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Ghrelin is an appetite-stimulating hormone secreted from the gastric mucosa in the fasting state, and secretion decreases in response to food intake. After sleeve gastrectomy (SG), plasma concentrations of ghrelin decrease markedly. Whether this affects appetite and glucose tolerance postoperatively is unknown. We investigated the effects of ghrelin infusion on appetite and glucose tolerance in individuals with obesity before and 3 mo after SG. Twelve participants scheduled for SG were included. Before and 3 mo after surgery, a mixed-meal test followed by an ad libitum meal test was performed with concomitant infusions of acyl-ghrelin (1 pmol/kg/min) or placebo. Infusions began 60 min before meal intake to reach a steady state before the mixed-meal and were continued throughout the study day. Two additional experimental days with 0.25 pmol/kg/min and 10 pmol/kg/min of acyl-ghrelin infusions were conducted 3 mo after surgery. Both before and after SG, postprandial glucose concentrations increased dose dependently during ghrelin infusions compared with placebo. Ghrelin infusions inhibited basal and postprandial insulin secretion rates, resulting in lowered measures of β-cell function, but no effect on insulin sensitivity was seen. Ad libitum meal intake was unaffected by the administration of ghrelin. In conclusion, ghrelin infusion increases postprandial plasma glucose concentrations and impairs β-cell function before and after SG but has no effect on ad libitum meal intake. We speculate that the lower concentration of ghrelin after SG may impact glucose metabolism following this procedure. NEW & NOTEWORTHY Ghrelin's effect on glucose tolerance and food intake following sleeve gastrectomy (SG) was evaluated. Acyl-ghrelin was infused during a mixed-meal and ad libitum meals before and 3 mo after surgery. Postprandial glucose concentrations increased during ghrelin infusions, both before and after surgery, while insulin production was inhibited. However, ad libitum meal intake did not differ during ghrelin administration compared with placebo. The decreased ghrelin concentration following SG may contribute to the glycemic control after surgery.

Background/objectives: After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure., Subjects/methods: Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting., Results: On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44])., Conclusions: Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB., (© 2023. The Author(s).)

Follistatin is secreted from the liver and may regulate muscle growth and insulin sensitivity. Protein intake stimulates follistatin secretion, which may be mediated by increased glucagon in the context of low insulin concentrations. We investigated circulating follistatin after mixed-meals in two cohorts of patients who were part of previously published studies and had undergone bariatric surgery with either simultaneous assessment of amino acid absorption or administration of the GLP-1 receptor antagonist exendin-(9-39), which increased glucagon concentrations and impaired insulin secretion. Study 1 comprised obese matched subjects with previous Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery and unoperated controls who underwent 6-hour mixed-meal tests with intravenous and oral tracers including intrinsically labelled caseinate in the meal. Study 2 comprised obese subjects with previous RYGB who underwent two 5-hour mixed-meal tests with concomitant exendin-(9-39) or saline infusion. In study 1, the secretion of follistatin as well as the amino acid absorption was accelerated after RYGB compared with SG and controls, but the glucagon-to-C-peptide ratios did not differ between the groups. In study 2, exendin-(9-39) administration increased postprandial glucagon concentrations and lowered insulin secretion, whereas the concentration of follistatin was unchanged. In conclusion, postprandial follistatin secretion is accelerated in patients after RYGB which might be explained by an accelerated protein absorption rate rather than the glucagon-to-insulin ratio., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB., (© 2023 by the American Diabetes Association.)

Introduction: Roux-en-Y gastric bypass (RYGB) surgery markedly increases the rate of intestinal nutrient exposure after food intake, accelerates intestinal absorption of dietary glucose and protein, and alters the postprandial gut hormone response. However, our understanding of postprandial fat absorption and metabolism after RYGB is incomplete., Methods: Stable palmitate tracers were administered intravenously (K-[2,2- 2 H 2 ]palmitate) and orally with a mixed meal ([U- 13 C 16 ]palmitate) to study fatty acid absorption and metabolism before and 3 months after RYGB in 10 participants with obesity and normal glucose tolerance., Results: There was a tendency toward reduced fasting plasma nonesterified palmitate concentrations after RYGB, but neither fasting palmitate kinetics nor fasting triacylglycerol (TAG) concentrations changed compared with before surgery. Postprandial TAG concentrations were numerically, but nonsignificantly, reduced 3-4 h after meal intake after compared with before RYGB. However, the postprandial appearance of the oral palmitate tracer in the plasma TAG pool and overflow into the nonesterified palmitate pool were initially faster but overall reduced after RYGB by 50% (median, IQR: [47;64], P = 0.004) and 46% (median, IQR: [33;70], P = 0.041), respectively. The maximal postprandial suppression of plasma nonesterified palmitate concentrations was slightly greater but shorter lasting after RYGB ('time × visit' interaction: P < 0.001), without detectable effects of surgery on the rate of appearance and disappearance of plasma palmitate., Conclusion: RYGB resulted in an initially accelerated but overall ~50% reduced 4-h postprandial systemic appearance of dietary palmitate in participants with obesity and normal glucose tolerance. This is likely a result of faster but incomplete intestinal fat absorption combined with enhanced chylomicron-TAG clearance, but it needs further investigation in studies specifically designed to investigate these mechanisms., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Impaired mitochondrial oxidative phosphorylation (OXPHOS) in liver tissue has been hypothesised to contribute to the development of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). It is unknown whether OXPHOS capacities in human visceral (VAT) and subcutaneous adipose tissue (SAT) associate with NAFLD severity and how hepatic OXPHOS responds to improvement in NAFLD. In biopsies sampled from 62 patients with obesity undergoing bariatric surgery and nine control subjects without obesity we demonstrate that OXPHOS is reduced in VAT and SAT while increased in the liver in patients with obesity when compared with control subjects without obesity, but this was independent of NAFLD severity. In repeat liver biopsy sampling in 21 patients with obesity 12 months after bariatric surgery we found increased hepatic OXPHOS capacity and mitochondrial DNA/nuclear DNA content compared with baseline. In this work we show that obesity has an opposing association with mitochondrial respiration in adipose- and liver tissue with no overall association with NAFLD severity, however, bariatric surgery increases hepatic OXPHOS and mitochondrial biogenesis., (© 2022. The Author(s).)

