Carel W. le Roux

Gut Hormone Profiles Following Bariatric Surgery Favor an Anorectic State, Facilitate Weight Loss, and Improve Metabolic Parameters

Objective:To study the effect of bariatric surgery on the entero-hypothalamic endocrine axis of humans and rodents. Background:Bariatric surgery is the most effective obesity treatment as it achieves substantial and sustained weight loss. Glycemic control and enhanced satiation improve before substantial weight loss occurs. Gut peptides, acting both peripherally and centrally, contribute to glycemic control and regulate food intake. Methods:We examined meal-stimulated responses of insulin, ghrelin, peptide YY (PYY), glucagon-like-peptide-1 (GLP-1), and pancreatic polypeptide (PP) in humans and rodents following different bariatric surgical techniques. Results:Compared with lean and obese controls, patients following Roux-en-Y gastric bypass (RYGB) had increased postprandial plasma PYY and GLP-1 favoring enhanced satiety. Furthermore, RYGB patients had early and exaggerated insulin responses, potentially mediating improved glycemic control. None of these effects were observed in patients losing equivalent weight through gastric banding. Leptin, ghrelin, and PP were similar in both the surgical groups. Using a rodent model of jejuno-intestinal bypass (JIB), we showed elevated PYY and GLP-1 in JIB rats compared with sham-operated rats. Moreover, exogenous PYY reduced food intake and blockade of endogenous PYY increased food intake. Thus, higher plasma PYY following JIB may contribute to reduced food intake and contribute to weight loss. Conclusions:Following RYGB and JIB, a pleiotropic endocrine response may contribute to the improved glycemic control, appetite reduction, and long-term changes in body weight.

Gut hormones as mediators of appetite and weight loss after roux-en-Y gastric bypass

Objective:To evaluate the physiologic importance of the satiety gut hormones. Background:Controversy surrounds the physiologic role of gut hormones in the control of appetite. Bariatric surgery remains the most effective treatment option for obesity, and gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass. Methods:We correlated peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) changes within the first week after gastric bypass with changes in appetite. We also evaluated the gut hormone responses of patients with good or poor weight loss after gastric bypass. Finally, we inhibited the gut hormone responses in gastric bypass patients and then evaluated appetite and food intake. Results:Postprandial PYY and GLP-1 profiles start rising as early as 2 days after gastric bypass (P < 0.05). Changes in appetite are evident within days after gastric bypass surgery (P < 0.05), and unlike other operations, the reduced appetite continues. However, in patients with poor weight loss after gastric bypass associated with increased appetite, the postprandial PYY and GLP-1 responses are attenuated compared with patients with good weight loss (P < 0.05). Inhibiting gut hormone responses, including PYY and GLP-1 after gastric bypass, results in return of appetite and increased food intake (P < 0.05). Conclusion:The attenuated appetite after gastric bypass is associated with elevated PYY and GLP-1 concentrations, and appetite returns when the release of gut hormones is inhibited. The results suggest a role for gut hormones in the mechanism of weight loss after gastric bypass and may have implications for the treatment of obesity.

A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management

BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P<0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.).

The Role of Bile After Roux-en-Y Gastric Bypass in Promoting Weight Loss and Improving Glycaemic Control

Gastric bypass leads to the remission of type 2 diabetes independently of weight loss. Our hypothesis is that changes in bile flow due to the altered anatomy may partly explain the metabolic outcomes of the operation. We prospectively studied 12 patients undergoing gastric bypass and six patients undergoing gastric banding over a 6-wk period. Plasma fibroblast growth factor (FGF)19, stimulated by bile acid absorption in the terminal ileum, and plasma bile acids were measured. In canine and rodent models, we investigated changes in the gut hormone response after altered bile flow. FGF19 and total plasma bile acids levels increased after gastric bypass compared with no change after gastric banding. In the canine model, both food and bile, on their own, stimulated satiety gut hormone responses. However, when combined, the response was doubled. In rats, drainage of endogenous bile into the terminal ileum was associated with an enhanced satiety gut hormone response, reduced food intake, and lower body weight. In conclusion, after gastric bypass, bile flow is altered, leading to increased plasma bile acids, FGF19, incretin. and satiety gut hormone concentrations. Elucidating the mechanism of action of gastric bypass surgery may lead to novel treatments for type 2 diabetes.

