Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.

BACKGROUND AND AIMS: Studies are needed to determine the long-term effects of bariatric surgery for patients with nonalcoholic steatohepatitis (NASH). We evaluated sequential liver samples, collected the time of bariatric surgery and 1 and 5 years later, to assess the long-term effects of bariatric surgery in patients with NASH. METHODS: We performed a prospective study of 180 severely obese patients with biopsy-proven NASH, defined by the NASH clinical research network histologic scores. The patients underwent bariatric surgery at a single center in France and were followed for 5 years. We obtained liver samples from 125 of 169 patients (76%) having reached 1 year and 64 of 94 patients (68%) having reached 5 years after surgery. The primary endpoint was the resolution of NASH without worsening of fibrosis at 5 years. Secondary end points were improvement in fibrosis (reduction of ≥1 stage) at 5 years and regression of fibrosis and NASH at 1 and 5 years. RESULTS: At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients (n = 64; 95% confidence interval, 73.1%-92.2%). Fibrosis decreased, compared with baseline, in samples from 70.2% of patients (95% CI, 56.6%-81.6%). Fibrosis disappeared from samples from 56% of all patients (95% CI, 42.4%-69.3%) and from samples from 45.5% of patients with baseline bridging fibrosis. Persistence of NASH was associated with no decrease in fibrosis and less weight loss (reduction in body mass index of 6.3 ± 4.1 kg/m2 in patients with persistent NASH vs reduction of 13.4 ± 7.4 kg/m2; P = .017 with resolution of NASH). Resolution of NASH was observed at 1 year after bariatric surgery in biopsies from 84% of patients, with no significant recurrence between 1 and 5 years (P = .17). Fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years (P < .001). CONCLUSIONS: In a long-term follow-up of patients with NASH who underwent bariatric surgery, we observed resolution of NASH in liver samples from 84% of patients 5 years later. The reduction of fibrosis is progressive, beginning during the first year and continuing through 5 years.

Efficacy and Safety of the Duodeno-Jejunal Bypass Liner in Patients With Metabolic Syndrome: A Multicenter Randomized Controlled Trial (ENDOMETAB).

OBJECTIVE: The aim of this study was to compare the efficacy and safety of 12-month implantation of a duodeno-jejunal bypass liner (DJBL) with conventional medical care in patients with metabolic syndrome (MS). SUMMARY BACKGROUND DATA: DJBL is an endoscopic device for treating obesity and related disorders. The persistence of favorable results after 6 months has not been tested in a controlled study. METHODS: We conducted a multicenter randomized controlled trial, stratified by center and diabetes status. The primary endpoint was the remission of MS at 12 months. The secondary endpoints included body mass index (BMI), glucose control, blood pressure, and lipids, assessed at 12 months after implantation, and again, at 12 months after the removal of the DJBL. Up to 174 subjects were planned to be randomized into either the DJBL or the control arm at a 2:1 ratio, respectively. Study enrollment was discontinued by the Scientific Monitoring Committee due to the early termination of the ENDO trial (NCT01728116) by the US Food and Drug Administration. The study was terminated after withdrawal of the device's European Conformity marking by the European Medicines Agency, and an interim analysis was performed. RESULTS: A total of 82 patients were enrolled (67.5% female, 48.8% with diabetes). At 12 months after randomization, the primary endpoint was met in 6 (12%) DJBL patients and 3 (10%) controls (P = 0.72). Patients in the DJBL group experienced greater BMI loss [mean adjusted difference (95% confidence interval, CI) -3.1 kg/m (-4.4 to -1.9) kg/m, P < 0.001] and HbA1c change [mean adjusted difference -0.5% (95% CI -0.9 to -0.2); P < 0.001] than those in the control group. No difference remained statistically significant at 12 months after the removal of the DJBL. In the DJBL group, 39% of patients experienced at least one device-related serious adverse event, which was classified as Grade III Dindo-Clavien in 22%, and required premature device explantation in 16%. CONCLUSIONS: The present study showed a transient clinical benefit of DJBL, which was only apparent at 1 year, when the device was still in situ, and was obtained at the risk of serious device-related adverse events in 39% of patients. These results do not support the routine use of DJBL for weight loss and glucose control in patients with MS.

