Redefining Statin Dosage Post-Gastric Bypass: Insights from a Population Pharmacokinetics-Pharmacodynamics Link Approach.

Roux-en-Y gastric bypass (RYGB) involves creating a small stomach pouch, bypassing part of the small intestine, and rerouting the digestive tract. These alterations can potentially change the drug exposure and response. Our primary aim was to assess the impact of RYGB on the pharmacokinetics of simvastatin lactone (SV) and its active metabolite, simvastatin hydroxy acid (SVA). Ultimately, we aimed to optimize dosing for this understudied population by employing a population pharmacokinetic-pharmacodynamic link approach. The study comprised patients who had undergone RYGB surgery and individuals without a previous history of RYGB. All participants received a single oral dose of simvastatin. Plasma concentration data were analyzed with a nonlinear mixed-effect modeling approach. A parent-metabolite model with first-order absorption, 2-compartments for SV and 1-compartment for SVA, linear elimination, and enterohepatic circulation best described the data. The model was linked to the turnover pharmacodynamic model to describe the SVA inhibition on LDL-cholesterol production. Our simulations indicated that following RYGB surgery, the exposure to SV and SVA decreased by 40%. Consequently, for low-intensity statin patients, we recommend increasing the dose from 10 to 20 mg in post-RYGB patients to maintain a comparable response to that of non-operated subjects. Moderate-intensity statin patients should require increasing doses to 40 or 60 mg or the addition of a non-statin medication to achieve similar therapeutic outcomes. In conclusion, individuals post-RYGB exhibit diminished exposure to SV and may benefit from increasing the dose or adjunctive therapy with non-statin drugs to attain equivalent responses and mitigate potential adverse events.

Long-term Comparative Evaluation of Weight Loss and Complications of Banded and Non-banded Roux-en-Y Gastric Bypass.

PURPOSE: The use of a nonadjustable silicone band around the gastric pouch of Roux-en-Y gastric bypass (RYGB) to reduce the recurrence of obesity is still being debated in the literature. The primary objective of this study was to evaluate banded and non-banded RYGB regarding % total weight loss (%TWL) and complications up to 10 years postoperatively and regarding the removal rate of the silicone band. MATERIAL AND METHODS: A retrospective study of the medical records of all patients submitted to banded and non-banded RYGB between 2000 and 2020 was conducted. Clinical data (age, gender, weight, body mass index-BMI, comorbidities, %TWL, and the prevalence of vomiting) and laboratory data (hemoglobin, serum iron, albumin, and vitamin B12) were obtained preoperatively and at 6 months, 1, 2, 3, 5, 7, and 10 years for both groups and at 12, 15, and 20 years after banded RYGB. RESULTS: In total, 858 patients underwent RYGB: 409 underwent banded RYGB and 449 underwent non-banded RYGB. In the preoperative period, banded RYGB patients were heavier and had higher rates of hypertension and dyslipidemia. The %TWL was higher in the banded RYGB group up to 7 years. The prevalence of vomiting is much higher in this group, which also had lower laboratory test values. Of the banded RYGB patients, 9.53% had to have the silicone ring removed after presenting complications. CONCLUSION: Banded RYGB promotes significantly higher rates of TWL at the expense of a higher frequency of food intolerance and vomiting.

Medium and Long-Term Weight Loss After Revisional Bariatric Surgery: A Systematic Review and Meta-Analysis.

Despite the current increase in revisional bariatric surgery (RBS), data on the sustainability of weight loss remain unclear. A systematic review and meta-analysis were performed to assess weight loss outcomes in adult patients undergoing RBS with follow-up > 2 years. Twenty-eight observational studies (n = 2213 patients) were included. The %TWL was 27.2 (95%CI = 23.7 to 30.6), and there was a drop in BMI of 10.2 kg/m2 (95%CI = - 11.6 to - 8.7). The %EWL was 54.8 (95%CI = 47.2 to 62.4) but with a high risk of publication bias (Egger's test = 0.003). The overall quality of evidence was very low. Our data reinforce that current evidence on RBS is mainly based on low-quality observational studies, and further higher-quality studies are needed to support evidence-based practice.

Sleeve Gastrectomy with Pyloroplasty in Wistar Rats: Assessment of Gastric Emptying, Intestinal Transit, and Possible Duodenogastric Alkaline Reflux.

