higher daily calorie intake experienced greater weight gain.

Conclusion: The longitudinal changes in weight affect the development of T2DM and abnormal glucose tolerance. The weight is a dynamic phenomenon affected by several social customs.
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http://dx.doi.org/10.1111/j.1365-2265.2012.04471.xDOI Listing
June 2013