Preoperative predictors of type 2 diabetes remission after bilio-pancreatic diversion with duodenal switch.

BACKGROUND: Many patients achieve short-term type 2 diabetes (T2D) remission after bariatric surgery, but relapses are common. Diabetes outcomes after bariatric surgery vary across procedures and populations. T2D remission scores are simple clinical tools developed to predict remission after bariatric surgery. However, they have never been tested after Biliopancreatic diversion with duodenal switch (BPD-DS). OBJECTIVES: The aim of this study was to compare the predictive value of T2D remission scores and preoperative diabetes characteristics in predicting T2D remission after BPD-DS. SETTING: Quebec Heart and Lung Institute - Laval University. METHODS: We retrospectively identified 918 patients with preoperative T2D who had undergone BPD-DS. Retrospective chart review was performed and variables used to calculate predictive scores were captured. T2D status was assessed annually for up to 10 years postop. Predictive values for each score (DiarRem, Ad Diarem, and Diabetter) and single preoperative diabetes characteristics used to construct these algorithms were evaluated by area under receiver operating characteristic curves (AUC). RESULTS: Diabetter showed greater performance for prediction of durable diabetes remission than other algorithms with acceptable discriminative ability (AUC between .69 and .79), but was not superior to T2D duration as a single predictor (P = .24 and P = .18). At 10 years, T2D duration had a better discriminative ability for the prediction of T2D remission than all 3 predictive models (AUC = .85, P < .05). CONCLUSIONS: Better chances for T2D remission following BPD-DS are associated with a shorter duration or T2D before surgery. Duration of T2D alone offers an excellent predictive ability and is a convenient alternative to diabetes remission scores to estimate chances of long-term diabetes remission after BPD-DS.

Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects.

OBJECTIVE: To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. METHODS: Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. RESULTS: BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. CONCLUSIONS: BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.

Molecular remodeling of adipose tissue is associated with metabolic recovery after weight loss surgery.

BACKGROUND: Bariatric surgery is an effective therapy for individuals with severe obesity to achieve sustainable weight loss and to reduce comorbidities. Examining the molecular signature of subcutaneous adipose tissue (SAT) following different types of bariatric surgery may help in gaining further insight into their distinct metabolic impact. RESULTS: Subjects undergoing biliopancreatic diversion with duodenal switch (BPD-DS) showed a significantly higher percentage of total weight loss than those undergoing gastric bypass or sleeve gastrectomy (RYGB + SG) (41.7 ± 4.6 vs 28.2 ± 6.8%; p = 0.00005). Individuals losing more weight were also significantly more prone to achieve both type 2 diabetes and dyslipidemia remission (OR = 0.75; 95%CI = 0.51-0.91; p = 0.03). Whole transcriptome and methylome profiling showed that bariatric surgery induced a profound molecular remodeling of SAT at 12 months postoperative, mainly through gene down-regulation and hypermethylation. The extent of changes observed was greater following BPD-DS, with 61.1% and 49.8% of up- and down-regulated genes, as well as 85.7% and 70.4% of hyper- and hypomethylated genes being exclusive to this procedure, and mostly associated with a marked decrease of immune and inflammatory responses. Weight loss was strongly associated with genes being simultaneously differentially expressed and methylated in BPD-DS, with the strongest association being observed for GPD1L (r2 = 0.83; p = 1.4 × 10-6). CONCLUSIONS: Present findings point to the greater SAT molecular remodeling following BPD-DS as potentially linked with higher metabolic remission rates. These results will contribute to a better understanding of the metabolic pathways involved in the response to bariatric surgery and will eventually lead to the development of gene targets for the treatment of obesity. Trial registration ClinicalTrials.gov NCT02390973.

Consistent gut bacterial and short-chain fatty acid signatures in hypoabsorptive bariatric surgeries correlate with metabolic benefits in rats.