BACKGROUND: Studies indicate sleeve gastrectomy (SG) as a factor of aggravation or even emergence of symptoms of gastroesophageal reflux disease. Accelerated gastric emptying is described as a mitigating factor. SG may be potentiated by adding a pyloroplasty, although with the potential risk of resulting in duodenogastric alkaline reflux. The objective was to standardize sleeve gastrectomy with pyloroplasty in rats, analyze the complementation in terms of mortality and weight evolution, and conduct assessments on gastric emptying, intestinal transit, and genesis of possible duodenogastric reflux. METHODS: Ninety-three male Wistar rats were divided into a pilot study (standardization of the surgical technique and the scintigraphic study), and the main study. They were then subdivided into the SHAM group, the sleeve gastrectomy (SG) group, and the sleeve gastrectomy with pyloroplasty (SGP) group. After 3 months, the animals were submitted to two scintigraphic experiments and histological analysis of gastric biopsies. RESULTS: The surgical groups (SG and SGP) lost initially more weight than the SHAM group, and the gastric emptying and intestinal transit in the first were more accelerated. However, no difference was found between the SG and SGP groups. Scintigraphic and histological analyses did not reveal statistical differences among the SG and SGP groups regarding gastroesophageal and duodenogastric refluxes. CONCLUSIONS: Pyloroplasty did not affect weight reduction or increase duodenogastric reflux, after three postoperative months in this animal model of sleeve gastrectomy.

Corrigendum: Novel Zinc-Related Differentially Methylated Regions in Leukocytes of Women With and Without Obesity.

[This corrects the article DOI: 10.3389/fnut.2022.785281.].

Novel Zinc-Related Differentially Methylated Regions in Leukocytes of Women With and Without Obesity.

Introduction: Nutriepigenetic markers are predictive responses associated with changes in "surrounding" environmental conditions of humans, which may influence metabolic diseases. Although rich in calories, Western diets could be linked with the deficiency of micronutrients, resulting in the downstream of epigenetic and metabolic effects and consequently in obesity. Zinc (Zn) is an essential nutrient associated with distinct biological roles in human health. Despite the importance of Zn in metabolic processes, little is known about the relationship between Zn and epigenetic. Thus, the present study aimed to identify the epigenetic variables associated with Zn daily ingestion (ZnDI) and serum Zinc (ZnS) levels in women with and without obesity. Materials and Methods: This is a case-control, non-randomized, single-center study conducted with 21 women allocated into two groups: control group (CG), composed of 11 women without obesity, and study group (SG), composed of 10 women with obesity. Anthropometric measurements, ZnDI, and ZnS levels were evaluated. Also, leukocyte DNA was extracted for DNA methylation analysis using 450 k Illumina BeadChips. The epigenetic clock was calculated by Horvath method. The chip analysis methylation pipeline (ChAMP) package selected the differentially methylated regions (DMRs). Results: The SG had lower ZnS levels than the CG. Moreover, in SG, the ZnS levels were negatively associated with the epigenetic age acceleration. The DMR analysis revealed 37 DMRs associated with ZnDI and ZnS levels. The DMR of PM20D1 gene was commonly associated with ZnDI and ZnS levels and was hypomethylated in the SG. Conclusion: Our findings provide new information on Zn's modulation of DNA methylation patterns and bring new perspectives for understanding the nutriepigenetic mechanisms in obesity.

Bariatric surgery can acutely modulate ER-stress and inflammation on subcutaneous adipose tissue in non-diabetic patients with obesity.

BACKGROUND: Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is the most effective and durable treatment option for severe obesity. The mechanisms involving adipose tissue may be important to explain the effects of surgery. METHODS: We aimed to identify the genetic signatures of adipose tissue in patients undergoing RYGB. We evaluated 13 obese, non-diabetic patients (mean age 37 years, 100% women, Body mass index (BMI) 42.2 kg/m2) one day before surgery, 3 and 6 months (M) after RYGB. RESULTS: Analysis of gene expression in adipose tissue collected at surgery compared with samples collected at 3 M and 6 M Post-RYGB showed that interleukins [Interleukin 6, Tumor necrosis factor-α (TNF-α), and Monocyte chemoattractant protein-1(MCP1)] and endoplasmic reticulum stress (ERS) genes [Eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) and Calreticulin (CALR)] decreased during the follow-up (P ≤ 0.01 for all). Otherwise, genes involved in energy homeostasis [Adiponectin and AMP-activated protein kinase (AMPK)], cellular response to oxidative stress [Sirtuin 1, Sirtuin 3, and Nuclear factor erythroid 2-related factor 2 (NRF2)], mitochondrial biogenesis [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)] and amino acids metabolism [General control nonderepressible 2 (GCN2)] increased from baseline to all other time points evaluated (P ≤ 0.01 for all). Also, expression of Peroxisome proliferator-activated receptor gamma (PPARϒ) (adipogenesis regulation) was significantly decreased after RYGB (P < 0.05). Additionally, we observed that PGC1α, SIRT1 and AMPK strongly correlated to BMI at 3 M (P ≤ 0.01 for all), as well as ADIPOQ and SIRT1 to BMI at 6 M (P ≤ 0.01 for all). CONCLUSIONS: Our findings demonstrate that weight loss is associated with amelioration of inflammation and ERS and increased protection against oxidative stress in adipose tissue. These observations are strongly correlated with a decrease in BMI and essential genes that control cellular energy homeostasis, suggesting an adaptive process on a gene expression level during the caloric restriction and weight loss period after RYGB. Trial registration CAAE: 73,585,317.0.0000.5440.