Decreased emotional eating behavior is associated with greater excess weight loss five years after gastric banding.

While significant weight loss has been observed in the first two years following adjustable gastric banding (AGB), research on the long-term effectiveness of gastric restriction (e.g., 5 years) both on weight loss and eating behavior changes is scarce. The present study examined obese patients' changes in eating behavior preoperatively and 5 years after AGB and examined their associations with excess weight loss (EWL). Specifically, we focused on the association between the modification of three eating behavior profiles (i.e., restrained eating, emotional eating and external eating) and %EWL at 5 years. Among the 197 participants who underwent AGB, 136 completed the clinical assessments (weight, depression with the BDI, eating behavior with the DEBQ) before surgery, and after 5 years. Resultsshowed that the mean percentage of EWL was 47% after 5 years. Moreover, patients reported lower emotional eating and external eating after 5 years in comparison to the baseline, whereas there were no differences concerning restrained eating. Importantly, patients who presented higher %EWL at 5 years also reported a greater decrease in emotional eating between the two sessions than those with low %EWL. Our study underlines that eating behaviors are major variables involved in weight loss after gastric restriction. Results showed that emotional and external eating decreased significantly at 5 years whereas restrained eating behaviors did not vary between the pre- and postoperative stages. Moreover, the data suggest that a decrease in emotional eating accounts for the extent of EWL.

Difficulties in emotion regulation and deficits in interoceptive awareness in moderate and severe obesity.

PURPOSE: Difficulties in emotion regulation and deficits in interoceptive awareness may be responsible for overeating and weight gain in obesity by increasing the risks of problematic eating behaviors. This study aimed to: (1) examine emotion regulation difficulties and interoceptive deficits in obesity; (2) compare the emotion regulation and interoceptive abilities of moderately and severely obese patients. METHODS: Participants were recruited through the university, diabetology centers and bariatric surgery departments. A total of 165 participants were categorized in three groups, matched by age and gender, according to their Body Mass Index (BMI). The severely obese (SO), moderately obese (MO) and normal weight (NW) groups were constituted of 55 participants each. Self-report questionnaires were used to assess emotion regulation difficulties (CERQ-DERS) and interoceptive awareness (MAIA-FFMQ). RESULTS: Overall, obese participants reported more emotion regulation difficulties and less interoceptive awareness than NW participants did. They also reported a lack of planning strategies and emotional awareness, as well as less ability to observe, notice and trust body sensations. No differences in emotion regulation and interoceptive abilities were found between MO and SO participants. CONCLUSIONS: Emotion regulation and interoceptive awareness should be targeted in the psychotherapeutic care of obese people, regardless of their BMI. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Incidence and Predictive Factors of Postprandial Hyperinsulinemic Hypoglycemia After Roux-en-Y Gastric Bypass: A Five year Longitudinal Study.

BACKGROUND: Postprandial hyperinsulinemic hypoglycemia (PHH) is often reported after Roux-en-Y gastric bypass (RYGB). In the absence of a prospective study, the clinical and biological determinants of PHH remain unclear. OBJECTIVE: To determine the incidence and predictive factors of PHH after RYGB. METHODS: Participants were 957 RYGB patients enrolled in an ongoing longitudinal cohort study. We analyzed the results of an oral glucose tolerance test (OGTT) routinely performed before surgery and 1 and/or 5 years after. PHH was defined as blood glucose < 50 mg/dL AND plasma insulin > 3 mU/L at 120 minutes post glucose challenge. Validated indices of insulin sensitivity (Matsuda index), beta-cell function (Insulinogenic index), and beta-cell mass (fasting C-peptide: glucose ratio) were calculated, from glucose, insulin, and c-peptide values measured during OGTT. RESULTS: OGTT results were available in all patients at baseline, in 85.6% at 12 months and 52.8% at 60 months. The incidence of PHH was 0.5% at baseline, 9.1% * and 7.9%* at 12 months and 60 months following RYGB (*: P < 0.001). In multivariate logistic regression analysis, PHH after RYGB was independently associated with lower age (P = 0.005), greater weight loss (P = 0.031), as well as higher beta-cell function (P = 0.002) and insulin sensitivity (P < 0.001), but not with beta-cell mass (P = 0.381). A preoperative elevated beta-cell function was an independent predictor of PHH after RYGB (receiver operating characteristics curve area under the curve 0.68, P = 0.04). CONCLUSIONS:: The incidence of PHH significantly increased after RYGB but remained stable between 1 and 5 years. The estimation of beta-cell function with an OGTT before surgery can identify patients at risk for developing PHH after RYGB.

Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients.

BACKGROUND & AIMS: The effects of bariatric surgery in patients with nonalcoholic fatty liver disease (NASH) are not well established. We performed a prospective study to determine the biological and clinical effects of bariatric surgery in patients with NASH. METHODS: From May 1994 through May 2013, one hundred and nine morbidly obese patients with biopsy-proven NASH underwent bariatric surgery at the University Hospital of Lille, France (the Lille Bariatric Cohort). Clinical, biological, and histologic data were collected before and 1 year after surgery. RESULTS: One year after surgery, NASH had disappeared from 85% of the patients (95% confidence interval [CI]: 75.8%-92.2%). Compared with before surgery, patients had significant reductions in mean ± SD body mass index (BMI, from 49.3 ± 8.2 to 37.4 ± 7) and level of alanine aminotransferase (from 52.1 ± 25.7 IU/L to 25.1 ± 20 IU/L); mean levels of γ-glutamyltransferases were reduced from 51 IU/L before surgery (interquartile range [IQR], 34-87 IU/L) to 23 IU/L afterward (IQR, 14-33 IU/L) and mean insulin resistance index values were reduced from 3.6 ± 0.5 to 2.9 ± 0.5 (P < .01 for each comparison). NASH disappeared from a higher proportion of patients with mild NASH before surgery (94%) than severe NASH (70%) (P < .05) according to Brunt score. In histologic analysis, steatosis was detected in 60% of the tissue before surgery (IQR, 40%-80%) but only 10% 1 year after surgery (IQR, 2.5%-21.3%); the mean nonalcoholic fatty liver disease score was reduced from 5 (IQR, 4-5) to 1 (IQR, 1-2) (each P < .001). Hepatocellular ballooning was reduced in 84.2% of samples (n = 69; 95% CI: 74.4-91.3) and lobular inflammation in 67.1% (n = 55; 95% CI: 55.8-77.1). According to Metavir scores, fibrosis was reduced in 33.8% of patients (95% CI: 23.6%-45.2%). Patients whose NASH persisted 1 year after surgery (n = 12) had lost significantly less weight (change in BMI, 9.1 ± 1.5) than those without NASH (change in BMI, 12.3 ± 0.6) (P = .005). Patients who underwent laparoscopic gastric banding lost less weight (change in BMI, 6.4 ± 0.7) than those who underwent gastric bypass (change in BMI, 14.0 ± 0.5) (P < .0001), and a higher proportion had persistent NASH (30.4% vs 7.6% of those with gastric bypass; P = .015). CONCLUSIONS: Bariatric surgery induced the disappearance of NASH from nearly 85% of patients and reduced the pathologic features of the disease after 1 year of follow-up. It could be a therapeutic option for appropriate morbidly obese patients with NASH who do not respond to lifestyle modifications. More studies are needed to determine the long-term effects of bariatric surgery in morbidly obese patients with NASH.

Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study.