OBJECTIVE: The study aimed at comparing how changes in the gut microbiota are associated to the beneficial effects of the most clinically efficient hypoabsorptive bariatric procedures, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). METHODS: Diet-induced obese (DIO) male Wistar rats were divided into seven groups. In addition to the groups subjected to RYGB, BPD-DS and SADI-S, the following four control groups were included: SHAM-operated rats fed a high-fat diet (SHAM HF), SHAM fed a low-fat diet (SHAM LF), SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW) and sleeve-gastrectomy (SG) rats. Body weight, food intake, glucose tolerance, insulin sensitivity/resistance, and L-cell secretion were assessed. The gut microbiota (16 S ribosomal RNA gene sequencing) as well as the fecal and cæcal contents of short-chain fatty acids (SCFAs) were also analyzed prior to, and after the surgeries. RESULTS: The present study demonstrates the beneficial effect of RYGB, BPD-DS and SADI-S on fat mass gain and glucose metabolism in DIO rats. These benefits were proportional to the effect of the surgeries on food digestibility (BPD-DS > SADI-S > RYGB). Notably, hypoabsorptive surgeries led to consonant microbial signatures characterized by decreased abundance of the Ruminococcaceae (Oscillospira and Ruminococcus), Oscillospiraceae (Oscillibacter) and Christensenellaceae, and increased abundance of the Clostridiaceae (Clostridium), Sutterellaceae (Sutterella) and Enterobacteriaceae. The gut bacteria following hypoabsorptive surgeries were associated with higher fecal levels of propionate, butyrate, isobutyrate and isovalerate. Increases in the fecal SCFAs were in turn positively and strongly correlated with the levels of peptide tyrosine-tyrosine (PYY) and with the beneficial effects of the surgery. CONCLUSION: The present study emphasizes the consistency with which the three major hypoabsorptive bariatric procedures RYGB, BPD-DS and SADI-S create a gut microbial environment capable of producing a SCFA profile favorable to the secretion of PYY and to beneficial metabolic effects.

IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery.

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.

Determinants of Cardiorespiratory Fitness After Bariatric Surgery: Insights From a Randomised Controlled Trial of a Supervised Training Program.

BACKGROUND: Severely obese patients have decreased cardiorespiratory fitness (CRF) and poor functional capacity. Bariatric surgery-induced weight loss improves CRF, but the determinants of this improvement are not well known. We aimed to assess the determinants of CRF before and after bariatric surgery and the impact of an exercise training program on CRF after bariatric surgery. METHODS: Fifty-eight severely obese patients (46.1 ± 6.1 kg/m2, 78% women) were randomly assigned to either an exercise group (n = 39) or usual care (n = 19). Exercise training was conducted from the 3rd to the 6th months after surgery. Anthropometric measurements, abdominal and mid-thigh computed tomographic scans, resting echocardiography, and maximal cardiopulmonary exercise testing was performed before bariatric surgery and 3 and 6 months after surgery. RESULTS: Weight, fat mass, and fat-free mass were reduced significantly at 3 and 6 months, without any additive impact of exercise training in the exercise group. From 3 to 6 months, peak aerobic power (V̇O2peak) increased significantly (P < 0.0001) in both groups but more importantly in the exercise group (exercise group: from 18.6 ± 4.2 to 23.2 ± 5.7 mL/kg/min; control group: from 17.4 ± 2.3 to 19.7 ± 2.4 mL/kg/min; P value, group × time = 0.01). In the exercise group, determinants of absolute V̇O2peak (L/min) were peak exercise ventilation, oxygen pulse, and heart rate reserve (r2 = 0.92; P < 0.0001), whereas determinants of V̇O2peak indexed to body mass (mL/kg/min) were peak exercise ventilation and early-to-late filling velocity ratio (r2 = 0.70; P < 0.0001). CONCLUSIONS: A 12-week supervised training program has an additive benefit on cardiorespiratory fitness for patients who undergo bariatric surgery.

Long Alimentary Limb Duodenal Switch (LADS): an Exploratory Randomized Trial, Results at 2 Years.