Background and Aims: The metabolic consequences after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are often studied using a liquid mixed meal. However, liquid meals may not be representative of the patients' everyday diet. We therefore examined postprandial glucose and gut hormone responses using mixed meals differing only with respect to meal texture., Methods: Twelve RYGB-operated, 12 SG-operated, and 12 unoperated individuals (controls) were enrolled in the study. Participants were matched on age, sex, and body mass index. In randomized order, each participant underwent a liquid and a solid 4-h mixed meal test on separate days. The meals were isocaloric (309 kcal), and with identical macronutrient composition (47 E% carbohydrate, 18 E% protein, 32 E% fat, and 3 E% dietary fibers). The liquid meal was blended to create a smooth liquid texture while the other meal retained its solid components., Results: Postprandial glucose concentrations (peak and incremental area under curve, iAUC) did not differ between the two meal textures in any group. In the control group, peak C-peptide was higher after the liquid meal compared with the solid meal ( p = 0.04), whereas iAUCs of C-peptide were similar between the two meals in all groups. Peak of glucagon-like peptide-1 (GLP-1) was higher after the liquid meal compared with the solid meal in RYGB- and SG-operated individuals (RYGB p = 0.02; SG p < 0.01), but iAUC of GLP-1 did not differ between meal textures within any group. Peak of glucose-dependent insulin tropic polypeptide (GIP) was higher after the liquid meal in the SG and control groups (SG p = 0.02; controls p < 0.01), but iAUCs of GIP were equal between meals. There were no differences in total AUC of ghrelin between the liquid and solid meals within any of the groups., Conclusion: A liquid and a solid meal with identical macronutrient composition result in similar postprandial glucose responses, both in operated and unoperated individuals. Small differences were observed for the postprandial peaks of C-peptide, GLP-1, and GIP concentrations. Overall, a liquid meal is suitable for evaluating glucose tolerance, β-cell function, and gut hormones responses, both after RYGB and SG and in unoperated individuals., Clinical Trial Registration: [www.clinicaltrials.gov], identifier [NCT04082923]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hedbäck, Hindsø, Bojsen-Møller, Linddal, Jørgensen, Dirksen, Møller, Kristiansen, Hartmann, Holst, Svane and Madsbad.)

Background: Bariatric surgery as treatment of obesity is increasing worldwide. No guidelines exist on which type of bariatric procedure to choose for the individual patient., Objectives: This study aims to compare Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) with respect to weight loss, complications, comorbidities, and quality of life., Setting: A nationwide multi-center register-based cohort study., Methods: We identified 16,053 patients treated by bariatric surgery from 2008 to 2021 (RYGB, n = 13,075; SG, n = 2978) from the Danish quality registry for treatment of severe obesity (DBSO). We calculated risk ratios (RRs) and prevalence ratios (PRs) comparing surgical complications, weight loss, and medical comorbidities by type of procedure up to 2 years after surgery., Results: Patients treated with RYGB experienced a greater weight loss than patients treated by SG both after 1 year (PR, .53; 95% confidence interval [CI], .48-.58) and 2 years (PR, .46; 95% CI, .39-.54). Compared with RYGB, SG yielded a lower risk of readmission (RR, .71; 95% CI, .60-.85). Likewise, the risk of reoperation between 30 days and 1 year (RR, .40; 95% CI, .30-.53) and 1 and 5 years (RR, .15; 95% CI, .12-.20]) were lower following SG. At 1-year follow-up, 76% of patients treated with RYGB and 63% of patients treated with SG experienced diabetes remission. Ten percent and 61% of patients were lost to follow-up after 1 and 2 years, respectively., Conclusion: The DBSO is an important resource in studying treatment of severe obesity. Weight loss is slightly greater after RYGB than after SG, but RYGB is associated with more frequent readmissions and reoperations., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions., Methods: We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively., Results: (I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p < 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p < 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p < 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p > 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p > 0.9)., Conclusion: Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide., (© 2021 John Wiley & Sons Ltd.)

Growth differentiating factor 15 (GDF15) is expressed in the intestine and is one of the most recently identified satiety peptides. The mechanisms controlling its secretion are unclear. The present study investigated whether plasma GDF15 concentrations are meal-related and if potential responses depend on macronutrient type or are affected by previous bariatric surgery. The study included 1 ) volunteers ingesting rapidly vs. slowly digested carbohydrates (sucrose vs. isomaltose; n = 10), 2 ) volunteers who had undergone Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery and unoperated matched controls ingesting a liquid mixed meal ( n = 9-10 in each group), and 3 ) individuals with previous RYGB compared with unoperated controls ingesting isocaloric glucose, fat, or protein ( n = 6 in each group). Plasma was collected after an overnight fast and up to 6 h after ingestion (≥12 time points). In cohort 1 , fasting GDF15 concentrations were ∼480 pg/mL. Concentrations after sucrose or isomaltose intake did not differ from baseline ( P = 0.26 to P > 0.99) and total area under the curves (tAUCs were similar between groups ( P = 0.77). In cohort 2 , fasting GDF15 concentrations were as follows (pg/mL): RYGB = 540 ± 41.4, SG = 477 ± 36.4, and controls = 590 ± 41.8, with no between-group differences ( P = 0.73). Concentrations did not increase at any postprandial time point (over all time factor: P = 0.10) and tAUCs were similar between groups ( P = 0.73). In cohort 3 , fasting plasma GDF15 was similar among the groups ( P > 0.99) and neither glucose, fat, nor protein intake consistently increased the concentrations. In conclusion, we find that plasma GDF15 was not stimulated by meal intake and that fasting concentrations did not differ between RYGB-, SG-, and body mass index (BMI)-matched controls when investigated during the weight stable phase after RYGB and SG. NEW & NOTEWORTHY Our combined data show that GDF15 does not increase in response to a liquid meal. Moreover, we show for the first time that ingestion of sucrose, isomaltose, glucose, fat, or protein also does not increase plasma GDF15 concentrations, questioning the role of GDF15 in regulation of food source preference. Finally, we find that neither fasting nor postprandial plasma GDF15 concentrations are increased in individuals with previous bariatric surgery compared with unoperated body mass index (BMI)-matched controls.

Roux-en-Y gastric bypass (RYGB) improves, and can sometimes resolve, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) but data based on histological assessment for the efficacy of sleeve gastrectomy (SG) in resolving NAFLD are sparse. Consequently, we aimed to compare the efficacy of RYGB vs. SG on NAFLD 12 months after surgery. In a prospective cohort study, 40 patients with obesity underwent bariatric surgery (16 RYGB and 24 SG). During surgery, a liver biopsy was taken and repeated 12 months later. NAFLD severity was evaluated using the NAFLD Activity Score (NAS) and Kleiner Fibrosis score. RYGB and SG patients were comparable at baseline. Mean (standard deviation, SD) NAS was 3.3 (0.9) in RYGB and 3.1 (1.4) in SG ( p = 0.560) with similar degrees of steatosis, inflammation, and ballooning. Two RYGB patients, and six SG patients, had NASH ( p = 0.439). Twelve months after surgery, NAS was significantly and comparably ( p = 0.241) reduced in both RYGB (-3.00 (95% CI -3.79--2.21), p < 0.001) and SG (-2.25 (95% CI -2.92--1.59), p < 0.001) patients. RYGB patients had significantly more reduced ( p = 0.007) liver steatosis (-0.91 (95% CI -1.47--1.2) than SG patients (-0.33 (95% CI -0.54--0.13) and greater improvement in the plasma lipid profile. Fibrosis declined non-significantly. NASH was resolved in seven of eight patients without a worsening of their fibrosis. RYGB and SG have similar beneficial effects on NAS and NASH without the worsening of fibrosis. RYGB is associated with a more pronounced reduction in liver steatosis.

Background: Altered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus., Methods: Two single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g × 2, or 4) no additions., Results: In study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones., Conclusion: In RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB., Competing Interests: RK works for Novo Nordisk A/S, but was at the time of his contribution exclusively employed by University of Copenhagen. TC works for Novo Nordisk A/S and own shares in Novo Nordisk A/S and Zealand Pharma A/S. All other authors declare no conflict of interest in relation to the current manuscript., (Copyright © 2021 Jonsson, Bojsen-Møller, Kristiansen, Veedfald, Wewer Albrechtsen, Clausen, Kuhre, Rehfeld, Holst, Madsbad and Svane.)

Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver-alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Plasma and liver biopsies from 33 individuals with obesity (collectively, OBE) were obtained before and 12 months after bariatric surgery (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). Nine healthy control individuals (collectively, CON) undergoing cholecystectomy were used as a comparison group. The NAFLD activity score (NAS) was used to subdivide study participants into the following groups: OBE-no steatosis, OBE+steatosis, and nonalcoholic steatohepatitis (NASH) and/or grade 2 fibrosis (Fib) (OBE-NASH-Fib). Measurements of amino acids by targeted metabolomics and glucagon were performed. Glucagon, amino acids ( P  < 0.05), and the glucagon-alanine index, a validated surrogate marker of glucagon resistance, were increased in OBE by 60%, 56%, and 61%, respectively, when compared with CON but irrespective of NAFLD severity. In contrast, markers of hepatic insulin resistance increased concomitantly with NAS. Hyperglucagonemia resolved in OBE-no steatosis and OBE+steatosis but not in OBE-NASH-Fib (median, 7.0; interquartile range, 5.0-9.8 pmol/L), regardless of improvement in insulin resistance and NAS. The type of surgery that participants underwent had no effect on metabolic outcomes. Conclusion: Glucagon resistance to amino acid metabolism exists in individuals with NAFLD independent of NAS severity. Patients with NASH showed persistent hyperglucagonemia 12 months after bariatric surgery, indicating that a disrupted liver-alpha cell may remain in NAFLD despite major improvement in liver histology., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Enhanced meal-related enteroendocrine secretion, particularly of glucagon-like peptide-1 (GLP-1), contributes to weight-loss and improved glycemia after Roux-en-Y gastric bypass (RYGB). Dietary glucose drives GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion postoperatively. Understanding how glucose triggers incretin secretion following RYGB could lead to new treatments of diabetes and obesity. In vitro, incretin release depends on glucose absorption via sodium-glucose cotransporter 1 (SGLT1). We investigated the importance of SGLT1/SGLT2 for enteropancreatic hormone concentrations and glucose metabolism after RYGB in a randomized, controlled, crossover study. Ten RYGB-operated patients ingested 50 g of oral glucose with and without acute pretreatment with 600 mg of the SGLT1/SGLT2-inhibitor canagliflozin. Paracetamol and 3- O -methyl-d-glucopyranose (3-OMG) were added to the glucose drink to evaluate rates of intestinal entry and absorption of glucose, respectively. Blood samples were collected for 4 h. The primary outcome was 4-h plasma GLP-1 (incremental area-under the curve, iAUC). Secondary outcomes included glucose, GIP, insulin, and glucagon. Canagliflozin delayed glucose absorption (time-to-peak 3-OMG: 50 vs. 132 min, P < 0.01) but did not reduce iAUC GLP-1 (6,067 vs. 7,273·min·pmol -1 ·L -1 , P = 0.23), although peak GLP-1 concentrations were lowered (-28%, P = 0.03). Canagliflozin reduced GIP (iAUC -28%, P = 0.01; peak concentrations -57%, P < 0.01), insulin, and glucose excursions, whereas plasma glucagon (AUC 3,216 vs. 4,160 min·pmol·L -1 , P = 0.02) and amino acids were increased. In conclusion, acute SGLT1/SGLT2-inhibition during glucose ingestion did not reduce 4-h plasma GLP-1 responses in RYGB-patients but attenuated the early rise in GLP-1, GIP, and insulin, whereas late glucagon concentrations were increased. The results suggest that SGLT1-mediated glucose absorption contributes to incretin hormone secretion after RYGB.

Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, FGF-21, and C-peptide were increased after glucose compared with the other meals. The neurotensin and bile acids responses were greater after fat, while the glucagon and CCK responses were greater after protein ingestion. Furthermore, compared with control subjects, RYGB subjects had greater responses of total PYY after glucose, glucagon after glucose and fat, glicentin after glucose and protein, and GLP-1 and neurotensin after all meals, while GIP and CCK responses were lower after fat. Ghrelin responses did not differ between meals or between groups. Orlistat reduced all hormone responses to fat ingestion, except for ghrelin in the RYGB group. In conclusion, after RYGB glucose is a more potent stimulator of most gut hormones, especially for the marked increased secretion of GLP-1 compared with fat and protein. NEW & NOTEWORTHY We investigated the impact of glucose, protein, and fat meals on intestinal and pancreatic hormones, bile acid, and fibroblast growth factor 21 (FGF-21) secretion in gastric bypass-operated patients compared with matched nonoperated individuals. The fat meal was administered with and without a pancreas lipase inhibitor. We found that the impact of the different meals on gut hormones, bile, and FGF 21 secretion differ and was different from the responses observed in nonoperated control subjects.

Background: Altered meal-related gut hormone secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB). Elucidating the responsible meal components and receptors could aid discovery of new treatments of obesity and diabetes. Enteroendocrine cells respond to digestion products of dietary triacylglycerol, especially long-chain fatty acids (LCFAs) and 2-oleoyl-glycerol (2-OG), but not medium-chain fatty acids (MCFAs)., Objective: We examined the impact of olive oil (20 mL) and its derivates, LCFAs and 2-OG, on enteroendocrine secretions [glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), and neurotensin (NT)] and on glucose, lipid, and bile acid metabolism in RYGB-operated and unoperated individuals., Methods: In an exploratory randomized crossover design, 10 RYGB-operated patients and 10 matched controls ingested 3 equimolar triacylglycerol formulations on separate days: olive oil (digested to 2-OG + LCFAs), C8-dietary oil (2-OG + MCFAs), and tricaprylin (MCFAs; negative control). Hormone responses were calculated as area under the curve (AUC)., Results: Independent of group status, olive oil had greater effects than C8-dietary oil on AUCs of plasma GLP-1 (+32%; 95% CI: 23%, 43%; P < 0.01), CCK (+53%, P < 0.01), and NT (+71%, P < 0.01), whereas the effect on GIP differed between groups (+90% in controls, P < 0.01; +24% in RYGB, P = 0.10). Independent of group status, C8-dietary oil had greater effects than tricaprylin on AUCs of plasma CCK (+40%, P < 0.01) and NT (+32%, P < 0.01), but not GLP-1 (+5%; 95% CI: -2.9%, 13%; P = 0.22), whereas the effect on GIP again differed between groups (+78% in controls, P < 0.01; +39% in RYGB, P = 0.01). Distal (GLP-1/PYY/NT), but not proximal (CCK/GIP), enteroendocrine responses were generally greater in RYGB patients than in controls., Conclusions: The combination of LCFAs plus 2-OG was substantially more effective than 2-OG plus MCFAs in stimulating enteroendocrine secretion in RYGB-operated and matched control individuals. Distal lipid-induced gut hormone release was greater after RYGB.This trial was registered at clinicaltrials.gov as NCT03223389., (Copyright © The Author(s) 2019.)