OBJECTIVES: To compare the long-term benefit of gastric bypass [Roux-en-Y gastric bypass (RYGB)] versus adjustable gastric banding (AGB) on nonalcoholic fatty liver disease (NAFLD) in severely obese patients. BACKGROUND: NAFLD improves after weight loss surgery, but no histological study has compared the effects of the various bariatric interventions. METHODS: Participants consisted of 1236 obese patients (body mass index=48.4±7.6 kg/m), enrolled in a prospective longitudinal study for up to 5 years after RYGB (n=681) or AGB (n=555). Liver biopsy samples were available for 1201 patients (97.2% of those at risk) at baseline, 578 patients (47.2%) at 1 year, and 413 patients (68.9%) at 5 years. RESULTS: At baseline, NAFLD was present in 86% patients and categorized as severe [NAFLD activity score (NAS)≥3] in 22% patients. RYGB patients had a higher body mass index (49.8±8.2 vs 46.8±6.5 kg/m, P<0.001) and more severe NAFLD (NAS: 2.0±1.5 vs 1.7±1.4, P=0.004) than AGB patients. Weight loss at 5 years was 25.5%±11.8% after RYGB versus 21.4%±12.7% after AGB (P<0.001). When analyzed with a mixed model, all NAFLD parameters improved after surgery (P<0.001) and improved significantly more after RYGB than after AGB [steatosis (%): 1 year, 7.9±13.7 vs 17.9±21.5, P<0.001/5 years, 8.7±7.1 vs 14.5±20.8, P<0.05; NAS: 1 year, 0.7±1.0 vs 1.1±1.2, P<0.001/5 years, 0.7±1.2 vs 1.0±1.3, P<0.05]. In multivariate analysis, the superiority of RYGB was primarily but not entirely explained by weight loss. CONCLUSIONS: The improvement of NAFLD was superior after RYGB than after AGB.

Performance of non-invasive tests for liver fibrosis resolution after bariatric surgery.

BACKGROUND & AIMS: The value of non-invasive tests for monitoring the resolution of significant liver fibrosis after treatment is poorly investigated. We compared the performances of six non-invasive tests to predict the resolution of significant fibrosis after bariatric surgery. METHODS: Participants were individuals with obesity submitted to needle liver biopsy at the time of bariatric surgery, and 12 and/or 60 months after surgery. We calculated the fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), AST to platelet ratio index (APRI), Hepatic fibrosis score (HFS), Fibrotic NASH index (FNI), and Liver risk score (LRS) at each time point, and compared their performances for predicting significant fibrosis (F ≥ 2) and its resolution following surgery. RESULTS: At baseline, 2436 patients had liver biopsy, including 261 (10.7 %) with significant fibrosis. Overall, 672 patients had pre- and post-operative biopsies (564 at M12 and 328 at M60). The fibrosis stage decreased at M12 and M60 (p < 0.001 vs M0). Resolution of significant fibrosis occurred in 58/121 (47.9 %) at M12 and 32/50 (64 %) at M60. The mean value of all tests decreased after surgery, except for FIB-4. Performances for predicting fibrosis resolution was higher at M60 than at M12 for all tests, and maximal at M60 for FNI and LRS: area under the curve 0.843 (95%CI 0.71-0.95) and 0.92 (95%CI 0.84-1.00); positive likelihood ratio 3.75 (95 % CI 1.33-10.59) and 4.58 (95 % CI 1.65-12.70), respectively. CONCLUSIONS: Results showed the value and limits of non-invasive tests for monitoring the evolution of liver fibrosis after an intervention. Following bariatric surgery, the best performances to predict the resolution of significant fibrosis were observed at M60 with tests combining liver and metabolic traits, namely FNI and LRS.

Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD.

Background & Aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. Methods: Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers. Results: Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity. Conclusion: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained. Impact and implications: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases.

Genetic Evidence of Causal Relation Between Intestinal Glucose Absorption and Early Postprandial Glucose Response: A Mendelian Randomization Study.

The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of -0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes.

An Evaluation of the Implementation of the European Calcified Tissue Society Recommendations on the Prevention and Treatment of Osteoporosis Secondary to Bariatric Surgery.