PURPOSE: The effectiveness of the standard biliopancreatic diversion with duodenal switch (BPD/DS) in terms of weight loss has been demonstrated. Increasing the strict alimentary limb length while maintaining the length of the common channel could lead to similar weight loss while reducing side effects. MATERIALS AND METHODS: The objective was to evaluate the effect of increasing the strict alimentary limb length on weight loss, comorbidities, nutritional deficiencies, and quality of life 2 years after surgery, compared with standard BPD/DS. An exploratory randomized, double-blind study evaluated the results of LADS at 2 years in comparison with the standard BPD/DS. Common channel was kept at 100 cm in both groups while alimentary limb was created at 100 cm from Treitz angle in the LADS group and at 150 cm total in the BPD/DS group. RESULTS: Twenty patients were recruited from May 2013 to June 2015. Mean percentage of excess weight loss was statistically significantly lower in the LADS group at 24 months (81.6 ± 6.6% in the LADS group and 97.1 ± 11.1% in the BPD/DS group (p = 0.001). No significant difference regarding the rate of remission of comorbidities was noted. Mean calcium, vitamin D, hemoglobin, zinc, and copper levels were statistically lower in the BPD/DS group. Quality of life was significantly improved in both groups, with no statistically significant difference between the two groups. CONCLUSIONS: At 24 months, weight loss was lower in the LADS group. However, no difference was observed in the improvement in quality of life. LADS technique was discontinued following this study. TRIAL REGISTRATION: ClinicalTrial.gov Ref. NCT03097926.

Ten-year remission rates in insulin-treated type 2 diabetes after biliopancreatic diversion with duodenal switch.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) confers the highest rate of type 2 diabetes (T2D) remission compared with other bariatric procedures. Previous studies suggest that type of antidiabetic therapy used before surgery and duration of disease influence postsurgical glycemic outcomes. Short-term, progressive improvement in insulin sensitivity and beta-cell function after metabolic surgery in patients with noninsulin-treated T2D has been demonstrated. Whether patients with more advanced disease can achieve sustained remission remains unclear. OBJECTIVE: The aim of this study was to assess long-term glycemic outcomes in insulin-treated patients with T2D after BPD-DS and identify predictors of sustained diabetes remission or relapse. SETTING: University-affiliated tertiary care center. METHODS: Data from 141 patients with insulin-treated T2D who underwent BPD-DS between 1994 and 2006 with 10 years of follow-up data were collected from a prospective electronic database. RESULTS: Follow-up was available in 132 patients (91%). At 10 years after metabolic surgery, 90 patients (68.1%) had a complete remission of diabetes, 3 (2.3%) had a partial remission, 21 (15.9%) had an improvement, and 3 (2.3%) were unchanged in their diabetes status. Fourteen patients died during the 10-year follow-up period. Relapse after an initial period of remission occurred in 15 (11.4%) patients. Insulin discontinuation was achieved in 97%. Duration of diabetes was an independent predictor of nonremission at 10 years. CONCLUSIONS: The BPD-DS maintains remission at 10 years postoperatively in patients with more advanced diabetes. Long-term benefits of the BPD-DS on weight loss and glycemic control should be considered when offering metabolic surgery to patients with insulin-treated T2D.

Acute and Chronic Impact of Biliopancreatic Diversion with Duodenal Switch Surgery on Plasma Lipoprotein(a) Levels in Patients with Severe Obesity.