Bariatric surgery for type 2 diabetes.

Bariatric surgery provides substantial, sustained weight loss and major improvements in glycaemic control in severely obese individuals with type 2 diabetes. However, uptake of surgery in eligible patients is poor, and the barriers are difficult to surmount. We examine the indications for and efficacy and safety of conventional bariatric surgical procedures and their effect on glycaemic control in type 2 diabetes. How surgical gastrointestinal interventions achieve these changes is of great research interest, and is evolving rapidly. Old classifications about restriction and malabsorption are inadequate, and we explore understanding of putative mechanisms. Some bariatric procedures improve glycaemic control in people with diabetes beyond that expected for weight loss, and understanding this additional effect could provide insights into the pathogenesis of type 2 diabetes and assist in the development of new procedures, devices, and drugs both for obese and non-obese patients.

Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation

Summary Bariatric surgery is currently the most effective procedure for the treatment of obesity. Given the role of the gut microbiota in regulating host metabolism and adiposity, we investigated the long-term effects of bariatric surgery on the microbiome of patients randomized to Roux-en-Y gastric bypass or vertical banded gastroplasty and matched for weight and fat mass loss. The two surgical procedures induced similar and durable changes on the gut microbiome that were not dependent on body mass index and resulted in altered levels of fecal and circulating metabolites compared with obese controls. By colonizing germ-free mice with stools from the patients, we demonstrated that the surgically altered microbiota promoted reduced fat deposition in recipient mice. These mice also had a lower respiratory quotient, indicating decreased utilization of carbohydrates as fuel. Our results suggest that the gut microbiota may play a direct role in the reduction of adiposity observed after bariatric surgery.

Gastric Bypass Increases Energy Expenditure in Rats

BACKGROUND & AIMS Mechanisms underlying weight loss maintenance after gastric bypass are poorly understood. Our aim was to examine the effects of gastric bypass on energy expenditure in rats. METHODS Thirty diet-induced obese male Wistar rats underwent either gastric bypass (n = 14), sham-operation ad libitum fed (n = 8), or sham-operation body weight-matched (n = 8). Energy expenditure was measured in an open circuit calorimetry system. RESULTS Twenty-four-hour energy expenditure was increased after gastric bypass (4.50 +/- 0.04 kcal/kg/h) compared with sham-operated, ad libitum fed (4.29 +/- 0.08 kcal/kg/h) and sham-operated, body weight-matched controls (3.98 +/- 0.10 kcal/kg/h, P < .001). Gastric bypass rats showed higher energy expenditure during the light phase than sham-operated control groups (sham-operated, ad libitum fed: 3.63 +/- 0.04 kcal/kg/h vs sham-operated, body weight-matched: 3.42 +/- 0.05 kcal/kg/h vs bypass: 4.12 +/- 0.03 kcal/kg/h, P < .001). Diet-induced thermogenesis was elevated after gastric bypass compared with sham-operated, body weight-matched controls 3 hours after a test meal (0.41% +/- 1.9% vs 10.5% +/- 2.0%, respectively, P < .05). The small bowel of gastric bypass rats was 72.1% heavier because of hypertrophy compared with sham-operated, ad libitum fed rats (P < .0001). CONCLUSIONS Gastric bypass in rats prevented the decrease in energy expenditure after weight loss. Diet-induced thermogenesis was higher after gastric bypass compared with body weight-matched controls. Raised energy expenditure may be a mechanism explaining the physiologic basis of weight loss after gastric bypass.

Remission of Type 2 Diabetes After Gastric Bypass and Banding: Mechanisms and 2 Year Outcomes