The purpose of this study was to evaluate the implementation of the European Calcified Tissue Society (ECTS) 2022 recommendations on the prevention and treatment of osteoporosis secondary to bariatric surgery. The ECTS 2022 recommendations were applied in a retrospective cohort of postmenopausal women and men aged 50 years and older who were undergoing or had already undergone bariatric surgery. Osteoporosis medication was indicated if any of the following criteria were met: (i) history of recent (within 2 years) fragility fracture after the age of 40 years, (ii) BMD T score ≤ -2 at any of the sites of measurement, and (iii) FRAX® ≥ 20% for major osteoporotic fractures and/or ≥3% for hip fractures. Of the 170 patients (144 women, mean age 59 (55 to 63) years) included between February 2019 and March 2022, 33 were eligible for osteoporosis medication based on the ECTS 2022 recommendations, i.e., a prevalence of 19.6% [CI95%: 13.9%; 26.5%]. Most patients met the BMD T score ≤ -2 criterion (n = 25/170, 14.7% [CI95%: 9.7%; 20.9%]) and/or the history of recent fragility fracture criterion (n = 12/170, 7.1% [CI95%: 3.7%; 12.0%]). In this study, a fifth of our population was found to be eligible for osteoporosis medication after the application of the ECTS 2022 recommendations.

Combining diabetes, sex, and menopause as meaningful clinical features associated with NASH and liver fibrosis in individuals with class II and III obesity: A retrospective cohort study.

OBJECTIVE: Steatotic liver disease (SLD) is frequent in individuals with obesity. In this study, type 2 diabetes (T2D), sex, and menopausal status were combined to refine the stratification of obesity regarding the risk of advanced SLD and gain further insight into disease physiopathology. METHODS: This study enrolled 1446 participants with obesity from the ABOS cohort (NCT01129297), who underwent extensive phenotyping, including liver histology and transcriptome profiling. Hierarchical clustering was applied to classify participants. The prevalence of metabolic disorders associated with steatohepatitis (NASH) and liver fibrosis (F ≥ 2) was determined within each identified subgroup and aligned to clinical and biological characteristics. RESULTS: The prevalence of NASH and F ≥ 2 was, respectively, 9.5% (N = 138/1446) and 11.7% (N = 159/1365) in the overall population, 20.3% (N = 107/726) and 21.1% (N = 106/502) in T2D patients, and 3.4% (N = 31/920) and 6.1% (N = 53/863) in non-T2D patients. NASH and F ≥ 2 prevalence was 15.4% (33/215) and 15.5% (32/206) among premenopausal women with T2D vs. 29.5% (33/112) and 30.3% (N = 36/119) in postmenopausal women with T2D (p < 0.01); and 21.0% (21/100) / 27.0% (24/89) in men with T2D ≥ age 50 years and 17.9% (17/95) / 18.5% (17/92) in men with T2D < age 50 years (NS). The distinct contribution of menopause was confirmed by the interaction between sex and age with respect to NASH among T2D patients (p = 0.048). Finally, several NASH-associated biological traits (lower platelet count; higher serum uric acid; gamma-glutamyl transferase; aspartate aminotransferase) and liver expressed genes AKR1B10 and CCL20 were significantly associated with menopause in women with T2D but not with age in men with T2D. CONCLUSIONS: This study unveiled a remarkably high prevalence of advanced SLD after menopause in women with T2D, associated with a dysfunctional biological liver profile.

Development and validation of an interpretable machine learning-based calculator for predicting 5-year weight trajectories after bariatric surgery: a multinational retrospective cohort SOPHIA study.