BACKGROUND: Elevated lipoprotein(a) (Lp(a)) level is an independent risk factor for cardiovascular diseases. Lifestyle intervention studies targeting weight loss revealed little to no significant changes in Lp(a) levels. The impact of interventions that induce substantial weight loss, such as bariatric surgery, on Lp(a) levels is currently unclear. OBJECTIVE: To determine the acute and long-term impact of bariatric surgery on Lp(a) levels in patients with severe obesity. METHODS: Sixty-nine patients with severe obesity underwent biliopancreatic diversion with duodenal switch (BPD-DS) surgery. The lipid profile was evaluated and Lp(a) levels were measured before surgery and at 6 and 12 months after BPD-DS surgery. RESULTS: Median Lp(a) levels at baseline were 11.1 (4.1-41.6) nmol/L. Six months and 12 months after the BDP-DS surgery, we observed an improvement of lipid profile. At 6 months, we observed a 13% decrease in Lp(a) levels (9.7 (2.9-25.6) nmol/L, p < 0.0001) but this decrease was not sustained at 12 months (11.1 (3.9-32.8) nmol/L, p = 0.8). When the patients were separated into tertiles according to Lp(a) levels at baseline, we observed that the Lp(a) reduction at 12 months after BPD-DS surgery remained significant but modest in patients of the top Lp(a) tertile. CONCLUSION: Our results suggest that BPD-DS surgery modestly reduces Lp(a) levels in the short term (6 months) in patients with severe obesity but this improvement is sustained over time only in patients with higher Lp(a) levels.

Impact of a 12-Week Randomized Exercise Training Program on Lipid Profile in Severely Obese Patients Following Bariatric Surgery.

PURPOSE: The benefit of exercise training on lipid profile in bariatric surgery patients is scarce. We assess the effect of a supervised exercise-training program on lipid profile following bariatric surgery. MATERIALS AND METHODS: A total of 60 patients were prospectively recruited, of those 49 completed the study (age 41 ± 11 years; body mass index 45.9 ± 6.1 kg/m2, 75% women). The bariatric surgery procedures performed were sleeve gastrectomy (SG) (n = 24) and biliopancreatic diversion with duodenal switch (BPD-DS) (n = 25). Of the 49 patients who completed the study, 34 had been randomized to a 12-week supervised exercise training program (exercise group) between the 3rd and the 6th month following bariatric surgery (SG = 17 and BPD-DS = 17). Fasting blood samples and anthropometric measurements were performed preoperatively and at 3, 6, and 12 months after bariatric surgery. RESULTS: At 6 months and 12 months, percentage of weight loss was similar between groups (6 months: - 29.6 ± 5.5 vs. - 27.8 ± 7.7%; P = 0.371; 12 months: - 38.4 ± 10.4 vs. - 37.9 ± 9.5%; P = 0.876 exercise vs. control). Both groups had an increase in HDL values between the 3nd and the 6th month following bariatric surgery. There was a significantly greater increment in HDL values in the exercise group (0.18 ± 0.14 vs. 0.07 ± 0.12 mmol/L, P = 0.014; exercise vs. control). CONCLUSION: Our results showed a beneficial effect of a 12-week supervised exercise-training program in bariatric surgery patients showing similar weight loss on HDL-cholesterol levels without additional effect on LDL-cholesterol levels.

Association between changes in bioactive osteocalcin and glucose homeostasis after biliopancreatic diversion.

PURPOSE: Bone may regulate glucose homeostasis via uncarboxylated bioactive osteocalcin (ucOCN). This study explored whether changes in ucOCN and bone remodeling are associated with change in glucose homeostasis after biliopancreatic diversion (BPD). METHODS: In this secondary exploratory analysis of a 1-year prospective observational study, 16 participants (11 men/5 women; 69% with type 2 diabetes; mean BMI 49.4 kg/m2) were assessed before, 3 days, 3 months and 12 months after BPD. Changes in plasma ucOCN and bone markers (C-terminal telopeptide (CTX), total osteocalcin (OCN)) were correlated with changes in insulin resistance or sensitivity indices (HOMA-IR; adipose tissue insulin resistance index (ADIPO-IR) and insulin sensitivity index (SI) from the hyperinsulinemic-euglycemic clamp), insulin secretion rate (ISR) from the hyperglycemic clamp, and disposition index (DI: SI × ISR) using Spearman correlations before and after adjustment for weight loss. RESULTS: ucOCN was unchanged at 3 days but increased dramatically at 3 months (+257%) and 12 months (+498%). Change in ucOCN correlated significantly with change in CTX at 3 months (r = 0.62, p = 0.015) and 12 months (r = 0.64, p = 0.025) before adjustment for weight loss. It also correlated significantly with change in fasting insulin (r = -0.53, p = 0.035), HOMA-IR (r = -0.54, p = 0.033) and SI (r = 0.52, p = 0.041) at 3 days, and ADIPO-IR (r = -0.69, p = 0.003) and HbA1c (r = -0.69, p = 0.005) at 3 months. Change in OCN did not correlate with any glucose homeostasis indices. Results were similar after adjustment for weight loss. CONCLUSION: The increase in ucOCN may be associated with the improvement in insulin resistance after BPD, independently of weight loss. These findings need to be confirmed in larger, less heterogeneous populations.

