Vitamin D and the Metabolic Phenotype in Weight Loss After Bariatric Surgery: A Longitudinal Study.

PURPOSE: To evaluate the influence of vitamin D (VD) concentrations coupled with metabolic phenotypes preoperatively and 6 months after Roux-en-Y gastric bypass (RYGB) on body variables and weight loss. MATERIALS AND METHODS: A longitudinal, retrospective, analytical study comprising 30 adult individuals assessed preoperatively (T0) and 6 months (T1) after undergoing Roux-en-Y gastric bypass. The participants were distributed preoperatively into metabolically healthy obese (MHO) and metabolically unhealthy obese individuals (MUHO) according to the HOMA-IR classification, as well as the adequacy and inadequacy of vitamin D concentrations in the form of 25(OH)D. All participants were assessed for weight, height, body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), visceral adiposity index (VAI), body circularity index (BCI), body adiposity index (BAI), weight loss, and assessment of 25(OH)D and 1,25(OH)2D concentrations using high-performance liquid chromatography with an ultraviolet detector (HPLC-UV). The statistical program used was SPSS version 21. RESULTS: VD adequacy and a healthy phenotype in the preoperative period may play an important role concerning body fat distribution, as the body averages for WHtR (0.020*) and BCI (0.020*) were lower in MHO participants. In comparison, those with VD inadequacy and MUHOs had higher BAI averages (0.000*) in the postoperative period. Furthermore, it is possible that VD inadequacy before and after RYGB, even in the presence of an unhealthy phenotype, may contribute to the increase in VAI values (0.029*) after this surgery. Only those with inadequate VD and MUHOs had higher 25(OH)D concentrations. Besides, this unhealthy phenotype had a greater reduction in BMI in the early postoperative period (p < 0.001). CONCLUSION: This study suggests that VD adequacy and the presence of a healthy phenotype appear to have a positive impact on the reduction of visceral fat in the context of pre- and postoperative obesity. In addition, there was a greater weight reduction in those with VD inadequacy and in MUHO, which suggests that the volumetric dilution effect of VD and catabolism after bariatric surgery is more pronounced in this specific metabolic phenotype.

Pharmacogenomic implications of the differential distribution of CYP2C9 metabolic phenotypes among Latin American populations.

The CYP2C9 gene encodes the major drug metabolism enzyme CYP2C9. This gene is highly polymorphic, and no-function (CYP2C9*3) plus decreased function (CYP2C9*2, *5, *8 and *11) star alleles (haplotypes) are commonly used to predict CYP2C9 metabolic phenotypes. This study explores the pharmacogenomic implications of the differential distribution of genotype-predicted CYP2C9 phenotypes across Latin American populations. Data from 1,404 individuals from the South American countries Brazil, Colombia and Peru, from Puerto Rico in the Caribbean and from persons with Mexican ancestry living in North America were analysed. The results showed that the distribution of CYP2C9 alleles and diplotypes, and diplotype-predicted CYP2C9 phenotypes vary significantly across the distinct country cohorts, as well as among self-identified White, Brown and Black Brazilians. Differences in average proportions of biogeographical ancestry across the study groups, especially Native American and African ancestry, are the likely explanation for these results. The differential distribution of genotype-predicted CYP2C9 phenotypes has potentially clinically-relevant pharmacogenomic implications, through its influence on the proportion of individuals at high risk for adverse response to medications that are CYP2C9 substrates, the proportion on individuals with CPIC therapeutic recommendations for dosing and choice of nonsteroidal antinflammatory drugs (NSAIDs) and the number of individuals that need to be genotyped in order to prevent adverse effects of NSAIDs. Collectively, these findings are likely to impact the perceived benefits, cost-effectiveness and clinical adoption of pharmacogenomic screening for drugs that are predominantly metabolized by CYP2C9.

Distribution of a novel CYP2C haplotype in Native American populations.