BACKGROUND: Weight loss trajectories after bariatric surgery vary widely between individuals, and predicting weight loss before the operation remains challenging. We aimed to develop a model using machine learning to provide individual preoperative prediction of 5-year weight loss trajectories after surgery. METHODS: In this multinational retrospective observational study we enrolled adult participants (aged ≥18 years) from ten prospective cohorts (including ABOS [NCT01129297], BAREVAL [NCT02310178], the Swedish Obese Subjects study, and a large cohort from the Dutch Obesity Clinic [Nederlandse Obesitas Kliniek]) and two randomised trials (SleevePass [NCT00793143] and SM-BOSS [NCT00356213]) in Europe, the Americas, and Asia, with a 5 year follow-up after Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric band. Patients with a previous history of bariatric surgery or large delays between scheduled and actual visits were excluded. The training cohort comprised patients from two centres in France (ABOS and BAREVAL). The primary outcome was BMI at 5 years. A model was developed using least absolute shrinkage and selection operator to select variables and the classification and regression trees algorithm to build interpretable regression trees. The performances of the model were assessed through the median absolute deviation (MAD) and root mean squared error (RMSE) of BMI. FINDINGS: 10 231 patients from 12 centres in ten countries were included in the analysis, corresponding to 30 602 patient-years. Among participants in all 12 cohorts, 7701 (75·3%) were female, 2530 (24·7%) were male. Among 434 baseline attributes available in the training cohort, seven variables were selected: height, weight, intervention type, age, diabetes status, diabetes duration, and smoking status. At 5 years, across external testing cohorts the overall mean MAD BMI was 2·8 kg/m2 (95% CI 2·6-3·0) and mean RMSE BMI was 4·7 kg/m2 (4·4-5·0), and the mean difference between predicted and observed BMI was -0·3 kg/m2 (SD 4·7). This model is incorporated in an easy to use and interpretable web-based prediction tool to help inform clinical decision before surgery. INTERPRETATION: We developed a machine learning-based model, which is internationally validated, for predicting individual 5-year weight loss trajectories after three common bariatric interventions. FUNDING: SOPHIA Innovative Medicines Initiative 2 Joint Undertaking, supported by the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, Type 1 Diabetes Exchange, and the Juvenile Diabetes Research Foundation and Obesity Action Coalition; Métropole Européenne de Lille; Agence Nationale de la Recherche; Institut national de recherche en sciences et technologies du numérique through the Artificial Intelligence chair Apprenf; Université de Lille Nord Europe's I-SITE EXPAND as part of the Bandits For Health project; Laboratoire d'excellence European Genomic Institute for Diabetes; Soutien aux Travaux Interdisciplinaires, Multi-établissements et Exploratoires programme by Conseil Régional Hauts-de-France (volet partenarial phase 2, project PERSO-SURG).

[Patient care pathway before bariatric surgery]. / Parcours de soins du patient avant une chirurgie bariatrique.

PATIENT CARE PATHWAY BEFORE BARIATRIC SURGERY In France, the preoperative period for bariatric surgery is the target of recommendations from the Haute Autorité de Santé (since 2009). During this period, which lasts at least 6 months, the multidisciplinary team must verify the indication (BMI, body mass index, greater than 40 kg/m2 or 35 kg/m2 with at least one comorbidity) and investigate possible contraindications, particularly psychological. This time is also necessary to understand the reasons for the excess weight and to initiate changes as part of a therapeutic education program. Medical examinations are carried out to detect possible co-morbidities and to establish a morphological assessment before surgery. At the end of this process, the patient must express his or her informed consent and the bariatric team will state the indication based on a multidisciplinary concertation. Experience shows the importance of the preoperative course in the patient's experience and for the good progress of the postoperative follow-up.

PARCOURS DE SOINS DU PATIENT AVANT UNE CHIRURGIE BARIATRIQUE En France, la période préopératoire d'une chirurgie bariatrique fait l'objet de recommandations de la haute autorité de santé (HAS) depuis 2009. Pendant cette phase, qui dure au moins six mois, l'équipe pluridisciplinaire doit vérifier l'indication (IMC supérieur à 40 kg/m2 ou à 35 kg/m2 avec au moins une comorbidité) et rechercher d'éventuelles contre-indications, notamment psychologiques. Ce temps est également nécessaire pour comprendre les raisons de la prise de poids et amorcer des changements dans le cadre d'un programme d'éducation thérapeutique. Des examens médicaux permettent de dépister d'éventuelles comorbidités et de réaliser le bilan morphologique avant la chirurgie. Au terme de ce parcours, le patient doit exprimer son consentement éclairé, et l'équipe bariatrique pose l'indication lors d'une concertation pluridisciplinaire. L'expérience montre l'importance du parcours préopératoire pour le vécu du patient et le bon déroulé du suivi postopératoire.