To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (RYGB) in patients with and without preoperative type 2 diabetes we invited 55 RYGB-operated persons from two existing cohorts to participate in a late follow-up study. 44 (24 with normal glucose tolerance (NGT)/20 with type 2 diabetes (T2D) before surgery) accepted the invitation (median follow-up 2.7 [Range 2.2-5.0 years]). Subjects were examined during an oral glucose stimulus and results compared to preoperative and 1-year (1 y) post RYGB results. Glucose tolerance, insulin resistance, beta-cell function and incretin hormone secretion were evaluated. 1 y weight loss was maintained late after surgery. Glycemic control, insulin resistance, beta-cell function and GLP-1 remained improved late after surgery in both groups. In NGT subjects, nadir glucose decreased 1 y after RYGB, but did not change further. In T2D patients, relative change in weight from 1 y to late after RYGB correlated with relative change in fasting glucose and HbA1c, whereas relative changes in glucose-stimulated insulin release correlated inversely with relative changes in postprandial glucose excursions. In NGT subjects, relative changes in postprandial nadir glucose correlated with changes in beta-cell glucose sensitivity. Thus, effects of RYGB on weight and glucose metabolism are maintained late after surgery in patients with and without preoperative T2D. Weight loss and improved beta-cell function both contribute to maintenance of long-term glycemic control in patients with type 2 diabetes, and increased glucose stimulated insulin secretion may contribute to postprandial hypoglycemia in NGT subjects.

Context: Exaggerated postprandial glucagon-like peptide-1 (GLP-1) secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB) and may result from carbohydrate absorption in the distal small intestine., Objective: To investigate distal [GLP-1; peptide YY (PYY)] and proximal [glucose-dependent insulinotropic polypeptide (GIP)] gut hormone secretion in response to carbohydrates hydrolyzed at different rates. We hypothesized that slow digestion restricts proximal absorption, facilitating distal delivery of carbohydrates and thereby enhanced GLP-1 secretion in unoperated individuals, whereas this may not apply after RYGB., Design: Single-blinded, randomized, crossover study., Setting: Hvidovre Hospital, Hvidovre, Denmark., Participants: Ten RYGB-operated patients and 10 unoperated matched subjects., Interventions: Four separate days with ingestion of different carbohydrate loads, either rapidly/proximally digested (glucose plus fructose; sucrose) or slowly/distally digested (isomaltulose; sucrose plus acarbose)., Main Outcome Measures: GLP-1 secretion (area under the curve above baseline). Secondary outcomes included PYY and GIP., Results: Isomaltulose enhanced secretion of GLP-1 nearly threefold (P = 0.02) and PYY ninefold (P = 0.08) compared with sucrose in unoperated subjects but had a modest effect after RYGB. Acarbose failed to increase sucrose induced GLP-1 secretion in unoperated subjects and diminished the responses by 50% after RYGB (P = 0.03). In both groups, GIP secretion was reduced by isomaltulose and even more so by sucrose plus acarbose when compared with sucrose intake., Conclusions: GLP-1 secretion depends on the rate of carbohydrate digestion, but in a different manner after RYGB. Enhanced GLP-1 secretion is central after RYGB, but it may also be obtained in unoperated individuals by delaying hydrolysis of carbohydrates, pushing their digestion and absorption distally in the small intestine., (Copyright © 2019 Endocrine Society.)

Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine-tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell-autonomous and phosphorylation-dependent manner. Insulin-stimulated Afadin-S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue-specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet-induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin-induced cellular feedback mechanism governed by the interaction of Afadin with HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance., (© 2019 The Authors.)

Background & Aims: Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) induce substantial weight loss and improve glycemic control in patients with type 2 diabetes, but it is not clear whether these occur via the same mechanisms. We compared absorption rates of glucose and protein, as well as profiles of gastro-entero-pancreatic hormones, in patients who had undergone SG or RYGB vs controls., Methods: We performed a cross-sectional study of 12 patients who had undergone sleeve gastrectomy, 12 patients who had undergone RYGB, and 12 individuals who had undergone neither surgery (controls), all in Denmark. Study participants were matched for body mass index, age, sex, and postoperative weight loss, and all had stable weights. They received continuous infusions of stable isotopes of glucose, glycerol, phenylalanine, tyrosine, and urea before and during a mixed meal containing labeled glucose and intrinsically phenylalanine-labeled caseinate. Blood samples were collected for 6 hours, at 10- to 60-minute intervals, and analyzed., Results: The systemic appearance of ingested glucose was faster after RYGB and SG vs controls; the peak glucose appearance rate was 64% higher after RYGB, and 23% higher after SG (both P < .05); the peak phenylalanine appearance rate from ingested casein was 118% higher after RYGB (P < .01), but similar between patients who had undergone SG and controls. Larger, but more transient increases in levels of plasma glucose and amino acids were accompanied by higher secretion of insulin, glucagon-like peptide 1, peptide YY, and cholecystokinin after RYGB, whereas levels of ghrelin were lower after SG, compared with RYGB and controls. Total 6-hour oral recovery of ingested glucose and protein was comparable among groups., Conclusions: Postprandial glucose and protein absorption and gastro-entero-pancreatic hormone secretions differ after SG and RYGB. RYGB was characterized by accelerated absorption of glucose and amino acids, whereas protein metabolism after SG did not differ significantly from controls, suggesting that different mechanisms explain improved glycemic control and weight loss after these surgical procedures. ClinicalTrials.gov ID NCT03046186., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Deterioration of the adipogenic potential of preadipocytes may contribute to adipose tissue dysfunction in obesity and type 2 diabetes (T2D). Here, we hypothesized that extracellular factors in obesity epigenetically reprogram adipogenesis potential and metabolic function of preadipocytes., Methods: The transcriptomic profile of visceral adipose tissue preadipocytes collected from Lean, Obese and Obese with T2D was assessed throughout in vitro differentiation using RNA sequencing. Reduced Representation Bisulfite Sequencing was used to establish the genome-wide DNA methylation profile of human preadipocytes and 3T3-L1 preadipocytes treated by the inflammatory cytokine Tumour Necrosis Factor-α (TNF-α) or palmitate., Results: While preadipocytes from all obese subjects (Obese+Obese T2D), compared to those of Lean, were transcriptionally different in response to differentiation in culture, preadipocytes from Obese T2D showed impaired insulin signalling and a further transcriptomic shift towards altered adipocyte function. Cultures with a lower expression magnitude of adipogenic genes throughout differentiation (PLIN1, CIDEC, FABP4, ADIPOQ, LPL, PDK4, APOE, LIPE, FABP3, LEP, RBP4 and CD36) were associated with DNA methylation remodelling at genes controlling insulin sensitivity and adipocytokine signalling pathways. Prior incubation of 3T3-L1 preadipocytes with TNF-α or palmitate markedly altered insulin responsiveness and metabolic function in the differentiated adipocytes, and remodelled DNA methylation and gene expression at specific genes, notably related to PPAR signalling., Conclusions: Our findings that preadipocytes retain the memory of the donor in culture and can be reprogrammed by extracellular factors support a mechanism by which adipocyte precursors are epigenetically reprogrammed in vivo. Epigenetic reprogramming of preadipocytes represents a mechanism by which metabolic function of visceral adipose tissue may be affected in the long term by past exposure to obesity- or T2D-specific factors.

