Effect of Laparoscopic Sleeve Gastrectomy vs Roux-en-Y Gastric Bypass on Weight Loss, Comorbidities, and Reflux at 10 Years in Adult Patients With Obesity: The SLEEVEPASS Randomized Clinical Trial.

Importance: Long-term results from randomized clinical trials comparing laparoscopic sleeve gastrectomy (LSG) with laparoscopic Roux-en-Y-gastric bypass (LRYGB) are limited. Objective: To compare long-term outcomes of weight loss and remission of obesity-related comorbidities and the prevalence of gastroesophageal reflux symptoms (GERD), endoscopic esophagitis, and Barrett esophagus (BE) after LSG and LRYGB at 10 years. Design, Setting, and Participants: This 10-year observational follow-up evaluated patients in the Sleeve vs Bypass (SLEEVEPASS) multicenter equivalence randomized clinical trial comparing LSG and LRYGB in the treatment of severe obesity in which 240 patients aged 18 to 60 years with median body mass index of 44.6 were randomized to LSG (n = 121) or LRYGB (n = 119). The initial trial was conducted from April 2008 to June 2010 in Finland, with last follow-up on January 27, 2021. Interventions: LSG or LRYGB. Main Outcomes and Measures: The primary end point was 5-year percentage excess weight loss (%EWL). This current analysis focused on 10-year outcomes with special reference to reflux and BE. Results: At 10 years, of 240 randomized patients (121 randomized to LSG and 119 to LRYGB; 167 women [69.6%]; mean [SD] age, 48.4 [9.4] years; mean [SD] baseline BMI, 45.9 [6.0]), 2 never underwent surgery and there were 10 unrelated deaths; 193 of the remaining 228 patients (85%) completed follow-up on weight loss and comorbidities, and 176 of 228 (77%) underwent gastroscopy. Median (range) %EWL was 43.5% (2.1%-109.2%) after LSG and 50.7% (1.7%-111.7%) after LRYGB. Mean estimate %EWL was not equivalent between the procedures; %EWL was 8.4 (95% CI, 3.1-13.6) higher in LRYGB. After LSG and LRYGB, there was no statistically significant difference in type 2 diabetes remission (26% and 33%, respectively; P = .63), dyslipidemia (19% and 35%, respectively; P = .23), or obstructive sleep apnea (16% and 31%, respectively; P = .30). Hypertension remission was superior after LRYGB (8% vs 24%; P = .04). Esophagitis was more prevalent after LSG (31% vs 7%; P < .001) with no statistically significant difference in BE (4% vs 4%; P = .29). The overall reoperation rate was 15.7% for LSG and 18.5% for LRYGB (P = .57). Conclusions and Relevance: At 10 years, %EWL was greater after LRYGB and the procedures were not equivalent for weight loss, but both LSG and LRYGB resulted in good and sustainable weight loss. Esophagitis was more prevalent after LSG, but the cumulative incidence of BE was markedly lower than in previous trials and similar after both procedures. Trial Registration: ClinicalTrials.gov Identifier: NCT00793143.

Effect of Laparoscopic Sleeve Gastrectomy vs Roux-en-Y Gastric Bypass on Weight Loss and Quality of Life at 7 Years in Patients With Morbid Obesity: The SLEEVEPASS Randomized Clinical Trial.