Data-driven subgroups of type 2 diabetes, metabolic response, and renal risk profile after bariatric surgery: a retrospective cohort study.

BACKGROUND: A novel data-driven classification of type 2 diabetes has been proposed to personalise anti-diabetic treatment according to phenotype. One subgroup, severe insulin-resistant diabetes (SIRD), is characterised by mild hyperglycaemia but marked hyperinsulinaemia, and presents an increased risk of diabetic nephropathy. We hypothesised that patients with SIRD could particularly benefit from metabolic surgery. METHODS: We retrospectively related the newly defined clusters with the response to metabolic surgery in participants with type 2 diabetes from independent cohorts in France (the Atlas Biologique de l'Obésite Sévère [ABOS] cohort, n=368; participants underwent Roux-en-Y gastric bypass or sleeve gastrectomy between Jan 1, 2006, and Dec 12, 2017) and Brazil (the metabolic surgery cohort of the German Hospital of San Paulo, n=121; participants underwent Roux-en-Y gastric bypass between April 1, 2008, and March 20, 2016). The study outcomes were type 2 diabetes remission and improvement of estimated glomerular filtration rate (eGFR). FINDINGS: At baseline, 34 (9%) of 368 patients, 314 (85%) of 368 patients, and 17 (5%) of 368 patients were classified as having SIRD, mild obesity-related diabetes (MOD), and severe insulin deficient diabetes (SIDD) in the ABOS cohort, respectively, and in the São Paulo cohort, ten (8%) of 121 patients, 83 (69%) of 121 patients, and 25 (21%) of 121 patients were classified as having SIRD, MOD, and SIDD, respectively. At 1 year, type 2 diabetes remission was reported in 26 (81%) of 32 and nine (90%) of ten patients with SIRD, 167 (55%) of 306 and 42 (51%) of 83 patients with MOD, and two (13%) of 16 and nine (36%) of 25 patients with SIDD, in the ABOS and São Paulo cohorts, respectively. The mean eGFR was lower in patients with SIRD at baseline and increased postoperatively in these patients in both cohorts. In multivariable analysis, SIRD was associated with more frequent type 2 diabetes remission (odds ratio 4·3, 95% CI 1·8-11·2; p=0·0015), and an increase in eGFR (mean effect size 13·1 ml/min per 1·73 m2, 95% CI 3·6-22·7; p=0·0070). INTERPRETATION: Patients in the SIRD subgroup had better outcomes after metabolic surgery, both in terms of type 2 diabetes remission and renal function, with no additional surgical risk. Data-driven classification might help to refine the indications for metabolic surgery. FUNDING: Agence Nationale de la Recherche, Investissement d'Avenir, Innovative Medecines Initiative, Fondation Cœur et Artères, and Fondation Francophone pour la Recherche sur le Diabète.

Interoceptive reliance as a major determinant of emotional eating in adult obesity.

This study examined the association between emotional eating, emotion dysregulations, and interoceptive sensibility in 116 patients with obesity by distinguishing an "awareness" and a "reliance" component of interoceptive sensibility. Deficits in interoceptive awareness were only associated with more emotional eating in obesity through less interoceptive reliance and more emotion dysregulations. The results suggest that good interoceptive awareness can increase the risk of emotional eating if not supported by good interoceptive reliance. Interoceptive reliance, like the ability to trust, positively consider, and positively use inner sensations, should be a privileged target of psychotherapeutic interventions in obesity.