Aim: To determine whether intestinal expression of guanylate cyclase activator 2A (GUCA2A) and guanylate cyclase activator 2B (GUCA2B) genes is regulated in obese humans following Roux-en-Y gastric bypass (RYGB), and to evaluate the corresponding guanylin (GN) and uroguanylin (UGN) peptides for potentially contributing to the beneficial metabolic effects of RYGB., Methods: Enteroendocrine cells were harvested peri- and post-RYGB, and GUCA2A/GUCA2B mRNA expression was compared. GN, UGN and their prohormones (proGN, proUGN) were administered subcutaneously in normal-weight mice to evaluate effects on food intake and glucose regulation. The effect of pro-UGN or UGN overexpression, using adeno-associated virus (AAV) vectors, was assessed in diet-induced obese (DIO) mice. Intracerebroventricular administration of GN and UGN was performed in rats for assessment of putative centrally mediated effects on food intake. GN and UGN, as well as their prohormones, were evaluated for effects on glucose-stimulated insulin secretion (GSIS) in rat pancreatic islets and perfused rat pancreas., Results: GUCA2A and GUCA2B mRNA expression was significantly upregulated in enteroendocrine cells after RYGB. Peripheral administration of guanylins or prohormones did not influence food intake, oral glucose tolerance, and GSIS. Central administration of GN and UGN did not affect food intake in rats. Chronic AVV-mediated overexpression of UGN and proUGN had no effect on body weight or glucose homeostasis in DIO mice., Conclusion: GN and UGN, as well as their prohormones, do not seem to play a significant role in body weight regulation and glycemic control, suggesting that guanylin-family peptides do not show promise as targets for the treatment of obesity or diabetes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Roux-en-Y gastric bypass is associated with an increased risk of postprandial hyperinsulinaemic hypoglycaemia, but the underlying pathophysiology remains poorly understood. We therefore examined the effect of re-routing of nutrient delivery on gut-islet cell crosstalk in a person with severe postprandial hypoglycaemia after Roux-en-Y gastric bypass., Case Report: A person with severe postprandial hypoglycaemia, who underwent surgical reversal of Roux-en-Y gastric bypass, was studied before reversal and at 2 weeks and 3 months after reversal surgery using liquid mixed meal tests and hyperinsulinaemic-euglycaemic clamps. The nadir of postprandial plasma glucose rose from 2.8 mmol/l to 4.1 mmol/l at 2 weeks and to 4.4 mmol/l at 3 months after reversal. Concomitant insulin- and glucagon-like peptide-1 secretion (peak concentrations and area under the curve) clearly decreased after reversal, while concentrations of glucose-dependent insulinotropic polypeptide and ghrelin increased. Insulin clearance declined after reversal, whereas clamp-estimated peripheral insulin sensitivity was unchanged. The person remained without symptoms of hypoglycaemia, but had experienced significant weight gain at 15-month follow-up., Discussion: Accelerated nutrient absorption may be a driving force behind postprandial hyperinsulinaemic hypoglycaemia after Roux-en-Y gastric bypass. Re-routing of nutrients by reversal of the Roux-en-Y gastric bypass diminished postprandial plasma glucose excursions, alleviated postprandial insulin and glucagon-like peptide-1 hypersecretion and eliminated postprandial hypoglycaemia, which emphasizes the importance of altered gut-islet cell crosstalk for glucose metabolism after Roux-en-Y gastric bypass., (© 2017 Diabetes UK.)

Postprandial secretion of glucagon-like peptide-1 (GLP-1) is enhanced after Roux-en-Y gastric bypass (RYGB), but the precise molecular mechanisms explaining this remain poorly understood. Plasma concentrations of bile acids (BAs) increase after RYGB, and BAs may act as molecular enhancers of GLP-1 secretion through activation of TGR5-receptors. We aimed to evaluate GLP-1 secretion after oral administration of the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid ursodeoxycholic acid (UDCA) (which are available for oral use) in RYGB-operated participants. Eleven participants (BMI 29.1 ± 1.2, age 37.0 ± 3.2 years, time from RYGB 32.3 ± 1.1 months, weight loss after RYGB 37.0 ± 3.1 kg) were studied in a placebo-controlled, crossover-study. On three different days, participants ingested (1) placebo (water), (2) UDCA 750 mg, (3) CDCA 1250 mg (highest recommended doses). Oral intake of CDCA increased plasma concentrations of GLP-1, C-peptide, glucagon, peptide YY, neurotensin, total bile acids, and fibroblast growth factor 19 significantly compared with placebo (all P  < 0.05 for peak and positive incremental area-under-the-curve (piAUC)). All plasma hormone concentrations were unaffected by UDCA Neither UDCA nor CDCA changed glucose, cholecystokinin or glucose-dependent insulinotropic polypeptide (GIP) concentrations. In conclusion, our findings demonstrate that the primary bile acid chenodeoxycholic acid is able to enhance secretion of gut hormones when administered orally in RYGB-operated patients-even in the absence of nutrients., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Roux-en-Y gastric bypass surgery is widely applied to ameliorate morbid obesity, including diabetes in people with type 2 diabetes. The latter vanish a few days after surgery for many, but not in all patients before any weight reduction has occurred. The explanation for this change in metabolic status is poorly understood, but the observation may suggest that the fate obesity and diabetes is only partly linked after surgery., Methods: The trajectories of weight reduction measured as reduced body mass index (BMI) in 741obese subjects with and without diabetes were evaluated. Evaluation was performed on three groups: 1) subjects that were non-diabetic before and after surgery; 2) subjects that were diabetics before surgery but non-diabetics after surgery; and 3) subjects that were diabetics before surgery and remained diabetics after surgery. The diabetic state was established at HbA1c above 48 mmol/mol., Results: The trajectories differ significantly between groups and any sub-populations of groups, the latter identified by the distance between individual trajectories using a k-means procedure. The results suggest that different domains in the enormous genetic network governing basic metabolism are perturbed in obesity and diabetes, and in fact some of the patients are affected by two distinct diseases: obesity and diabetes mellitus type 2., Conclusion: Although RYGB "normalized" many glycaemic parameters in some of the diabetic subjects apparently converting to a non-diabetics state, other diabetic subjects stay diabetic in the context of the new gut anatomy after surgery. Thus, the obesity part of the glycaemic derangement may have been ameliorated, but some defects of the diabetic state had not.

Background/objectives: Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY 3-36 ., Subjects/methods: Appetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1, nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2, 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYY 3-36 and (4) Ex-9/sitagliptin combined., Results: In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY 3-36 increased food intake by ~20% in RYGB patients, whereas neither GLP-1 receptor blockage nor DPP-4 inhibition alone affected food intake, perhaps because of concomitant marked increases in the unblocked hormone., Conclusions: Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY 3-36 , resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.

Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and β-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin-(9-39) (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose-tolerant patients were studied after RYGB in a randomized, placebo-controlled, 4-day crossover study with standard mixed-meal tests and concurrent administration of placebo, oral sitagliptin, Ex-9 infusion, or combined Ex-9-sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated β-cell function, and aggravated postprandial hyperglucagonemia compared with placebo, whereas sitagliptin had no effect despite two- to threefold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or β-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4-sensitive glucose-lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB., (Copyright © 2016 the American Physiological Society.)

Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized that weight loss remodels the epigenetic signature of spermatozoa in human obesity. Comprehensive profiling of the epigenome of sperm from lean and obese men showed similar histone positioning, but small non-coding RNA expression and DNA methylation patterns were markedly different. In a separate cohort of morbidly obese men, surgery-induced weight loss was associated with a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite. Our data provide evidence that the epigenome of human spermatozoa dynamically changes under environmental pressure and offers insight into how obesity may propagate metabolic dysfunction to the next generation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims/hypothesis: We studied the impact of Roux-en-Y gastric bypass (RYGB) on the density and hormonal gene expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes., Methods: Twelve patients with diabetes and 11 age- and BMI-matched controls underwent RYGB followed by enteroscopy ~10 months later. Mucosal biopsies taken during surgery and enteroscopy were immunohistochemically stained for glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and prohormone convertase 2 (PC2) and the expression of GCG (encoding preproglucagon), PYY, CCK, GIP, GHRL (encoding ghrelin), SCT (encoding secretin), NTS (encoding neurotensin) and NR1H4 (encoding farnesoid X receptor) was evaluated., Results: The density of cells immunoreactive for GLP-1, CCK and GIP increased in patients after RYGB and the density of those immunoreactive for GLP-1, PYY, CCK and PC2 increased in controls. In both groups, GHRL, SCT and GIP mRNA was reduced after RYGB while PYY, CCK, NTS and NR1H4 gene expression was unaltered. GCG mRNA was upregulated in both groups., Conclusions/interpretation: Numerous alterations in the distribution of enteroendocrine cells and their expression of hormonal genes are seen after RYGB and include increased density of GLP-1-, PYY-, CCK-, GIP- and PC2-positive cells, reduced gene expression of GHRL, SCT and GIP and increased expression of GCG.

The median arcuate ligament syndrome is a rare entity and poorly described in Danish literature. The syndrome is a diagnosis of exclusion and is characterized by chronic abdominal pain, postprandial pain and weight loss. It is believed that the median arcuate ligament, being a fibrous structure of diaphragm, compresses the coeliac trunk thus causing stenosis and malperfusion of the gastrointestinal organs. Until recently, there has been some reluctance to consider intervention with revascularization or ligament release. Within the latest decade minimally invasive techniques, including laparoscopic release of the median arcuate ligament, have shown promising results.

Background: Concerns regarding nutritional deficiencies have recently emerged after Roux-en-Y gastric bypass (RYGB)., Methods: A total of 835 subjects underwent RYGB, age 43.3 years, body mass index (BMI) 47.2 kg/m(2). Hematological and calcium metabolic variables were measured before, 6, 12, and 24 months after surgery. Daily supplement of 800 mg calcium, 800 U vitamin D, a multivitamin, and a vitamin B12 injection (1 mg) every third month was recommended. In subjects with low ferritin and decreasing hemoglobin levels, oral, or intravenous iron was administered., Results: Hemoglobin concentration decreased from before surgery to month 24 for both men (9.3 ± 0.05 vs. 8.3 ± 0.08 mmol/L, p < 0.001) and women (8.4 ± 0.03 vs. 7.7 ± 0.06 mmol/L, p < 0.001). At 24 months, anemia was present in 25.8 % of women and 22.1 % of men. Predictors of anemia in both sexes were baseline hemoglobin (p < 0.001), excessive weight loss in men, and younger age in women (p < 0.001). Plasma ferritin levels decreased in both sexes (p < 0.01), whereas concentrations of folic acid and vitamin B12 increased from before surgery to 24 months after surgery (p < 0.001). Vitamin D increased from baseline to month 24 in both sexes (p < 0.01). In women, PTH increased from baseline to month 24 (p < 0.05) with no changes in calcium or magnesium., Conclusions: Supplementation of calcium and vitamin D was sufficient. Iron substitution did not prevent anemia, which especially affected premenopausal women. More attention should be given to iron substitution after RYGB.

Background: Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption., Objective: We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release., Design: Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry., Results: After RYGB, basal plasma leucine concentration did not change, but marked changes were seen postprandially with 1.7-fold increased peak concentrations (before—mean: 217 μmol/L; 95% CI: 191, 243 μmol/L; 3 mo—mean: 377 μmol/L; 95% CI: 252, 502 μmol/L; P = 0.012) and 2-fold increased incremental AUC (before-mean: 4.1 mmol ∙ min/L; 95% CI: 2.7, 5.5 mmol ∙ min/L; 3 mo-mean: 9.5 mmol ∙ min/L; 95% CI: 4.9, 14.2 mmol ∙ min/L; P = 0.032). However, the postprandial hyperleucinemia was transient, and concentrations were below basal concentrations in the fourth postprandial hour. These concentration differences were mainly caused by changes in leucine appearance rate from orally ingested caseinate: peak rate increased nearly 3-fold [before—mean: 0.5 μmol/(kg fat-free mass ∙ min); 95% CI: 0.4, 0.5 μmol/(kg fat-free mass ∙ min); 3 mo—mean 1.4 μmol/(kg fat-free mass ∙ min); 95% CI: 0.8, 1.9 μmol/(kg fat-free mass ∙ min); P = 0.002], and time to peak was much shorter (before—mean: 173 min; 95% CI: 137, 209 min; 3 mo—mean: 65 min; 95% CI: 46, 84 min; P < 0.001). Only minor changes were seen in endogenous leucine release after RYGB., Conclusions: RYGB accelerates caseinate digestion and amino acid absorption, resulting in faster and higher but more transient postprandial elevation of plasma amino acids. Changes are likely mediated by accelerated intestinal nutrient entry and clearly demonstrate that protein digestion is not impaired after RYGB. This trial was registered at clinicaltrials.gov as NCT01559792., (© 2015 American Society for Nutrition.)

Objective: To examine 24-h blood pressure (24BP), systemic haemodynamics and the effect of sodium intake on 24BP in obese patients before and after gastric bypass surgery [laparoscopic Roux-en-Y gastric bypass (LRYGB)], and to determine whether weight loss from LRYGB might be related to an increase in plasma concentrations of atrial natriuretic peptide., Methods: Twelve hypertensive and 12 normotensive morbidly obese patients underwent LRYGB: 24BP, systemic haemodynamics and mid-regional pro-atrial natriuretic peptide (MRproANP) were assessed before, 6 weeks and 12 months after surgery. The effect of high versus low sodium intake on 24BP was evaluated before and 12 months after LRYGB., Results: Six weeks after LRYGB, the average weight loss was 20 kg, with a further 21 kg weight loss 1 year after surgery. In hypertensive patients, 24BP was significantly reduced at 6 weeks, but not 1 year after LRYGB. However, antihypertensive medications were successively reduced from baseline to 1 year after surgery. In normotensive patients, there was no change in 24BP 6 weeks after LRYGB, but a tendency towards a reduction 1 year after the operation. Plasma concentrations of MRproANP were subnormal prior to surgery in hypertensive patients and increased by 77% 1 year after the operation. In normotensive patients, preoperative concentrations were normal and increased only by 6%. High sodium intake induced plasma volume expansion, increased stroke volume and cardiac output, but no significant change in 24BP - neither before nor after LRYGB., Conclusions: LRYGB resulted in a significant 24BP reduction and a substantial increase in MRproANP plasma concentrations in hypertensive, obese patients 6 weeks after surgery, suggesting a causal link between obesity-hypertension and altered release/degradation of cardiac natriuretic peptides.