Importance: Laparoscopic sleeve gastrectomy (LSG) is currently the predominant bariatric procedure, although long-term weight loss and quality-of-life (QoL) outcomes compared with laparoscopic Roux-en-Y gastric bypass (LRYGB) are lacking. Objective: To determine weight loss equivalence of LSG and LRYGB at 7 years in patients with morbid obesity, with special reference to long-term QoL. Design, Setting, and Participants: The SLEEVE vs byPASS (SLEEVEPASS) multicenter, multisurgeon, open-label, randomized clinical equivalence trial was conducted between March 10, 2008, and June 2, 2010, in Finland. The trial enrolled 240 patients with morbid obesity aged 18 to 60 years who were randomized to undergo either LSG or LRYGB with a 7-year follow-up (last follow-up, September 26, 2017). Analysis was conducted on an intention-to-treat basis. Statistical analysis was performed from June 4, 2018, to November 8, 2019. Interventions: Laparoscopic sleeve gastrectomy (n = 121) or LRYGB (n = 119). Main Outcomes and Measures: The primary end point was percentage excess weight loss (%EWL) at 5 years. Secondary predefined follow-up time points were 7, 10, 15, and 20 years, with included 7-year secondary end points of QoL and morbidity. Disease-specific QoL (DSQoL; Moorehead-Ardelt Quality of Life questionnaire [range of scores, -3 to 3 points, where a higher score indicates better QoL]) and general health-related QoL (HRQoL; 15D questionnaire [0-1 scale for all 15 dimensions, with 1 indicating full health and 0 indicating death]) were measured preoperatively and at 1, 3, 5, and 7 years postoperatively concurrently with weight loss. Results: Of 240 patients (167 women [69.6%]; mean [SD] age, 48.4 [9.4] years; mean [SD] baseline body mass index, 45.9 [6.0]), 182 (75.8%) completed the 7-year follow-up. The mean %EWL was 47% (95% CI, 43%-50%) after LSG and 55% (95% CI, 52%-59%) after LRYGB (difference, 8.7 percentage units [95% CI, 3.5-13.9 percentage units]). The mean (SD) DSQoL total score at 7 years was 0.50 (1.14) after LSG and 0.49 (1.06) after LRYGB (P = .63), and the median HRQoL total score was 0.88 (interquartile range [IQR], 0.78-0.95) after LSG and 0.87 (IQR, 0.78-0.95) after LRYGB (P = .37). Greater weight loss was associated with better DSQoL (r = 0.26; P < .001). At 7 years, mean (SD) DSQoL scores improved significantly compared with baseline (LSG, 0.50 [1.14] vs 0.10 [0.94]; and LRYGB, 0.49 [1.06] vs 0.12 [1.12]; P < .001), unlike median HRQoL scores (LSG, 0.88 [IQR, 0.78-0.95] vs 0.87 [IQR, 0.78-0.90]; and LRYGB, 0.87 [IQR, 0.78-0.92] vs 0.85 [IQR, 0.77-0.91]; P = .07). The overall morbidity rate was 24.0% (29 of 121) for LSG and 28.6% (34 of 119) for LRYGB (P = .42). Conclusions and Relevance: This study found that LSG and LRYGB were not equivalent in %EWL at 7 years. Laparoscopic Roux-en-Y gastric bypass resulted in greater weight loss than LSG, but the difference was not clinically relevant based on the prespecified equivalence margins. There was no difference in long-term QoL between the procedures. Bariatric surgery was associated with significant long-term DSQoL improvement, and greater weight loss was associated with better DSQoL. Trial Registration: ClinicalTrials.gov Identifier: NCT00793143.

Two-Year Nutrition Data in Terms of Vitamin D, Vitamin B12, and Albumin After Bariatric Surgery and Long-term Fracture Data Compared with Conservatively Treated Obese Patients: a Retrospective Cohort Study.

INTRODUCTION: Nutritional deficiencies may occur after bariatric surgery despite supplementation. Fracture risk may also be elevated after bariatric surgery. OBJECTIVES: To compare 25-hydroxyvitamin D [25(OH)D], vitamin B12, and albumin serum concentrations in severely obese patients who had undergone either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Fracture data was compared with data for a conservatively treated group of severely obese patients. METHODS: We considered 253 RYGB and 142 SG performed between 2007 and 2010. At 1- and 2-year control follow-ups, weight was measured and blood samples were drawn. The control group of 199 obese patients received lifestyle intervention and weight was measured at 1 and 2 years post-intervention between 2002 and 2006. We retrospectively collected fracture data for all patients through the end of 2016. RESULTS: At follow-ups, the mean serum 25(OH)D and albumin levels were within reference ranges and were similar between the RYGB and SG groups. Serum median vitamin B12 level was significantly higher in the SG group compared with the RYBG group, 319 versus 286 pmol/L at 2 years, respectively, p = 0.04. The cumulative risk for fracture was higher in the bariatric groups compared with the control group. The Cox multivariate model showed higher age, bariatric surgery, and lower body mass index (BMI) at the 2-year control increased the risk for fracture after obesity treatment. CONCLUSION: Vitamin 25(OH)D, B12, and albumin levels were mainly within recommended levels during the 2 years after bariatric surgery. The cumulative fracture risk was higher in bariatric patients.

Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss at 5 Years Among Patients With Morbid Obesity: The SLEEVEPASS Randomized Clinical Trial.

Importance: Laparoscopic sleeve gastrectomy for treatment of morbid obesity has increased substantially despite the lack of long-term results compared with laparoscopic Roux-en-Y gastric bypass. Objective: To determine whether laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass are equivalent for weight loss at 5 years in patients with morbid obesity. Design, Setting, and Participants: The Sleeve vs Bypass (SLEEVEPASS) multicenter, multisurgeon, open-label, randomized clinical equivalence trial was conducted from March 2008 until June 2010 in Finland. The trial enrolled 240 morbidly obese patients aged 18 to 60 years, who were randomly assigned to sleeve gastrectomy or gastric bypass with a 5-year follow-up period (last follow-up, October 14, 2015). Interventions: Laparoscopic sleeve gastrectomy (n = 121) or laparoscopic Roux-en-Y gastric bypass (n = 119). Main Outcomes and Measures: The primary end point was weight loss evaluated by percentage excess weight loss. Prespecified equivalence margins for the clinical significance of weight loss differences between gastric bypass and sleeve gastrectomy were -9% to +9% excess weight loss. Secondary end points included resolution of comorbidities, improvement of quality of life (QOL), all adverse events (overall morbidity), and mortality. Results: Among 240 patients randomized (mean age, 48 [SD, 9] years; mean baseline body mass index, 45.9, [SD, 6.0]; 69.6% women), 80.4% completed the 5-year follow-up. At baseline, 42.1% had type 2 diabetes, 34.6% dyslipidemia, and 70.8% hypertension. The estimated mean percentage excess weight loss at 5 years was 49% (95% CI, 45%-52%) after sleeve gastrectomy and 57% (95% CI, 53%-61%) after gastric bypass (difference, 8.2 percentage units [95% CI, 3.2%-13.2%], higher in the gastric bypass group) and did not meet criteria for equivalence. Complete or partial remission of type 2 diabetes was seen in 37% (n = 15/41) after sleeve gastrectomy and in 45% (n = 18/40) after gastric bypass (P > .99). Medication for dyslipidemia was discontinued in 47% (n = 14/30) after sleeve gastrectomy and 60% (n = 24/40) after gastric bypass (P = .15) and for hypertension in 29% (n = 20/68) and 51% (n = 37/73) (P = .02), respectively. There was no statistically significant difference in QOL between groups (P = .85) and no treatment-related mortality. At 5 years the overall morbidity rate was 19% (n = 23) for sleeve gastrectomy and 26% (n = 31) for gastric bypass (P = .19). Conclusions and Relevance: Among patients with morbid obesity, use of laparoscopic sleeve gastrectomy compared with use of laparoscopic Roux-en-Y gastric bypass did not meet criteria for equivalence in terms of percentage excess weight loss at 5 years. Although gastric bypass compared with sleeve gastrectomy was associated with greater percentage excess weight loss at 5 years, the difference was not statistically significant, based on the prespecified equivalence margins. Trial Registration: clinicaltrials.gov Identifier: NCT00793143.

A Retrospective 2-Year Follow-up of Late Complications Treated Surgically and Endoscopically After Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) and Laparoscopic Sleeve Gastrectomy (LSG) for Morbid Obesity.