The CYP2C19 gene, located in the CYP2C cluster, encodes the major drug metabolism enzyme CYP2C19. This gene is highly polymorphic and no-function (CYP2C19*2 and CYP2C19*3), reduced function (CYP2C19*9) and increased function (CYP2C19*17) star alleles (haplotypes) are commonly used to predict CYP2C19 metabolic phenotypes. CYP2C19*17 and the genotype-predicted rapid (RM) and ultrarapid (UM) CYP2C19 metabolic phenotypes are absent or rare in several Native American populations. However, discordance between genotype-predicted and pharmacokinetically determined CYP2C19 phenotypes in Native American cohorts have been reported. Recently, a haplotype defined by rs2860840T and rs11188059G alleles in the CYP2C cluster has been shown to encode increased rate of metabolism of the CYP2C19 substrate escitalopram, to a similar extent as CYP2C19*17. We investigated the distribution of the CYP2C:TG haplotype and explored its potential impact on CYP2C19 metabolic activity in Native American populations. The study cohorts included individuals from the One Thousand Genomes Project AMR superpopulation (1 KG_AMR), the Human Genome Diversity Project (HGDP), and from indigenous populations living in Brazil (Kaingang and Guarani). The frequency range of the CYP2C:TG haplotype in the study cohorts, 0.469 to 0.598, is considerably higher than in all 1 KG superpopulations (range: 0.014-to 0.340). We suggest that the high frequency of the CYP2C:TG haplotype might contribute to the reported discordance between CYP2C19-predicted and pharmacokinetically verified CYP2C19 metabolic phenotypes in Native American cohorts. However, functional studies involving genotypic correlations with pharmacokinetic parameters are warranted to ascertain the importance of the CYP2C:TG haplotype.

Metabolically unhealthy and overweight phenotypes are associated with increased levels of inflammatory cytokines: a population-based study.

OBJECTIVE: The aim of this study was to determine the association between cytokine levels in metabolic phenotypes. Our hypothesis was that an unhealthy metabolic profile is associated to higher levels of proinflammatory cytokines. METHODS: The study sample was composed of 743 Brazilian adults classified in four phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), and metabolically unhealthy overweight (MUOW). Sociodemographic, anthropometric, clinical, and biochemical parameters were collected. Six different cytokines were analyzed from blood samples using the CBA Human Inflammatory cytokines kit and the values divided in quartiles for analysis. Logistic regression models were constructed to assess the association between metabolic phenotypes and cytokines concentrations, adjusted for potential confounders and P < 0.05 was used. RESULTS: The MUOW phenotype showed a higher risk for increased levels of all cytokines analyzed compared with the reference group (MHNW). CONCLUSIONS: These results indicated that excess weight and altered metabolic profile are related to inflammation, especially when both conditions are associated, possibly linked to visceral adiposity. Therefore, the categorization of metabolic phenotypes in populations is an important factor for prevention of chronic diseases, as inflammation is associated with cardiovascular risk and obesity is not the only influencing factor.

The Heterogeneity of Liver Cancer Metabolism.

Primary liver cancer is the fourth leading cause of cancer death around the world. Histologically, it can be divided into two major groups, hepatocellular carcinoma (75% of all liver cancer) and intrahepatic cholangiocarcinoma (15% of all liver cancer) [1, 2]. Primary liver cancer usually happens in liver disease or cirrhosis patients [1], and the risk factors for developing HCC depend on the etiology [3] and the country of provenance [1]. There is an urgent need for an accurate diagnostic test given the high proportion of false positives and false negatives for alpha-fetoprotein (AFP), a common HCC biomarker [4]. Due to often being diagnosed in advanced stages, HCCrelated deaths per year have doubled since 1999 [3]. With the use of metabolomics technologies [5], the aberrant metabolism characteristics of cancer tissues can be discovered and exploited for the new biomarkers and new therapies to treat HCC [6, 7].

Biochemical and clinical characterization of metabolic phenotypes: a cross-sectional study from Maracaibo city, Venezuela.

Background: In 1980, Reuben Andresen observed that in certain individuals, obesity did not increase mortality, introducing an atypical phenotype called "healthy obese". Other studies reported that 10-15 % of lean individuals presented insulin resistance, hyperglycemia and dyslipidemia. The objective of this study was to evaluate biochemical and clinical characteristics of metabolic phenotypes in Maracaibo city. Methods: A descriptive, cross-sectional study with a randomized multistage sampling was performed including 1226 non diabetic individuals from both sexes. For phenotype definition, the subjects were first classified according to their BMI into Normal-Weight, Overweight and Obese; then divided in metabolically healthy and unhealthy using a two-step analysis cluster. To evaluate the relationship with coronary risk, a multiple logistic regression model was performed. Results: In the studied population, 5.2% (n=64) corresponded to unhealthy lean subjects, and 17.4% (n=217) to healthy obese subjects. Metabolically unhealthy normal-weight (MUNW) phenotype was found in males in 53.3% in contrast to 51.3% of metabolically unhealthy obese (MUO) phenotype found in females. An association between metabolically unhealthy phenotypes and a higher risk of a coronary event was found, especially for obese individuals (MHO: OR=1.85 CI95%: 1.11-3.09; p=0.02 and MUO: OR=2.09 CI95%: 1.34-3.28; p<0.01). Conclusion: Individuals with atypical metabolic phenotypes exist in Maracaibo city. Related factors may include insulin resistance, basal glucose levels, and triglycerides levels. Lastly, cardiovascular risk exhibited by healthy obese individuals should be classified in categories of major coronary risk related to lean subjects.