Bariatric Surgery Rapidly Decreases Cardiac Dietary Fatty Acid Partitioning and Hepatic Insulin Resistance Through Increased Intra-abdominal Adipose Tissue Storage and Reduced Spillover in Type 2 Diabetes.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8-12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39-2.57) before to 1.09 (1.04-1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04-0.31] before to 0.49 (0.20-0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = -0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity.

BACKGROUND: There is solid evidence that obesity induces the acceleration of liver epigenetic aging. However, unlike easily accessible blood or subcutaneous adipose tissue, little is known about the impact of obesity on epigenetic aging of metabolically active visceral adipose tissue (VAT). Herein, we aimed to test whether obesity accelerates VAT epigenetic aging in subjects with severe obesity. RESULTS: A significant and positive correlation between chronological age and epigenetic age, estimated with a reduced version of the Horvath's epigenetic clock, was found in both blood (r = 0.78, p = 9.4 × 10-12) and VAT (r = 0.80, p = 1.1 × 10-12). Epigenetic age acceleration, defined as the residual resulting from regressing epigenetic age on chronological age, was significantly correlated with body mass index (BMI) in VAT (r = 0.29, p = 0.037). Multivariate linear regression analysis showed that, after adjusting for chronological age, sex and metabolic syndrome status, BMI remained significantly associated with epigenetic age acceleration in VAT (beta = 0.15, p = 0.035), equivalent to 2.3 years for each 10 BMI units. Binomial logistic regression showed that BMI-adjusted epigenetic age acceleration in VAT was significantly associated with a higher loss of excess body weight following biliopancreatic diversion with duodenal switch surgery (odds ratio = 1.21; 95% CI = 1.04-1.48; p = 0.03). CONCLUSIONS: Epigenetic age acceleration increases with BMI in VAT, but not in blood, as previously reported in liver. These results suggest that obesity is associated with epigenetic age acceleration of metabolically active tissues. Further studies that deepen the physiological relevance of VAT epigenetic aging will help to better understand the onset of metabolic syndrome and weight loss dynamics following bariatric surgery.

Acute and chronic effect of bariatric surgery on circulating autotaxin levels.

Autotaxin (ATX), an adipose tissue-derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short- (24 h, 5 days) and longer-term (6 and 12 months) impact of bariatric surgery; as well as the short-term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m2 ), before and after biliopancreatic diversion with duodenal switch surgery (BPD-DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3-day CR protocol before their BPD-DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA-IR) as well as insulin and leptin levels and negatively with fat-free mass. ATX concentrations decreased 26.2% at 24 h after BPD-DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P < 0.0001) and by 16.4% at 12 months after BPD-DS (342.9 ± 152.3 pg/mL to 286.8 ± 182.6 pg/mL, P = 0.04). ATX concentrations were unchanged during follow-up in the control group (P = 0.4), and not influenced by short-term CR. In patients with severe obesity, bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Acute changes in ATX may not be explained by bariatric surgery-induced CR.

Effects of Biliopancreatic Diversion on Bone Turnover Markers and Association with Hormonal Factors in Patients with Severe Obesity.