BACKGROUND: The laparoscopic Roux-en-Y gastric bypass (LRYGB) has been the gold standard for bariatric surgery, but recently, the laparoscopic sleeve gastrectomy (LSG) has gained popularity. At present, limited data is available on the long-term complications of these two types of surgery. The aim of this retrospective study was to compare the 2-year data about late (more than 30 days after surgery) complications that were treated surgically or endoscopically after LRYGB and LSG operations in a large hospital area with a single patient database. MATERIALS: This was a retrospective, non-randomized, single-center study of 760 (545 LRYGB and 215 LSG) bariatric patients surgically treated between 2008 and 2013 in the Bariatric Surgery Unit of Helsinki University Central Hospital. METHODS: The patients were followed for 2 years, and late complications (more than 30 days after surgery) that were surgically and/or endoscopically treated were registered. Weight loss and the risk factors for complications were also monitored. RESULTS: The study found a difference between the LRYGB and LSG patients in a number of late complications treated by both intervention types: surgical intervention were required in 9.4% of LRYGB patients vs. 0.9 of LSG patients, and endoscopic intervention were required by 4.6% of LRYGB patients vs. 1.4% of LSG patients (both p < 0.05). The risk of surgical complications was increased by better weight loss results in 12 months. CONCLUSIONS: LRYGB was found to be associated with a greater risk of late complications. If larger databases confirm these results, the trend toward LSG is justified.

Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD.

BACKGROUND: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2EK/KK) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. METHODS: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. RESULTS: The TM6SF2EK/KK and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2EK/KK than the TM6SF2EE group (p<0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p<0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p<0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs. CONCLUSIONS: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers.

Bile Reflux Scintigraphy After Mini-Gastric Bypass.

BACKGROUND: Significant weight-loss and diabetes remission have been reported after mini-gastric bypass (MGB). Concern has been raised regarding postoperative bile reflux (BR), but it has not been demonstrated in previous studies. We set out to find out if BR is evident in hepatobiliary scintigraphy after MGB. METHODS: Nine consecutive patients, seven with type 2 diabetes, underwent MGB (15 cm gastric tube, 250-275 cm biliary limb) at our institution with a 12-month follow-up, with none lost to follow-up. Then, 10.7 months (8.6-13.0) after MGB, all patients underwent hepatobiliary scintigraphy and a reflux symptom questionnaire (GerdQ) was filled out. A gastroscopy with biopsies was done for all patients with a bile-reflux-positive scintigraphy. RESULTS: Mean age at operation was 56 years (41-65) and preoperative BMI 43.1 kg/m2 (34.2-54.6). Mean %EWL was 83.9 (49.5-128.3) at 12 months. Four patients reached diabetes remission and two became insulin-independent. Hepatobiliary scintigraphy showed a transient BR into the gastric tube for five patients. Bile tracer was found in the gastric tube at 23-58 min after the tracer injection and highest activity was 8% (1-8%) at 58 min. Bile tracer was not found in the esophagus of any of the patients. One patient with a positive scintigraphy in the gastric tube required re-operation. Two patients with reflux symptoms had a negative scintigraphy. CONCLUSION: Our results indicate that transient bile reflux is common after MGB in the gastric tube, but not in the esophagus. The clinical relevance of bile reflux needs further studies.

Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans.

Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant ('IR') versus insulin-sensitive ('IS')] and PNPLA3 genotype (PNPLA3148MM/MI vs PNPLA3148II). Liver fat content (1H-MRS) was similarly increased in 'IR' (13 ± 1 %) and PNPLA3148MM/MI (12 ± 2 %) as compared to 'IS' (6 ± 1 %, p<0.05) and PNPLA3148II (8 ± 1 %, p<0.05), respectively. FVIII, FIX, FXIII, fibrinogen and VWF:RCo activities were increased, and PT and APTT shortened in 'IR' versus 'IS', in contrast to these factors being similar between PNPLA3148MM/MI and PNPLA3148II groups. In subjects undergoing a liver biopsy and entirely lacking the I148M variant, insulin-resistant subjects had higher hepatic expression of F8, F9 and FGG than equally obese insulin-sensitive subjects. Expression of pro-inflammatory genes in adipose tissue correlated positively with PT (% of normal), circulating FVIII, FIX, FXI, VWR:RCo and fibrinogen, and expression of anti-inflammatory genes negatively with PT (%), FIX and fibrinogen. We conclude that obesity/insulin resistance rather than an increase in liver fat is associated with a procoagulant plasma profile. This reflects adipose tissue inflammation and increased hepatic production of coagulation factors and their susceptibility for activation.