Erratum to "Maximum Phonation Time in People with Obesity Not Submitted or Submitted to Bariatric Surgery".

[This corrects the article DOI: 10.1155/2019/5903621.].

Changes in DNA Methylation and Gene Expression of Insulin and Obesity-Related Gene PIK3R1 after Roux-en-Y Gastric Bypass.

Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how the gene expression and DNA methylation of PIK3R1, an obesity and insulin-related gene, change after RYGB. Blood samples were obtained from 13 women (35.9 ± 9.2 years) with severe obesity before and six months after surgical procedure. Whole blood transcriptome and epigenomic patterns were assessed by microarray-based, genome-wide technologies. A total of 1966 differentially expressed genes were identified in the pre- and postoperative periods of RYGB. From these, we observed that genes involved in obesity and insulin pathways were upregulated after surgery. Then, the PIK3R1 gene was selected for further RT-qPCR analysis and cytosine-guanine nucleotide (CpG) sites methylation evaluation. We observed that the PI3KR1 gene was upregulated, and six DNA methylation CpG sites were differently methylated after bariatric surgery. In conclusion, we found that RYGB upregulates genes involved in obesity and insulin pathways.

Maximum Phonation Time in People with Obesity Not Submitted or Submitted to Bariatric Surgery.

Background: Our aim in this investigation was to evaluate maximum phonation time in people with obesity not submitted to surgery and in people with obesity submitted to bariatric surgery and compare it with maximum phonation time of healthy volunteers. The hypothesis was that the reduced maximum phonation time in people with obesity would be corrected after surgery due to weight loss. Method: Maximum phonation time was evaluated in 52 class III patients (Group A), 62 class III patients who were treated by surgery 3 to 115 months before (Group B), 20 controls (Group C), and 15 class III patients whose maximum phonation time was evaluated before and two to six months after surgery (Group D). Maximum phonation time was measured in the sitting position with the vowels /A/, /I/, and /U/. Results: Maximal phonation time was shorter in groups A and B compared with that of controls. There was an increase in maximal phonation time after surgery (Group B); however, the difference was not significant when compared with that in group A. In group D, maximal phonation time for /A/ increased after the surgery. In group A, there was a negative correlation between maximal phonation time and weight or body mass index and a positive correlation between maximal phonation time and height. In group B, there was an almost significant positive relation between percentage of weight loss and maximal phonation time for /A/ (p=0.08) and /I/ (p=0.07). Mean values of spirometry testing (FEV1, FVC, and FEV1/FVC) in people with obesity (groups A and B), expressed as percentage of the predicted value, were within the normal range. Conclusion: Compared with healthy controls, maximal phonation time is shorter in people with obesity, with a tendency to increase after bariatric surgery, as a possible consequence of weight loss.

Mammalian target of rapamycin complex 2 signaling in obese women changes after bariatric surgery.

OBJECTIVES: After bariatric surgery, modifications to signaling pathway networks including those of the metabolic regulator called mammalian or mechanistic target of rapamycin (mTOR) may lead to molecular alterations related to energy source availability, systemic nutrients, and catabolic and anabolic cellular processes. This study aimed to identify gene expression changes with regard to the mTOR complex 2 subunit signaling pathway in obese patients before and after bariatric surgery. METHODS: The experimental group included 13 obese women who were examined before (preoperative) and 6 mo after (postoperative) Roux-en-Y gastric bypass (RYGB) surgery. The control group included nine apparently eutrophic women matched by age and without any other metabolic diseases (i.e., no diabetes and no liver or kidney diseases). Peripheral blood mononuclear cell samples were collected for RNA extraction and subsequent microarray analysis. RESULTS: After this methodological procedure, we identified 47 000 differentially expressed genes. A subsequent bioinformatic analysis showed that three diferentially expressed genes (rapamycin-insensitive companion of mTOR [RICTOR], phosphoinositide-3-kinase regulatory subunit 1 [PIK3 R1], and hypoxia inducible factor 1 alpha subunit 1A [HIF1 A]) participated in the mTOR signaling pathway. Real-time quantitative polymerase chain reaction revealed that RICTOR, PIK3 R1, and HIF1 A were upregulated 6 mo after RYGB surgery (P <0.05). In addition, patients in the experimental group lost weight significantly and presented significant improvement in biochemical/metabolic variables. CONCLUSIONS: The weight loss that was induced by RYGB surgery alters the mTOR signaling pathway and specifically the mTOR complex 2 subunit. The increased expression of genes that act in this pathway such as RICTOR, PIK3 R1, and HIF1 A reflects the induced weight loss and improved metabolic indicators (e.g., insulin resistance and lipolysis) that are evidenced in this study.