Objective: To investigate the rate of type 2 diabetes remission after gastric bypass and banding and establish the mechanism leading to remission of type 2 diabetes after bariatric surgery. Summary Background Data: Glycemic control in type 2 diabetic patients is improved after bariatric surgery. Methods: In study 1, 34 obese type 2 diabetic patients undergoing either gastric bypass or gastric banding were followed up for 36 months. Remission of diabetes was defined as patients not requiring hypoglycemic medication, fasting glucose below 7 mmol/L, 2 hour glucose after oral glucose tolerance test below 11.1 mmol/L, and glycated haemoglobin (HbA1c) <6%. In study 2, 41 obese type 2 diabetic patients undergoing either bypass, banding, or very low calorie diet were followed up for 42 days. Insulin resistance (HOMA-IR), insulin production, and glucagon-like peptide 1 (GLP-1) responses after a standard meal were measured. Results: In study 1, HbA1c as a marker of glycemic control improved by 2.9% after gastric bypass and 1.9% after gastric banding at latest follow-up (P < 0.001 for both groups). Despite similar weight loss, 72% (16/22) of bypass and 17% (2/12) of banding patients (P = 0.001) fulfilled the definition of remission at latest follow-up. In study 2, within days, only bypass patients had improved insulin resistance, insulin production, and GLP-1 responses (all P < 0.05). Conclusions: With gastric bypass, type 2 diabetes can be improved and even rapidly put into a state of remission irrespective of weight loss. Improved insulin resistance within the first week after surgery remains unexplained, but increased insulin production in the first week after surgery may be explained by the enhanced postprandial GLP-1 responses.

A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis

BACKGROUND & AIMS Primary (idiopathic) bile acid malabsorption (BAM) is a common, yet underrecognized, chronic diarrheal syndrome. Diagnosis is difficult without selenium homocholic acid taurine (SeHCAT) testing. The diarrhea results from excess colonic bile acids, but the pathogenesis is unclear. Fibroblast growth factor 19 (FGF19), produced in the ileum in response to bile acid absorption, regulates hepatic bile acid synthesis. We proposed that FGF19 is involved in bile acid diarrhea and measured its levels in patients with BAM. METHODS Blood was collected from fasting patients with chronic diarrhea; BAM was diagnosed by SeHCAT. Serum FGF19 was measured by enzyme-linked immunosorbent assay. Serum 7alpha-hydroxy-4-cholesten-3-one (C4) was determined using high-performance liquid chromatography, to quantify bile acid synthesis. Data were compared between patients and subjects without diarrhea (controls). Samples were taken repeatedly after meals from several subjects. RESULTS The median C4 level was significantly higher in patients with primary BAM than in controls (51 vs 18 ng/mL; P < .0001). The median FGF19 level was significantly lower in patients with BAM (120 vs 231 pg/mL; P < .0005). There was a significant inverse relationship between FGF19 and C4 levels (P < .0004). Low levels of FGF19 were also found in patients with postcholecystectomy and secondary bile acid diarrhea. Abnormal patterns of FGF19 levels were observed throughout the day in some patients with primary BAM. CONCLUSIONS Patients with BAM have reduced serum FGF19 which may be useful in diagnosis. We propose a mechanism whereby impaired FGF19 feedback inhibition causes excessive bile acid synthesis that exceeds the normal capacity for ileal reabsorption, producing bile acid diarrhea.

Gastric bypass reduces fat intake and preference

Roux-en-Y gastric bypass is the most effective therapy for morbid obesity. This study investigated how gastric bypass affects intake of and preference for high-fat food in an experimental (rat) study and within a trial setting (human). Proportion of dietary fat in gastric bypass patients was significantly lower 6 yr after surgery compared with patients after vertical-banded gastroplasty (P = 0.046). Gastric bypass reduced total fat and caloric intake (P < 0.001) and increased standard low-fat chow consumption compared with sham controls (P < 0.001) in rats. Compared with sham-operated rats, gastric bypass rats displayed much lower preferences for Intralipid concentrations > 0.5% in an ascending concentration series (0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%) of two-bottle preference tests (P = 0.005). This effect was demonstrated 10 and 200 days after surgery. However, there was no difference in appetitive or consummatory behavior in the brief access test between the two groups (P = 0.71) using similar Intralipid concentrations (0.005% through 5%). Levels of glucagon-like peptide-1 (GLP-1) were increased after gastric bypass as expected. An oral gavage of 1 ml corn oil after saccharin ingestion in gastric bypass rats induced a conditioned taste aversion. These findings suggest that changes in fat preference may contribute to long-term maintained weight loss after gastric bypass. Postingestive effects of high-fat nutrients resulting in conditioned taste aversion may partially explain this observation; the role of GLP-1 in mediating postprandial responses after gastric bypass requires further investigation.