Do Changes in Perioperative and Postoperative Treatment Protocol Influence the Frequency of Pulmonary Complications? A Retrospective Analysis of Four Different Bariatric Groups.

The current understanding of prophylaxis of pulmonary complications in bariatric surgery is weak. PURPOSE: The aim of this study was to observe how changes in perioperative and postoperative treatments affect the incidence of pulmonary complications in bariatric patients. MATERIALS: This is a retrospective clinical study of 400 consecutive bariatric patients. The patients, who either underwent a sleeve gastrectomy or a Roux-en-Y gastric bypass, were divided consecutively into four subgroups with different approaches to perioperative treatment. METHODS: The first group (patients 0-100) was recovered in the intensive care unit with minimal mobilization (ICU). They had a urinary catheter and a drain. The second group (patients 101-200) was similar to the first group, but the patients used a continuous positive airway pressure (CPAP) device intermittently (ICU-CPAP). The third group (patients 201-300) was recovered on a normal ward without a urinary catheter or a drain and used a CPAP device (ward-slow). The fourth group (patients 301-400) walked to the operating theater and was mobilized in the recovery room during the first 2 h after the operation (ward-fast). CPAP was also used. Primary endpoints were pulmonary complications, pneumonia, and infection, non-ultra descriptus (NUD). RESULTS: The number of pulmonary complications among the groups was significantly different. A long operation time increased the risk for infection (p < 0.001 95 % CI from 2.02 to 6.59 %). CONCLUSIONS: Operation time increases the risk for pulmonary complications. Changes in perioperative care toward the ERAS protocol may have a positive effect on the number of pulmonary complications.

Noninvasive Detection of Nonalcoholic Steatohepatitis Using Clinical Markers and Circulating Levels of Lipids and Metabolites.

BACKGROUND & AIMS: Use of targeted mass spectrometry (MS)-based methods is increasing in clinical chemistry laboratories. We investigate whether MS-based profiling of plasma improves noninvasive risk estimates of nonalcoholic steatohepatitis (NASH) compared with routinely available clinical parameters and patatin-like phospholipase domain-containing protein 3 (PNPLA3) genotype at rs738409. METHODS: We used MS-based analytic platforms to measure levels of lipids and metabolites in blood samples from 318 subjects who underwent a liver biopsy because of suspected NASH. The subjects were divided randomly into estimation (n = 223) and validation (n = 95) groups to build and validate the model. Gibbs sampling and stepwise logistic regression, which fulfilled the Bayesian information criterion, were used for variable selection and modeling. RESULTS: Features of the metabolic syndrome and the variant in PNPLA3 encoding I148M were significantly more common among subjects with than without NASH. We developed a model to identify subjects with NASH based on clinical data and PNPLA3 genotype (NASH Clin Score), which included aspartate aminotransferase (AST), fasting insulin, and PNPLA3 genotype. This model identified subjects with NASH with an area under the receiver operating characteristic of 0.778 (95% confidence interval, 0.709-0.846). We then used backward stepwise logistic regression analyses of variables from the NASH Clin Score and MS-based factors associated with NASH to develop the NASH ClinLipMet Score. This included glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6, AST, and fasting insulin, along with PNPLA3 genotype. It identified patients with NASH with an area under the receiver operating characteristic of 0.866 (95% confidence interval, 0.820-0.913). The NASH ClinLipMet score identified patients with NASH with significantly higher accuracy than the NASH Clin Score or MS-based profiling alone. CONCLUSIONS: A score based on MS (glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6) and knowledge of AST, fasting insulin, and PNPLA3 genotype is significantly better than a score based on clinical or metabolic profiles alone in determining the risk of NASH.