Correction to: Omeprazole Absorption and Fasting Gastrinemia After Roux-en-Y Gastric Bypass.

Larissa Alves dos Reis Dias wasmistakenly included in the 13 acknowledgment section of this article, and was mistakenly.

Omeprazole Absorption and Fasting Gastrinemia After Roux-en-Y Gastric Bypass.

PURPOSE: Roux-en-Y gastric bypass (RYGB) is one of the bariatric surgeries most frequently performed worldwide. Since this operation may predispose to the formation of peptic ulcer of the gastrojejunal anastomosis, the use of proton pump inhibitors (PPI) is recommended during the first postoperative year. However, so far, there is no detailed knowledge about the absorption of this medication during the immediate postoperative period and consequently about its effectiveness in blocking acid secretion. The objective was to assess the possible endoscopic peptic changes, the absorption of omeprazole (OME), and the status of fasting gastrinemia before and after RYGB operation. MATERIALS AND METHODS: OME absorption, the production of its metabolites omeprazole sulfone (OMES) and 5-hydroxyomeprazole (HOME), and basal (fasting) gastrinemia were determined in patients submitted to RYGB before and 2 months after the operation. Upper digestive endoscopy (UDE) was also performed before and 6 months after the operation. RESULTS: Twenty patients were studied. Preoperatively, all these patients had some peptic changes and 55% tested positive for Helicobacter pylori. Six months after surgery, ten patients still showed endoscopic changes and one patient tested positive for H. pylori. During the postoperative period, there was a reduction of OME absorption and of the production of its metabolites 90 min after administration of the drug, and reduction of serum gastrin levels. CONCLUSION: The standard OME dose (40 mg) administered after bariatric surgery is insufficient to achieve serum levels that can effectively block the production of hydrochloric acid, permitting the formation of peptic injuries in many patients.

The Ala55Val and -866G>A polymorphisms of the UCP2 gene could be biomarkers for weight loss in patients who had Roux-en-Y gastric bypass.

OBJECTIVE: The aim of this study was to investigate whether the Ala55Val and -866G>A polymorphisms of the UCP2 gene are related to weight loss and changes in body composition after bariatric surgery performed by Roux-en-Y gastric bypass (RYGB). METHODS: This longitudinal study enrolled obese patients submitted to RYGB. Data regarding weight (kg), body mass index (kg/m2), fat-free mass (FFM; kg), fat mass (kg), weight loss (kg and %), and percent excess weight loss were collected from both preoperative and 1-y postoperative medical records. Polymorphisms were genotyped by allelic discrimination using real-time polymerase chain reaction and TaqMan-predesigned single nucleotide polymorphism Genotyping Assay kits (Applied Biosystems, Foster City, CA, USA). The t test was used to compare variables between genotypes of each polymorphism to analyze the dominant and recessive models. Linear regression models were used to adjust the effects of initial weight, age, and sex on the variation of weight and body composition (P < 0.05). RESULTS: We analyzed 150 severely obese individuals (age 47.2 ± 10.5 y; 80% women). Genotype analysis showed a greater prevalence of heterozygous GA (41.3%) for -866G>A polymorphism and CT (39.3%) for Ala55Val polymorphism. Individuals who carried the T (CT+TT) and A (GA+AA) mutated alleles for Ala55Val and -866G>A, respectively, showed a higher weight and FFM loss. CONCLUSION: The mutated alleles T for Ala55Val and A for -866G>A polymorphism could be biomarkers of weight loss 1 y after RYGB.

Bioelectrical impedance vector analysis in obese women before and after bariatric surgery: changes in body composition.