BACKGROUND: This study evaluated early and medium-term changes in bone turnover markers, and their associations with weight loss, total bone mineral density (BMD), and hormonal changes after biliopancreatic diversion (BPD). METHODS: Ancillary study from a one-year prospective cohort of 16 individuals assessed before, 3 days, 3 and 12 months after BPD. Bone turnover markers (C-terminal telopeptide (CTX), intact osteocalcin (OC), sclerostin, and osteoprotegerin (OPG)) and several hormones were measured at each visit. Total BMD by DXA was assessed at baseline, 3 and 12 months after BPD. Three participants were lost to follow-up. RESULTS: CTX increased significantly at 3 days (+ 66%), 3 months (+ 219%), and 12 months (+ 295%). OC decreased at 3 days (- 19%) then increased at 3 months (+ 69%) and 12 months (+ 164%). Change in sclerostin was only significant between 3 days and 3 months (+ 13%), while change in OPG was significant between baseline and 3 days (+ 48%) and baseline and 12 months (+ 45%). CTX increase correlated negatively with weight loss at 3 (r = - 0.63, p = 0.009) and 12 months (r = - 0.58, p = 0.039), and total BMD decrease (r = - 0.67, p = 0.033) at 12 months. Change in insulin and adiponectin correlated with changes in bone turnover markers independently of weight loss. CONCLUSION: BPD causes an earlier and greater increase in bone resorption over bone formation markers and a decrease in total BMD. Sclerostin did not increase as expected following extensive weight loss. Changes in insulin and adiponectin seem to play a role in the activation of bone remodeling after BPD.

Characterization and visualization of the liposecretion process taking place during ceiling culture of human mature adipocytes.

OBJECTIVE: To investigate and further characterize the process of mature adipocyte dedifferentiation. Our hypothesis was that dedifferentiation does not involve mitosis but rather a phenomenon of liposecretion. METHODS: Mature adipocytes were isolated by collagenase digestion of human adipose tissue samples. Ceiling cultures were established using our six-well plate model. Cells were treated with cytosine ß-d-arabinofuranoside (AraC) or vincristine (VCR), two agents blocking cell division, and were compared with vehicle. Liposecretion events were visualized by time-lapse microscopy, with and without AraC in adipocytes transducted with a baculovirus. Microscopic analyses were performed after labeling phosphorylated histone 3 and cyclin B1 in ceiling cultures. RESULTS: Treatment with AraC almost entirely prevented the formation of fibroblasts up to 12 days of ceiling culture. Similar results were obtained with VCR. The antimitotic effectiveness of the treatment was confirmed in fibroblast cultures from the adipose tissue stromal-vascular fraction by proliferation assays and colony-forming unit experiments. Using time-lapse microscopy, we visualized liposecretion events in which a large lipid droplet was rapidly secreted from isolated mature adipocytes. The same phenomenon was observed with AraC. This was observed in conjunction with histone 3 phosphorylation and cyclin B1 segregation to the nucleus. CONCLUSION: Our results support the notion that dedifferentiation involves rapid secretion of the lipid droplet by the adipocytes with concomitant generation of fibroblast-like cells that subsequently proliferate to generate the dedifferentiated adipocyte population during ceiling culture. The presence of mitotic markers suggests that this process involves cell cycle progression, although cell division does not occur.

Second-stage duodenal switch for sleeve gastrectomy failure: A matched controlled trial.