Effect of metformin on obesity associated metabolic phenotypes / Efecto de la metformina sobre la obesidad asociada a fenotipos metabólicos

Background: It is known that there are different metabolic phenotypes associated with obesity, each of them imposing distinct cardiovascular risk. Metformin is a drug with wide and diverse applications in cardiometabolic disorders. Aims: To determine the effect of metformin on lipid profile, glucose metabolism and anthropometric variables of different phenotypes of obesity. Material and methods: We conducted a "before and after" clinical trial in order to evaluate the response to metformin treatment (850 mg/day for 24 weeks). Variables like body weight, body mass index (BMI), waist-hip index (WHI), blood pressure, glycemia, total cholesterol (TC) and its fractions, HDL, LDL as well as triglycerides and TC/HDL-c and TG/HDL-c lipoprotein indexes were analyzed at baseline and at the end of the trial. Results: HDL-c and TC/HDL-c ratios showed a considerable improvement after treatment. A reduction in LDL fraction was observed. Triglyceride levels had no significant changes. An average weight reduction of 0.48 Kg was obtained alongside with an improvement of the BMI. Both systolic and diastolic blood pressures did not show meaningful changes. Conclusions: Sustained administration of metformin had a beneficial effect on lipid profile, weight reduction and cardiovascular risk predictors.

Antecedentes: Se sabe que los diferentes fenotipos metabólicos asociados a la obesidad imponen un riesgo cardiovascular distinto. La metformina es un fármaco con amplias y diversas aplicaciones en trastornos cardiometabólicos. Objetivos: Determinar el efecto del tratamiento con metformina sobre el perfil lipídico, las alteraciones del metabolismo de carbohidratos, y sobre las variables antropométricas observadas en los fenotipos metabólicos de la obesidad. Material y métodos: Se realizó un ensayo clínico "antes y después" para evaluar la respuesta al tratamiento con metformina (850 mg/día durante 24 semanas). Variables como peso, índice de masa corporal (IMC), índice cintura-cadera (ICC), presión arterial, glucemia, colesterol total y sus fracciones HDL, LDL, triglicéridos e índices lipoproteicos CT/c-HDL y TG/c-HDL fueron analizados al inicio y al final del estudio. Resultados: El c-HDL y el índice CT/c-HDL tuvieron una mejoría significativa posterior al tratamiento. Se observó un descenso en c-LDL. Se obtuvo un descenso de peso promedio de 0.48 kg y paralelo a ello una mejora del IMC. La presión arterial tanto sistólica como diastólica no mostró cambios significativos. Conclusiones: La administración de metformina tuvo un efecto benéfico sobre el perfil lipídico, la reducción del peso corporal y algunos predictores de riesgo cardiovascular.

Population pharmacogenetics of Ibero-Latinoamerican populations (MESTIFAR 2014).

MESTIFAR 2014 28-30 November 2014, Panama City, Panama The CEIBA consortium was created within the Ibero-American network of Pharmacogenetics (RIBEF) to study population pharmacogenetics. The current status of these initiatives and results of the MESTIFAR project were analyzed in Panama, 28-30 November 2014. The MESTIFAR project focused on studying CYPs genetic polymorphisms in populations of different ethnic origin. So far, more than 6000 healthy volunteers have been evaluated, making this one of the largest population pharmacogenomic studies worldwide. Three symposia were organized, 'Pharmacogenetics of indigenous and mestizos populations and its clinical implications', 'Methodological innovation in pharmacogenetics and its application in health', and 'General discussion and concluding remarks', about mechanisms and proposals for training, diffusion of pharmacogenetics for Spanish- and Portuguese-speaking health professionals, and 'bench to bedside' pilot projects.