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study., (Copyright © 2015 the American Physiological Society.)

Context: Bile acids and fibroblast growth factor 19 (FGF19) have been suggested as key mediators of the improvements in glucose metabolism after Roux-en-Y gastric bypass (RYGB)., Objective: To describe fasting and postprandial state total bile acid (TBA) and FGF19 concentrations before and after RYGB and relate them to parameters of glucose metabolism, glucagon-like peptide-1, cholecystokinin, and cholesterol fractions., Design and Setting: A prospective descriptive study was performed at the Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark., Patients: Thirteen type 2 diabetic (T2D) patients and 12 normal glucose tolerant (NGT) subjects participated in the study., Intervention: A 4-hour liquid meal test was performed before and 1 week, 3 months, and 1 year after RYGB., Main Outcome Measures: We measured fasting and postprandial TBA and FGF19 concentrations., Results: Fasting TBA concentrations decreased in NGT subjects (P < .001) and were unchanged in T2D patients 1 week after surgery, but then increased gradually in both groups with time from surgery (ANOVA Ptime < .001). Area under the curve (AUC) TBA was decreased in NGT subjects 1 week after RYGB (before surgery, 567 mmol * min/L [interquartile range, 481-826]; 1 wk, 419 [381-508]; P = .009) and was unchanged in T2D patients (894 [573-1002]; 695 [349-1147]; P = .97) but then increased with time from surgery in both groups (Ptime < .001). Fasting FGF19 concentrations were unchanged acutely after RYGB (NGT, 140 pg/mL [100-162], 134 [119-204], P = .42; T2D, 162 [130-196], 154 [104-164], P = .68) and remained unchanged throughout the follow-up period. AUC FGF19 increased gradually with time after surgery (Ptime < .001), resembling the changes seen with AUC TBA. One week after RYGB, glucose metabolism improved, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol decreased, and cholecystokinin and glucagon-like peptide-1 secretion increased, whereas FFA concentrations were unchanged., Conclusion: TBA and FGF19 do not explain acute changes in glucose metabolism, cholesterol fractions, and gut hormone secretion after RYGB.

The prevalence of hidradenitis suppurativa (HS) has been estimated to be 1% of the population. Obesity is considered a co-morbidity, but the prevalence of HS in obese population is not known. A retrospective questionnaire was distributed to 383 patients over 2 years after bariatric surgery. Data on pre- and post-surgery HS symptoms and disease severity were studied. Disease severity was assessed by number of involved sites. General skin problems rated numerically on an anchored 1-10 scale. Valid responses were obtained from 249/383 (65%). A point prevalence of 18.1% (45/249) HS was found. The number of patients reporting HS symptoms after weight loss decreased by 35% and the mean number of involved sites was reduced from 1.93 to 1.22 following weight loss (p = 0.003). The prevalence of HS appears higher in the obese than in the background population, and a weight loss of more than 15% is associated with a significant reduction of disease severity.

Roux-en-Y gastric bypass (RYGB) improves glycemic control within days after surgery, and changes in insulin sensitivity and β-cell function are likely to be involved. We studied 10 obese patients with type 2 diabetes (T2D) and 10 obese glucose-tolerant subjects before and 1 week, 3 months, and 1 year after RYGB. Participants were included after a preoperative diet-induced total weight loss of -9.2 ± 1.2%. Hepatic and peripheral insulin sensitivity were assessed using the hyperinsulinemic- euglycemic clamp combined with the glucose tracer technique, and β-cell function was evaluated in response to an intravenous glucose-glucagon challenge as well as an oral glucose load. Within 1 week, RYGB reduced basal glucose production, improved basal hepatic insulin sensitivity, and increased insulin clearance, highlighting the liver as an important organ responsible for early effects on glucose metabolism after surgery. Insulin-mediated glucose disposal and suppression of fatty acids did not improve immediately after surgery but increased at 3 months and 1 year; this increase likely was related to the reduction in body weight. Insulin secretion increased after RYGB only in patients with T2D and only in response to oral glucose, underscoring the importance of the changed gut anatomy.

Aims/hypothesis: Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon-like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones, including GLP-1, is altered., Methods: Eleven severely obese glucose-tolerant individuals underwent three hyperglycaemic clamps with arginine bolus and co-infusion of either GLP-1, glucose-dependent insulinotropic polypeptide (GIP) or saline before, and at 1 week and 3 months after RYGB. In addition, an OGTT was performed before and 3 months after surgery., Results: After RYGB, insulin sensitivity improved at 1 week and 3 months, while insulin stimulation and glucagon suppression in response to the clamp with saline co-infusion were largely unaltered. The influence of i.v. GLP-1 and GIP on insulin and glucagon secretion was also unchanged postoperatively. In response to the postoperative OGTT at 3 months, insulin and GLP-1, but not GIP, secretion increased. Furthermore, the glucose profile during the OGTT was altered, with a substantial reduction in 2 h plasma glucose and a paradoxical hypersecretion of glucagon., Conclusions/interpretation: After RYGB, insulin hypersecretion is linked to the oral, but not the i.v., route of administration and is associated with exaggerated release and preserved insulinotropic action of GLP-1, while both the secretion and action of GIP are unchanged. The results highlight the importance of increased GLP-1 secretion for improving postoperative glucose metabolism., Trial Registration: ClinicalTrials.gov NCT01559779.

Diastasis rectus abdominis is a common condition, which may be mistaken for a ventral hernia. The literature is generally of poor quality. The evidence for the effect of conservative and surgical treatment is controversial and long-term results are unknown. Present analyses find that complication rates range from 4% to 88% and the most frequent complication is seroma formation. The risk of recurrence is up to 40%. Treatment of rectus diastasis should preferably follow scientific protocols and be restricted to patients with severe physical complaints.

Background: Many patients with morbid obesity (BMI > 40 kg/m) have hypertension. The complex pathophysiological abnormalities linking hypertension to obesity have not been fully clarified, but abnormal sodium handling could be an important mechanism., Method: Therefore, we examined changes in body fluid compartments and haemodynamic responses (at rest and during exercise) after 5 days of a low-sodium diet (90 mmol/day) and 5 days of a high-sodium diet (250 mmol/day) in 12 morbidly obese, hypertensive patients; 12 morbidly obese, normotensive patients and 12 nonobese controls., Results: High sodium intake as compared to low sodium intake was associated with an increase in plasma volume (obese, hypertensive patients: 5 ± 4%; obese, normotensive patients: 10 ± 11%; nonobese controls: 7 ± 6%), cardiac output (CO) (obese, hypertensive patients: 17 ± 12%; obese, normotensive patients: 20 ± 16%; nonobese controls: 13 ± 14%) and stroke volume (SV) (obese, hypertensive patients: 27 ± 26%; obese, normotensive patients: 27 ± 24%; nonobese controls: 18 ± 27%) in all three groups with no differences between the groups. Despite an increase in CO during high salt intake, 24-h blood pressure (BP) was unchanged in patients and controls as a result of a reduction in total peripheral resistance (obese, hypertensive patients: -11 ± 11%; obese, normotensive patients: -10 ± 12%; nonobese controls: -5 ± 14%). Similar changes were observed during an incremental bicycle exercise test wherein CO and SV were higher, whereas mean arterial BP was unchanged at each exercise level during high sodium intake., Conclusion: Despite substantial increases in CO and SV, we did not observe any significant change in BP during high sodium intake, neither in morbid obese patients nor in lean individuals.