BACKGROUND: Sleeve gastrectomy (SG) has become the predominant bariatric surgery worldwide. However, the surgical management in case of failure is still debated. OBJECTIVES: To evaluate the risks and benefits of converting SG to biliopancreatic diversion with duodenal switch (BPD-DS) for suboptimal outcome after SG. SETTING: University-affiliated tertiary care center. METHODS: We included all patients who underwent a laparoscopic second-stage duodenal switch (DS) for weight loss failure after SG and had a minimal follow-up of 2 years. Patients were matched 1:1 for age, sex, body mass index, and year of surgery with a group of patients who underwent a single-stage laparoscopic BPD-DS. Data were obtained from our prospective electronic database and are reported as the mean ± standard deviation, comparing 2- versus 1-stage BPD-DS. RESULTS: A total of 118 patients were included (59 in each group). There was no significant difference in initial body mass index (53.8 ± 9.7 versus 52.7 ± 7.8 kg/m2, P = .4), age (44.0 ± 10.2 versus 43.4 ± 9.6 yr, P = .5), and sex ratio (37 female/22 male, P > .9) between the 2 groups. Mean follow-up was 59.9 ± 27 months, with an 85% (n = 100) follow-up rate. Patients were converted to BPD-DS after a mean 24.4 ± 10.2 months. There was no short- or long-term mortality. Major 90-days complications occurred in 2%, 5%, and 5% after SG, second-stage DS and single-stage BPD-DS, respectively (P > .05). At the time of conversion, the excess weight loss for SG was 39 ± 17% and total weight loss was 20 ± 9%. After DS or single-stage BPD-DS, the excess weight loss was 74.8 ± 18% versus 87.9 ± 18% at 1 year (n = 107, P = .00021), 80.2 ± 17% versus 92.3 ± 14% at 2 years (n = 100, P = .002), and 80.2 ± 18% versus 87.2 ± 16% at 3 years (n = 70, P = .6). Total weight loss was 38.7 ± 9% versus 44.5 ± 8% at 1 year (P = .0004), 41.2 ± 9% versus 46.8 ± 7% at 2 years (P = .001), and 42.3 ± 9% versus 45.1 ± 9% at 3 years (P = .2). The incidence of type 2 diabetes and hypertension before surgery were 61% versus 54% and 58% versus 47%. Remission rate for type 2 diabetes increased from 59% to 94% after second-stage DS (P = .001), which is identical to first-stage BPD-DS (94%). Remission of hypertension increased from 42% to 77% after second-stage DS (P = .03) and was 71% after first-stage BPD-DS (P = .8). CONCLUSION: Second-stage DS is an effective option for the management of suboptimal outcomes of SG, with an additional 41% excess weight loss and 35% remission rate for type 2 diabetes. At 3 years, the global outcomes of staged approach did not significantly differ from single-stage BPD-DS; however, longer-term outcomes are still needed.

Warfarin Dose Adjustment After Biliopancreatic Diversion/Duodenal Switch Bariatric Surgery.

BACKGROUND: The absorption of drugs and fat-soluble vitamins is impaired after bariatric surgery on which intestinal length and function are altered. In this context, the anticoagulant effect of warfarin is difficult to predict in the postoperative period. OBJECTIVE: This study aimed at describing the average weekly warfarin dose required to maintain a therapeutic international normalized ratio (INR) before and up to 1 year after sleeve gastrectomy with biliopancreatic diversion and duodenal switch (BPD/DS). Secondary end points included the number of patients requiring a minimal 20% reduction in their weekly dose of warfarin following the BPD/DS. METHODS: This descriptive and retrospective longitudinal population study included 20 patients using warfarin who underwent BPD/DS. An INR was considered nontherapeutic if it was below or above 15% of the targeted therapeutic range for any given patient. RESULTS: One month after the surgery, the median weekly dose of warfarin was 55% lower than the preoperative dose ( P < 0.0001). In the 9 patients with full follow-up data, the warfarin dose at 1 year was still 39% lower than the preoperative dose ( P < 0.05). At that time, all patients presented a minimal dose reduction of 20%. CONCLUSIONS: BPD/DS robustly reduced the requirement of warfarin, which resulted in lower doses after surgery. This persisted over the first year after the surgery, likely because of enhanced sensitivity. The mechanisms for this effect remain multifactorial, and the exact extent of change in dose cannot be predicted.