Long-term outcomes of bariatric surgery in patients with bi-allelic mutations in the POMC, LEPR, and MC4R genes.

BACKGROUND: Gene mutations in the leptin-melanocortin signaling cascade lead to hyperphagia and severe early onset obesity. In most cases, multimodal conservative treatment (increased physical activity, reduced caloric intake) is not successful to stabilize body weight and control hyperphagia. OBJECTIVES: To examine bariatric surgery as a therapeutic option for patients with genetic obesity. SETTING: Three major academic, specialized medical centers. METHODS: In 3 clinical centers, we retrospectively analyzed the outcomes of bariatric surgery performed in 8 patients with monogenic forms of obesity with bi-allelic variants in the genes LEPR (n = 5), POMC (n = 2), and MC4R (n = 1). RESULTS: In this group of patients with monogenic obesity, initial bariatric surgery was performed at a median age of 19 years (interquartile range [IQR], 16-23.8 yr). All patients initially experienced weight loss after each bariatric surgery, which was followed by substantial weight regain. In total, bariatric surgery led to a median maximum reduction of body weight of -21.5 kg (IQR, -36.3 to -2.9 kg), median percent excess weight loss (%EWL) of -47.5 %EWL (IQR, -57.6 to -28.9 %EWL). This body weight reduction was followed by median weight regain of 24.1 kg (IQR: 10.0 to 42.0 kg), leading to a final weight change of -24.2 % EWL (IQR: -37.6 to -5.4 %EWL) after a maximum duration of 19 years post surgery. In one patient, bariatric surgery was accompanied by significant complications, including vitamin deficiencies and hernia development. CONCLUSION: The indication for bariatric surgery in patients with monogenic obesity based on bi-allelic gene mutations and its benefit/risk balance has to be evaluated very cautiously by specialized centers. Furthermore, to avoid an unsuccessful operation, preoperative genetic testing of patients with a history of early onset obesity might be essential, even more since novel pharmacological treatment options are expected.

NASH-related increases in plasma bile acid levels depend on insulin resistance.

BACKGROUND & AIMS: Plasma bile acids (BAs) have been extensively studied as pathophysiological actors in non-alcoholic steatohepatitis (NASH). However, results from clinical studies are often complicated by the association of NASH with type 2 diabetes (T2D), obesity, and insulin resistance (IR). Here, we sought to dissect the relationship between NASH, T2D, and plasma BA levels in a large patient cohort. METHODS: Four groups of patients from the Biological Atlas of Severe Obesity (ABOS) cohort (Clinical Trials number NCT01129297) were included based on the presence or absence of histologically evaluated NASH with or without coincident T2D. Patients were matched for BMI, homeostatic model assessment 2 (HOMA2)-assessed IR, glycated haemoglobin, age, and gender. To study the effect of IR and BMI on the association of plasma BA and NASH, patients from the HEPADIP study were included. In both cohorts, fasting plasma BA concentrations were measured. RESULTS: Plasma BA concentrations were higher in NASH compared with No-NASH patients both in T2D and NoT2D patients from the ABOS cohort. As we previously reported that plasma BA levels were unaltered in NASH patients of the HEPADIP cohort, we assessed the impact of BMI and IR on the association of NASH and BA on the combined BA datasets. Our results revealed that NASH-associated increases in plasma total cholic acid (CA) concentrations depend on the degree of HOMA2-assessed systemic IR, but not on ß-cell function nor on BMI. CONCLUSIONS: Plasma BA concentrations are elevated only in those NASH patients exhibiting pronounced IR. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a progressive liver disease that frequently occurs in patients with obesity and type 2 diabetes. Reliable markers for the diagnosis of NASH are needed. Plasma bile acids have been proposed as NASH biomarkers. Herein, we found that plasma bile acids are only elevated in patients with NASH when significant insulin resistance is present, limiting their utility as NASH markers.

Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle.

BACKGROUND: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans. METHODS: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html). RESULTS: We identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age-related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate. CONCLUSIONS: We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).