Retrospective analysis of 3 different antithrombotic prophylaxis regimens in bariatric surgery.

BACKGROUND: The optimal amount of thromboembolic prophylaxis to use in bariatric surgery is still unresolved. OBJECTIVE: The aim of this study was to determine the optimal pharmacologic prophylaxis with minimal bleeding complications for bariatric patients. SETTING: A nonrandomized clinical study of 400 consecutive bariatric patients surgically treated between 2008 and 2013 at Peijas Hospital. METHODS: The patients, who either underwent mainly a sleeve gastrectomy or a Roux-en-Y gastric bypass, were divided consecutively into 3 subgroups with different approaches to pharmacologic enoxaparin prophylaxis. For the first 100 operated patients (high-dose group), enoxaparin was given at a dose of 40 mg twice daily, starting 1 day before the operation. The next 100 patients (intermediate-dose group) received 40 mg of enoxaparin twice daily, without the dose on the morning of the operation. The last 200 patients (low-dose group) received enoxaparin 40 mg once daily, starting 1 day before the operation and without the dose on the morning of the operation. The primary endpoints in this study were a major bleeding complication and a venous thromboembolism. RESULTS: There were no thromboembolic complications in this study. The difference in bleeding complications between the high-dose group and low-dose group was -10.5% (95% CI from -18.1% to -3.0%), and the difference between high-dose group and intermediate-dose group was -9% (95% CI from -17.4% to -.6%). Age and preoperative weight had no effect on bleeding complications, but hypertension significantly increased the amount of bleeding complications (P = .01, 95% CI from 1.55% to 29.7%). CONCLUSION: Thromboembolic complications are avoidable. Enoxaparin (40 mg) given once daily was the safest with regard to bleeding complications. High blood pressure elevates the risk for bleeding.

Long-Term Effect of Gastric Bypass and Sleeve Gastrectomy on Severe Obesity: Do Preoperative Weight Loss and Binge Eating Behavior Predict the Outcome of Bariatric Surgery?

BACKGROUND: Few studies have examined weight loss sustainability after sleeve gastrectomy (SG). The purpose of this study was to determine long-term outcome after SG and gastric bypass (GBP) and learn whether preoperative weight loss and binge eating behavior can be used to predict outcome. MATERIALS AND METHODS: Together, 257 patients (64 % women) were operated, 163 by GBP and 94 by SG. Binge eating was assessed by binge eating scale (BES) and preoperative weight loss was advised to all, including very low-calorie diet for 5 weeks. Postoperative visits took place at 1 and 2 years, and long-term outcome was at median 5 years (range 2.29-6.85). Multivariate linear regression analysis was used to predict outcome at 2-year and long-term control. RESULTS: Median age was 48 years, weight 141.1 kg, and BMI 48.2 kg/m(2). Preoperative weight loss was median 4.9 % before GBP and 3.8 % before SG, P = 0.04. Total weight loss at year one was 24.1 % in GBP and 23.7 % in SG (P = 0.40), at year two 24.4 and 23.4 % (P = 0.26), and at long-term control 23.0 and 20.2 % (P = 0.006), respectively. Weight was analyzed in 93, 88, and 89 % of those alive, respectively. BES did not predict weight outcome, but larger preoperative weight loss predicted less postoperative weight loss at 2 years. CONCLUSION: On long term, weight loss was better maintained after GBP compared with SG. Binge eating behavior was not a significant predictor, but larger preoperative weight loss predicted less postoperative weight loss for the next 2 years.

Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. METHODS: Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. RESULTS: Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI)vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. CONCLUSIONS: Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease.

MicroRNA-192* impairs adipocyte triglyceride storage.