Aims/hypothesis: Roux-en-Y gastric bypass surgery (RYGB) improves glucose tolerance in patients with type 2 diabetes, but also changes the glucose profile in response to a meal in glucose-tolerant individuals. We hypothesised that the driving force for the changed postprandial glucose profiles after RYGB is rapid entry of glucose into the systemic circulation due to modified gastrointestinal anatomy, causing hypersecretion of insulin and other hormones influencing glucose disappearance and endogenous glucose production., Methods: We determined glucose absorption and metabolism and the rate of lipolysis before and 3 months after RYGB in obese glucose-tolerant individuals using the double-tracer technique during a mixed meal., Results: After RYGB, the postprandial plasma glucose profile changed, with a higher peak glucose concentration followed by a faster return to lower than basal levels. These changes were brought about by changes in glucose kinetics: (1) a more rapid appearance of ingested glucose in the systemic circulation, and a concomitant increase in insulin and glucagon-like peptide-1 secretion; (2) postprandial glucose disappearance was maintained at a high rate for a longer time after RYGB. Endogenous glucose production was similar before and after surgery. Postoperative glucagon secretion increased and showed a biphasic response after RYGB. Adipose tissue basal rate of lipolysis was higher after RYGB., Conclusions/interpretation: A rapid rate of absorption of ingested glucose into the systemic circulation, followed by increased insulin secretion and glucose disappearance appears to drive the changes in the glucose profile observed after RYGB, while endogenous glucose production remains unchanged., Trial Registration: ClinicalTrials.gov NCT01559792., Funding: The study was part of the UNIK program: Food, Fitness & Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk ). Funding was received from the Novo Nordisk foundation and the Strategic Research Counsel for the Capital Area and Danish Research Agency. The primary investigator received a PhD scholarship from the University of Copenhagen, which was one-third funded by Novo Nordisk.

β-Cell function improves in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to the exaggerated secretion of glucagon-like peptide 1 (GLP-1), but causality has not been established. The aim of this study was to investigate the role of GLP-1 in improving β-cell function and glucose tolerance and regulating glucagon release after RYGB using exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R)-specific antagonist. Nine patients with type 2 diabetes were examined before and 1 week and 3 months after surgery. Each visit consisted of two experimental days, allowing a meal test with randomized infusion of saline or Ex-9. After RYGB, glucose tolerance improved, β-cell glucose sensitivity (β-GS) doubled, the GLP-1 response greatly increased, and glucagon secretion was augmented. GLP-1R blockade did not affect β-cell function or meal-induced glucagon release before the operation but did impair glucose tolerance. After RYGB, β-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion. Thus, the exaggerated effect of GLP-1 after RYGB is of major importance for the improvement in β-cell function, control of glucagon release, and glucose tolerance in patients with type 2 diabetes.

Context: The analgesic effect of transversus abdominis plane (TAP) block after inguinal hernia repair is unclear., Objective: The aim of this randomised and double-blind study was to evaluate the analgesic effect of a TAP block in patients scheduled for primary inguinal hernia repair. The TAP block was evaluated versus placebo and versus an active comparator (ilioinguinal block and wound infiltration)., Design: Randomised controlled trial., Setting: Single centre trial. Study period from June 2010 to November 2011., Patients: Adults (18 to 75 years) with American Society of Anesthesiologists' status 1-3 scheduled for primary inguinal hernia repair as day case surgery were included in the study., Interventions: Ninety patients were allocated to one of three groups: group TAP, group infiltration (ilioinguinal nerve block and wound infiltration) and group placebo., Main Outcome Measures: The primary outcome measure was pain scores while coughing between group TAP and group placebo calculated as area under the curve for the first 24  h (AUC24 h). Secondary outcomes were pain scores while coughing and at rest, opioid consumption and side effects in groups TAP, infiltration and placebo., Results: Visual analogue pain scores while coughing and at rest demonstrated no difference between groups. Pain scores in groups infiltration, TAP and placebo were 19 versus 22 versus 15  mm at rest (P = 1.00) and 37 versus 41 versus 37  mm while coughing (P = 1.00). Pain scores at 6 h (AUC6 h) were significantly lower in group infiltration than in group TAP (10 versus 25 mm at rest, P < 0.001; 17 versus 40  mm while coughing, P < 0.001), and than in group placebo (10 versus 20  mm at rest, P = 0.003; 17 versus 38  mm while coughing, P < 0.001). Median morphine consumption was lower in group infiltration than in group placebo (0 versus 5 mg, P < 0.003). No differences among groups were demonstrated for ketobemidone consumption or side effects., Conclusion: Ultrasound-guided TAP block did not reduce postoperative pain after inguinal hernia repair., Trial Registration: Clinicaltrials.gov identifier: NCT01052285. EudraCT number 2010-018403-29.

Context: Roux-en-Y gastric bypass (RYGB) improves glucose tolerance and ameliorates fasting hyperinsulinemia within days after surgery. Improvements in hepatic insulin sensitivity and insulin clearance could contribute importantly to these effects., Objective: The objective of the investigation was to study changes in insulin clearance after RYGB., Design: This was a prospective study of fasting hepatic insulin clearance and, in a subgroup of patients, postprandial insulin clearance after a meal test before and 1 week, 3 months, and 1 year after RYGB., Setting: The study was conducted at Hvidovre Hospital (Hvidovre, Denmark)., Patients: Patients included 2 groups of obese RYGB-patients: 1) type 2 diabetes (T2D) group: 32 patients with T2D (meal test, n = 13), 2) normal glucose tolerance (NGT) group: 32 patients with NGT (meal test, n = 12)., Intervention: The intervention was RYGB., Main Outcome Measure: Fasting hepatic insulin clearance (fasting C-peptide/fasting insulin). Postprandial insulin clearance (incremental areas under the curve of insulin secretion rates/incremental areas under the curve of insulin)., Results: Fasting hepatic insulin clearance increased after 1 week (P < .01) and further at 3 months (P < .01), remaining elevated 1 year postoperatively (P < .01) with no difference between the T2D and NGT groups. Postprandial insulin clearance changed only in the T2D group with an increase at 1 week (P < .01) that was maintained at 3 months (P = .06) and 1 year (P < .01)., Conclusions: RYGB increases insulin clearance within 1 week after surgery, highlighting the liver as a key organ involved in the early beneficial effect on glucose metabolism. Postprandial insulin secretion may be underestimated postoperatively in patients with type 2 diabetes when evaluated by peripheral insulin concentrations instead of insulin secretion rates or C-peptide.