OBJECTIVE: Because of the inefficacy of standard methods for the evaluation of body composition of grade III obese individuals, it is difficult to analyze the quality of weight loss after bariatric surgery in these patients. Electrical bioimpedance vector analysis and the RXc graph uses crude resistance (R) and reactance (Xc) values, like components of the Z vector, to monitor variations in body fluid and the nutritional status of obese individuals. Using bioelectrical impedance vector analysis (BIVA) and the RXc graph, the objective of the present study was to evaluate long-term changes in weight and body composition of obese women after Roux-en-Y bariatric surgery. METHODS: A study was conducted on 43 grade III obese women submitted to bariatric surgery. Anthropometric and bioimpedance (800 mA-50 kHz) data were obtained during the preoperative period and 1, 2, 3, and 4 y after surgery. BIVA was performed by plotting resistance and reactance values corrected for body height (R/H and Xc/H, Ohm/m) as bivariates on the RXc graph. BIVA software was used to plot the vectors of the RXc plane. RESULTS: Surgery promoted changes in body composition, with a reduction of fat mass and of fat-free mass. During the postoperative period, the vectors demonstrated migration to the right lower quadrant of the graph, corresponding to the classification of cachexia and water retention. CONCLUSION: Weight loss due to surgery results in an important reduction of fat-free mass characterized by the position of most individuals in the cachexia quadrant throughout the postoperative period.

The expression of LEP, LEPR, IGF1 and IL10 in obesity and the relationship with microRNAs.

Obesity is a multifactorial disease, with epigenetic alterations. Have been described modifications in the expression of some microRNAs, and some proteins related to obesity. The objective was to determine and correlate, in obese patients, the gene expression of LEP, LEPR, IGF1, IL10 and of miR-27a, miR-27b, miR-143 and miR-145. RNA was extracted from biopsies of subcutaneous fat, liver and visceral fat of 15 obese subjects submitted to bariatric surgery and of 15 non-obese subjects submitted to cholecystectomy for cDNA synthesis and for RT-PCR. The microRNAs were chosen using the TargetScan software. An increased expression of LEP and IGF1 was detected in the subcutaneous fat of the obese group compared to control, while the expression of IGF1 was higher in the control group than in the obese one. MiRNA-27a had a higher expression in the omentum of the obese patients and there was also a correlation in the expression of miRNA-145 and LEPR in the omentum of this group.

Anemia and iron deficiency before and after bariatric surgery.

BACKGROUND: Iron deficiency and anemia are changes often associated with obesity. Bariatric surgery is responsible for increasing the iron loss and reducing its absorption. The objective of this study was to evaluate anemia and iron deficiency before and after bariatric surgery and to relate them to possible predisposing factors. METHODS: A retrospective study was conducted on obese patients submitted to open Roux-en-Y gastric bypass, in which clinical and laboratory data were obtained up to 48 months postoperatively. Patients were divided into groups according to the presence or absence of anemia and to the presence or absence of iron deficiency (even without anemia), and all data were compared between these groups. RESULTS: Preoperatively, 21.5% of patients had anemia and 20% had iron deficiency. The number of patients with anemia did not vary through the 4 years of the study, but ferritin levels significantly decreased with time (P<.01). Younger patients and patients with greater weight loss had a higher incidence of anemia. Female gender was a variable associated with a greater incidence of iron deficiency. CONCLUSIONS: Anemia and iron deficiency are frequent in obese patients and must be treated before surgery. Medical and nutritional surveillance is important in the postoperative period of bariatric surgery. Management of each condition must be directed at correcting the 2 major sources of iron deficiency and anemia: food intolerance (mostly meat intolerance) and losses (frequently due to menstruation). These are the factors more related to iron deficient anemia.

Protein and amino acid status before and after bariatric surgery: a 12-month follow-up study.

BACKGROUND: Patients with obesity submitted to bariatric surgery present altered ingestion of macronutrient and micronutrient levels and nutrients deficiency. The objective of this study was to evaluate the protein and amino acid nutritional status of obese adults before and after bariatric surgery, with emphasis on plasma free amino acids. METHODS: Thirty obese women were submitted to Roux-en-Y gastric shunt (bariatric surgery). Food and protein intake, anthropometric and bioimpedance data (body composition analysis), and serum total protein, albumin, and plasma amino acids levels were collected before the surgery (preoperative) and 3, 6, and 12 months after the surgical procedure. RESULTS: The mean protein intake was 47±2 g/day. The total weight loss during the study period was 39±8 kg; the fat-free mass decreased 7±5 kg. The amino acid profile showed increased concentrations of most amino acids 3 months after surgery; at 6 months, glutamic acid, serine, arginine, alanine, methionine, valine, phenylalanine, isoleucine, and tyrosine concentrations decreased. The total protein and albumin concentrations dropped along the 12-month follow-up. CONCLUSION: The amino acid profile changes after RYGB are evidence that total protein and albumin levels may not be good indicators of protein profile after the surgery.