We investigated the expression of miR-192* (miR-192-3p) in the visceral adipose tissue (VAT) of obese subjects and its function in cultured human adipocytes. This miRNA is a 3' arm derived from the same pre-miRNA as miR-192 (miR-192-5p) implicated in type 2 diabetes, liver disease and cancers, and is predicted to target key genes in lipid metabolism. In morbidly obese subjects undergoing bariatric surgery preceded by a very low calorie diet, miR-192* in VAT correlated negatively (r=-0.387; p=0.046) with serum triglyceride (TG) and positively with high-density lipoprotein (HDL) concentration (r=0.396; p=0.041). In a less obese patient cohort, the miRNA correlated negatively with the body mass index (r=-0.537; p=0.026). To characterize the function of miR-192*, we overexpressed it in cultured adipocytes and analyzed the expression of adipogenic differentiation markers as well as cellular TG content. Reduced TG and expression of the adipocyte marker proteins aP2 (adipocyte protein 2) and perilipin 1 were observed. The function of miR-192* was further investigated by transcriptomic profiling of adipocytes expressing this miRNA, revealing impacts on key lipogenic genes. A number of the mRNA alterations were validated by qPCR. Western analysis confirmed a marked reduction of the lipogenic enzyme SCD (stearoyl coenzyme A desaturase-1), the fatty aldehyde dehydrogenase ALDH3A2 (aldehyde dehydrogenase 3 family member A2) and the high-density lipoprotein receptor SCARB1 (scavenger receptor B, type I). SCD and ALDH3A2 were demonstrated to be direct targets of miR-192*. To conclude, the present data identify miR-192* as a novel controller of adipocyte differentiation and lipid homeostasis.

Novel hepatic microRNAs upregulated in human nonalcoholic fatty liver disease.

MicroRNAs (miRNAs) control gene expression by reducing mRNA stability and translation. We aimed to identify alterations in human liver miRNA expression/function in nonalcoholic fatty liver disease (NAFLD). Subjects with the highest (median liver fat 30%, n = 15) and lowest (0%, n = 15) liver fat content were selected from >100 obese patients for miRNA profiling of liver biopsies on microarrays carrying probes for 1438 human miRNAs (a cross-sectional study). Target mRNAs and pathways were predicted for the miRNAs most significantly upregulated in NAFLD, their cell-type-specific expression was investigated by quantitative PCR (qPCR), and the transcriptome of immortalized human hepatocytes (IHH) transfected with the miRNA with the highest number of predicted targets, miR-576-5p, was studied. The screen revealed 42 miRNAs up- and two downregulated in the NAFLD as compared to non-NAFLD liver. The miRNAs differing most significantly between the groups, miR-103a-2*, miR-106b, miR-576-5p, miRPlus-I137*, miR-892a, miR-1282, miR-3663-5p, and miR-3924, were all upregulated in NAFLD liver. Target pathways predicted for these miRNAs included ones involved in cancer, metabolic regulation, insulin signaling, and inflammation. Consistent transcriptome changes were observed in IHH transfected with miR-576-5p, and western analysis revealed a marked reduction of the RAC1 protein belonging to several miR-576-5p target pathways. To conclude, we identified 44 miRNAs differentially expressed in NAFLD versus non-NAFLD liver, 42 of these being novel in the context of NAFLD. The study demonstrates that by applying a novel study set-up and a broad-coverage array platform one can reveal a wealth of previously undiscovered miRNA dysregulation in metabolic disease.

Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin.