Serum Parathyroid Hormone and 25-Hydroxyvitamin D Concentrations Before and After Biliopancreatic Diversion.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) decreases vitamin D and calcium absorption, which may result in secondary hyperparathyroidism. This study aimed at evaluating the prevalence of vitamin D deficiency and secondary hyperparathyroidism before and after BPD-DS. METHODS: A retrospective analysis of patients who had undergone BPD-DS at a tertiary bariatric center between 2003 and 2010 and for whom simultaneous measurements of serum 25-hydroxyvitamin D and parathyroid hormone were available within 5 years post-op was performed. The prevalence of vitamin D deficiency (< 20 ng/ml) and secondary hyperparathyroidism (> 65 pg/mL) at different time points was calculated. RESULTS: Included were 1436 patients (mean ± SD, age 42.7 ± 10.4 years; BMI 51.5 ± 8.6 kg/m2; 69.8% women). Prevalence of vitamin D deficiency decreased up to 6-12 months after surgery (from 35.8% at baseline down to 6-9%) then rose progressively, plateauing at 15.5% after 36 months. Prevalence of hyperparathyroidism was 28.5% before surgery and rose progressively after surgery, reaching 68.6% at 5 years. Mean serum corrected calcium increased from 0 to 6 months then decreased up to 36 months. Preoperatively, the prevalence of hypocalcemia was 7.3%. It increased after 12 months, attaining 26.9% at 48 months. CONCLUSIONS: Prevalence of vitamin D deficiency and secondary hyperparathyroidism is high before BPD-DS. Despite a low prevalence of vitamin D deficiency after surgery, prevalence of hyperparathyroidism increased steadily 1 year after surgery, preceded by a decrease in serum calcium. Factors explaining the high prevalence of secondary hyperparathyroidism after BPD-DS and its long-term impact on bone health should be addressed.

Long alimentary limb duodenal switch (LADS): a short-term prospective randomized trial.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) is one of the most effective bariatric surgeries, in terms of weight loss and remission of co-morbidities. It is however associated with a significant risk of protein and nutritional deficiency, as well as gastrointestinal side effects. OBJECTIVES: To assess the effect of increasing the strict alimentary limb on weight loss, nutritional deficiency and quality of life, compared with standard BPD-DS. SETTINGS: University-affiliated tertiary care center. METHODS: Prospective randomized double blind (patient-evaluator) trial in which patients were assigned in a 1:1 ratio to undergo a modified BPD-DS with a long alimentary limb (1 m from Treitz ligament, n = 10) or a standard biliopancreatic diversion (strict alimentary limb of 1.5 m, n = 10). Common channel was kept at 100 cm in both groups. Follow-up at 12 months was completed in all patients. RESULTS: Initial weight (126 ± 10 versus 125 ± 17, P = .92), age (40 ± 7 versus 37 ± 8, P = .35), and sex ratio (1 female/9 males) were similar in both groups. Excess weight loss and total weight loss were significantly higher in the standard BPD-DS group (93.4 ± 12% versus 73.3 ± 7%, P = .0007 and 46 ± 5.6% versus 37 ± 3.4%, P = .0004). The study group had significantly higher vitamin D, manganese, and copper levels at 12 months. Both groups had similar drop in glycated hemoglobin, cholesterol levels, and resolution of co-morbidities at 12 months. Long alimentary limb was associated with significantly less bowel movements a day (1.6 ± .97 versus 2.55 ± 1.01, P = .01), less gastrointestinal side effects (bloating and gas, P<.05) and required less pancreatic enzymes supplements (0 versus 40%, P = .04) and calcium supplement. Quality of life was significantly improved in both groups in all domains (all P<.05). CONCLUSION: At 12 months, weight loss was lesser in the long alimentary limb group. There was however no difference in the remission of co-morbidities and higher levels of vitamin D, manganese, and copper. Gastrointestinal adverse effects and the need for pancreatic enzymes were less with similarly excellent quality of life at 12 months. Longer follow-up is necessary to evaluate long-term weight loss and nutritional deficiencies.