OBJECTIVE: Circulating ANGPTL8 has recently been used as a marker of insulin action. We studied expression and insulin regulation of ANGPTL8 and ANGPTL3 in vivo and in vitro. DESIGN AND METHODS: Expression of ANGPTL8 and ANGPTL3 was studied in 34 paired samples of human liver and adipose tissue. Effects of insulin on 1) plasma concentrations and adipose tissue expression of ANGPTL8 and ANGPTL3 (in vivo 6-h euglycemic hyperinsulinemia; n = 18), and 2) ANGPTL8 and ANGPTL3 gene and protein expression in immortalized human hepatocytes (IHH) and adipocytes were measured. Effect of ANGPTL3 on secretion of ANGPTL8 in cells stably overexpressing ANGPTL3, -8, or both was determined. RESULTS: ANGPTL3 was only expressed in the liver, whereas ANGPTL8 was expressed in both tissues. In vivo hyperinsulinemia significantly decreased both plasma ANGPTL8 and ANGPTL3 at 3 and 6 hours. Insulin increased ANGPTL8 expression in human adipose tissue 14- and 18-fold at 3 and 6 hours and ANGPTL8 was the most insulin-responsive transcript on microarray. Insulin also increased ANPGTL8 in cultured adipocytes and IHH but the protein mainly remained intracellular. In vitro in IHH, insulin decreased ANGPTL3 gene expression and secretion of ANGPTL3 into growth medium. Overexpression of ANGPTL8 in CHO cells did not result in its release into culture medium while abundant secretion occurred in cells co-expressing ANGPTL3 and -8. CONCLUSIONS: Insulin decreases plasma ANGPTL3 by decreasing ANGPTL3 expression in the liver. Insulin markedly increases ANGPTL8 in adipose tissue and the liver but not in plasma. These data show that measurement of plasma ANGPTL3 but not -8 reflects insulin action in target tissues.

Circulating triacylglycerol signatures in nonalcoholic fatty liver disease associated with the I148M variant in PNPLA3 and with obesity.

We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3(I148M) gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3(I148M) gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3(148MM/148MI) compared with the PNPLA3(148II) group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulin-resistant. Liver fat was similarly increased in obese and PNPLA3(148MM/148MI) groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3(I148M) versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.

A population-based study on the prevalence of NASH using scores validated against liver histology.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. Diagnosis of NASH requires a liver biopsy. We estimated the prevalence of NASH non-invasively in a population-based study using scores validated against liver histology. METHODS: Clinical characteristics, PNPLA3 genotype at rs738409, and serum cytokeratin 18 fragments were measured in 296 consecutive bariatric surgery patients who underwent a liver biopsy to discover and validate a NASH score ('NASH score'). We also defined the cut-off for NASH for a previously validated NAFLD liver fat score to diagnose NASH in the same cohort ('NASH liver fat score'). Both scores were validated in an Italian cohort comprising of 380, mainly non-bariatric surgery patients, who had undergone a liver biopsy for NASH. The cut-offs were utilized in the Finnish population-based D2D-study involving 2849 subjects (age 45-74 years) to estimate the population prevalence of NASH. RESULTS: The final 'NASH Score' model included PNPLA3 genotype, AST and fasting insulin. It predicted NASH with an AUROC 0.774 (0.709, 0.839) in Finns and 0.759 (0.711, 0.807) in Italians (NS). The AUROCs for 'NASH liver fat score' were 0.734 (0.664, 0.805) and 0.737 (0.687, 0.787), respectively. Using 'NASH liver fat score' and 'NASH Score', the prevalences of NASH in the D2D study were 4.2% (95% CI: 3.4, 5.0) and 6.0% (5.0, 6.9%). Sensitivity analysis was performed by taking into account stochastic false-positivity and false-negativity rates in a Bayesian model. This analysis yielded population prevalences of NASH of 3.1% (95% stimulation limits 0.2-6.8%) using 'NASH liver fat score' and 3.6% (0.2-7.7%) using 'NASH Score'. CONCLUSIONS: The population prevalence of NASH in 45-74 year old Finnish subjects is ∼ 5%.

[The effect of gastric sleeve and bypass surgery on the use and costs of medications for type 2 diabetes]. / Mahalaukun kavennus- ja ohitus- leikkauksen vaikutus tyypin 2 diabeetikon lääikkeiden käyttöön ja kustannuksiin--kahden vuoden seurantatutkimus.

The study group consisted of 96 patients who had used a medication for type 2 diabetes; of them, 33 had undergone gastric sleeve surgery and 63 bypass surgery. Both surgical methods resulted in a similar weight loss among the patients. In follow-up 39 out of 88 patients were able to manage without antidiabetic drugs two years after surgery. The costs of antidiabetic drugs two years after surgery were 79% lower than before the operation. Weight reduction surgery decreases the need for antidiabetic drugs. The greatest cost-efficiency is achieved by targeting weight-loss operations to patients using insulin therapy.