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• W2912094716 abstract "•Increased postprandial GLP-1 triggers higher insulin levels after bariatric surgery•Bariatric surgery does not change enteroendocrine cell identity or hormone content•Increased nutrient flow to the distal gut after surgery enhances GLP-1 secretion Bariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion. Bariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion. Bariatric surgery is widely used to treat obesity and is particularly effective because it results in dramatic improvements in type 2 diabetes (Sjöström, 2013Sjöström L. Review of the key results from the Swedish obese subjects (SOS) trial—a prospective controlled intervention study of bariatric surgery.J. Intern. Med. 2013; 273: 219-234Google Scholar). Reduced plasma glucose after bariatric surgery can be attributed partly to loss of body weight and adiposity, which in turn improves insulin sensitivity (Sjöström, 2013Sjöström L. Review of the key results from the Swedish obese subjects (SOS) trial—a prospective controlled intervention study of bariatric surgery.J. Intern. Med. 2013; 273: 219-234Google Scholar). In addition, bariatric patients have elevated post-prandial insulin secretion, and there are increasing reports of bariatric surgery being used to treat type 2 diabetes in patients who are not severely obese (Pok and Lee, 2014Pok E.H. Lee W.J. Gastrointestinal metabolic surgery for the treatment of type 2 diabetes mellitus.World J. Gastroenterol. 2014; 20: 14315-14328Google Scholar), as well as of post-prandial hypoglycemia occurring years after surgery when increased insulin release occurs on a background of improved insulin sensitivity following loss of body weight (Salehi et al., 2018Salehi M. Vella A. McLaughlin T. Patti M.E. Hypoglycemia after gastric bypass surgery: current concepts and controversies.J. Clin. Endocrinol. Metab. 2018; 103: 2815-2826Google Scholar). Understanding the physiological basis for elevated post-prandial insulin secretion after bariatric surgery is therefore important both for preventing hypoglycemia in susceptible post-surgical populations and for developing new therapeutic strategies to treat type 2 diabetes. We have studied the endocrinology of lean patients who underwent gastrectomy with Roux-en-Y gastric bypass (RYGB) reconstruction for the treatment or prophylaxis of gastric cancer (Roberts et al., 2018bRoberts G.P. Kay R.G. Howard J. Hardwick R.H. Reimann F. Gribble F.M. Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery.Surg. Obes. Relat. Dis. 2018; 14: 562-568Google Scholar). The surgical procedure is similar to a standard RYGB performed for obesity, with the exception that the stomach is removed in its entirety. Post-gastrectomy patients have elevated plasma glucagon-like peptide (GLP) 1, peptide YY (PYY), and insulin levels after an oral glucose tolerance test (OGTT), mirroring the endocrine changes seen in bariatric patients, but because these patients are not generally obese, the excessive insulin secretion is associated with significant rates of post-prandial hypoglycemia (Roberts et al., 2018bRoberts G.P. Kay R.G. Howard J. Hardwick R.H. Reimann F. Gribble F.M. Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery.Surg. Obes. Relat. Dis. 2018; 14: 562-568Google Scholar). The contribution of GLP-1 to the observed post-surgical changes in plasma glucose and insulin concentrations has been debated, as detailed in several reviews (Hutch and Sandoval, 2017Hutch C.R. Sandoval D. The role of GLP-1 in the metabolic success of bariatric surgery.Endocrinology. 2017; 158: 4139-4151Google Scholar, Smith et al., 2018Smith E.P. Polanco G. Yaqub A. Salehi M. Altered glucose metabolism after bariatric surgery: what’s GLP-1 got to do with it?.Metabolism. 2018; 83: 159-166Google Scholar). In obese post-bariatric patients, blocking GLP-1 action using Exendin-9 reduced insulin secretion and the incidence of hypoglycemia (Jørgensen et al., 2013Jørgensen N.B. Dirksen C. Bojsen-Møller K.N. Jacobsen S.H. Worm D. Hansen D.L. Kristiansen V.B. Naver L. Madsbad S. Holst J.J. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes.Diabetes. 2013; 62: 3044-3052Google Scholar, Salehi et al., 2014Salehi M. Gastaldelli A. D’Alessio D.A. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass.Gastroenterology. 2014; 146: 669-680Abstract Full Text Full Text PDF Scopus (175) Google Scholar), but corresponding data from mouse models have been conflicting. Mice with global GLP-1 receptor (Glp1r) knockout, for example, exhibited similar weight loss and glucose tolerance to wild-type controls after vertical sleeve gastrectomy (VSG) (Wilson-Pérez et al., 2013Wilson-Pérez H.E. Chambers A.P. Ryan K.K. Li B. Sandoval D.A. Stoffers D. Drucker D.J. Pérez-Tilve D. Seeley R.J. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide 1 receptor deficiency.Diabetes. 2013; 62: 2380-2385Google Scholar), whereas another group reported that mice with inducible β cell-specific Glp1r knockout had impaired insulin secretion and higher plasma glucose after VSG (Garibay et al., 2016Garibay D. McGavigan A.K. Lee S.A. Ficorilli J.V. Cox A.L. Michael M.D. Sloop K.W. Cummings B.P. β-cell glucagon-like peptide-1 receptor contributes to improved glucose tolerance after vertical sleeve gastrectomy.Endocrinology. 2016; 157: 3405-3409Scopus (36) Google Scholar). Why post-prandial GLP-1 and PYY levels are elevated after bariatric surgery remains incompletely elucidated. GLP-1 and PYY are produced from enteroendocrine cells (EECs), which comprise ∼1% of the intestinal epithelium (Gribble and Reimann, 2016Gribble F.M. Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium.Annu. Rev. Physiol. 2016; 78: 277-299Google Scholar). These cell types have been extensively characterized in mice, because they can be tagged with fluorescent reporters driven by cell-specific hormonal or transcription factor promoters in transgenic mouse models (Gribble and Reimann, 2016Gribble F.M. Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium.Annu. Rev. Physiol. 2016; 78: 277-299Google Scholar), but data on human EECs are limited, because cell purification requires antibody staining for identification (Roberts et al., 2018aRoberts G. Larraufie P. Richards P. Kay R. Galvin S. Miedzybrodzka E. Leiter A. Li J. Glass L. Ma M. et al.Comparison of Human and Murine Enteroendocrine Cells by Transcriptomic and Peptidomic Profiling. Bioarchives, 2018Google Scholar). One potential explanation for the post-surgical changes in gut hormone release is that EECs undergo adaptive changes, producing more GLP-1 and PYY that can be mobilized after food intake, or changing their response to nutrients due to different receptor expression. Although immunostaining of intestinal biopsies from bariatric patients and obese rodent models does not support the concept that major shifts occur in the numbers of EECs producing different gut hormones (Mumphrey et al., 2013Mumphrey M.B. Patterson L.M. Zheng H. Berthoud H.R. Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats.Neurogastroenterol. Motil. 2013; 25: e70-e79Google Scholar, Rhee et al., 2015Rhee N.A. Wahlgren C.D. Pedersen J. Mortensen B. Langholz E. Wandall E.P. Friis S.U. Vilmann P. Paulsen S.J. Kristiansen V.B. et al.Effect of Roux-en-Y gastric bypass on the distribution and hormone expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes.Diabetologia. 2015; 58: 2254-2258Google Scholar), staining methods are semiquantitative at best and do not inform on receptor expression. However, an important role for intestinal adaptation was not supported by the finding that GLP-1 levels after gastric bypass surgery were higher when a liquid meal was delivered via the oral route than it was when delivered via the gastroduodenal route on consecutive days (Dirksen et al., 2010Dirksen C. Hansen D.L. Madsbad S. Hvolris L.E. Naver L.S. Holst J.J. Worm D. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion: a case report.Diabetes Care. 2010; 33: 375-377Google Scholar). An alternative explanation is that ingested nutrients make contact with and thereby stimulate more EECs from the distal gut after surgery, due to anatomic intestinal rearrangement and/or increased intestinal transit. In both humans and mice, GLP-1 and PYY production is higher in more distal regions of the small intestine (Roberts et al., 2018aRoberts G. Larraufie P. Richards P. Kay R. Galvin S. Miedzybrodzka E. Leiter A. Li J. Glass L. Ma M. et al.Comparison of Human and Murine Enteroendocrine Cells by Transcriptomic and Peptidomic Profiling. Bioarchives, 2018Google Scholar), so increased distal nutrient delivery has the potential to activate a greater number of GLP-1 and PYY-producing EECs. The objectives of this study were to explore the importance of GLP-1 in post-bariatric physiology and the mechanisms underlying elevated post-prandial GLP-1 secretion in this group. Studies were performed in lean human and mouse models to reduce the confounding effects of metabolic changes due to loss of body weight and adiposity. We hypothesized that elevated plasma GLP-1 levels triggered by glucose ingestion were responsible for the high insulin secretion rates and subsequent hypoglycemia observed in our lean human cohort after gastrectomy (Roberts et al., 2018bRoberts G.P. Kay R.G. Howard J. Hardwick R.H. Reimann F. Gribble F.M. Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery.Surg. Obes. Relat. Dis. 2018; 14: 562-568Google Scholar), as reported previously in bariatric patients (Craig et al., 2017Craig C.M. Liu L.F. Deacon C.F. Holst J.J. McLaughlin T.L. Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia.Diabetologia. 2017; 60: 531-540Google Scholar, Jørgensen et al., 2013Jørgensen N.B. Dirksen C. Bojsen-Møller K.N. Jacobsen S.H. Worm D. Hansen D.L. Kristiansen V.B. Naver L. Madsbad S. Holst J.J. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes.Diabetes. 2013; 62: 3044-3052Google Scholar, Salehi et al., 2014Salehi M. Gastaldelli A. D’Alessio D.A. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass.Gastroenterology. 2014; 146: 669-680Abstract Full Text Full Text PDF Scopus (175) Google Scholar). Five post-gastrectomy patients were enrolled into a randomized, double-blind, placebo-controlled cross-over study, in which they received infusions of the GLP1R antagonist Exendin-9 or placebo on separate visits. Forty minutes after starting the infusion, they consumed a 50 g glucose drink, and 125 min later, they had an ad libitum test meal. Nadir glucose concentrations after the OGTT increased significantly from the control to the Exendin-9 day (Figures 1A and 1B ). Elevated insulin concentrations were seen in the control arm and were significantly blunted by Exendin-9, reaching levels similar to those measured previously in a non-surgical control group (Roberts et al., 2018bRoberts G.P. Kay R.G. Howard J. Hardwick R.H. Reimann F. Gribble F.M. Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery.Surg. Obes. Relat. Dis. 2018; 14: 562-568Google Scholar) (Figures 1C and 1D). The inhibitory effect of Exendin-9 on insulin release was also observed as a reduced slope of the insulin secretory rate versus glucose concentration graph (Figure 1E). Glucagon concentrations 30 min after the OGTT were increased by Exendin-9 (Figure 1F), consistent with the known inhibitory effect of GLP-1 on glucagon secretion (Nauck et al., 1993Nauck M.A. Heimesaat M.M. Orskov C. Holst J.J. Ebert R. Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.J. Clin. Invest. 1993; 91: 301-307Google Scholar). GLP-1 concentrations were higher with Exendin-9 (Figure 1G), consistent with previous reports that GLP-1 inhibits its own secretion (likely indirectly, e.g., via local somatostatin release) (Hansen et al., 2000Hansen L. Hartmann B. Bisgaard T. Mineo H. Jørgensen P.N. Holst J.J. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum.Am. J. Physiol. Endocrinol. Metab. 2000; 278: E1010-E1018Google Scholar, Heruc et al., 2014Heruc G.A. Horowitz M. Deacon C.F. Feinle-Bisset C. Rayner C.K. Luscombe-Marsh N. Little T.J. Effects of dipeptidyl peptidase IV inhibition on glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to fat in healthy males.Am. J. Physiol. Endocrinol. Metab. 2014; 307: E830-E837Google Scholar, Sze et al., 2011Sze L. Purtell L. Jenkins A. Loughnan G. Smith E. Herzog H. Sainsbury A. Steinbeck K. Campbell L.V. Viardot A. Effects of a single dose of exenatide on appetite, gut hormones, and glucose homeostasis in adults with Prader-Willi syndrome.J. Clin. Endocrinol. Metab. 2011; 96: E1314-E1319Google Scholar). Steady-state Exendin-9 concentrations (Figure 1H) were ∼0.4 μg/mL (∼120 nmol/L), ∼2-fold above the binding affinity of Exendin-9 for GLP1R in human insulinoma cells (Waser and Reubi, 2011Waser B. Reubi J.C. Value of the radiolabelled GLP-1 receptor antagonist exendin(9–39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans.Eur. J. Nucl. Med. Mol. Imaging. 2011; 38: 1054-1058Google Scholar). PYY concentrations were higher after Exendin-9 than after placebo (Figure 1I), mirroring the elevated GLP-1 levels and likely reflecting that PYY and GLP-1 are released from the same EEC type (Billing et al., 2018Billing L.J. Smith C.A. Larraufie P. Goldspink D.A. Galvin S. Kay R.G. Howe J.D. Walker R. Pruna M. Glass L. et al.Co-storage and release of insulin-like peptide-5, glucagon-like peptide-1 and peptideYY from murine and human colonic enteroendocrine cells.Mol. Metab. 2018; 16: 65-75Google Scholar, Habib et al., 2013Habib A.M. Richards P. Rogers G.J. Reimann F. Gribble F.M. Co-localisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells.Diabetologia. 2013; 56: 1413-1416Google Scholar). Glucose-dependent insulinotropic polypeptide (GIP) concentrations were reduced by Exendin-9 (Figure 1J), suggesting that endogenous GLP-1 enhances GIP secretion—a finding not previously reported. Hunger scores were less suppressed by glucose ingestion in the Exendin-9 than in the placebo arm, without corresponding changes in fullness, suggesting that elevated GLP-1 concentrations contribute to reduced sensations of hunger in this cohort (Figures 1K and 1L). We established a model of gastrectomy in lean mice, in which animals had either a VSG or a sham control operation (McGavigan et al., 2017McGavigan A.K. Garibay D. Henseler Z.M. Chen J. Bettaieb A. Haj F.G. Ley R.E. Chouinard M.L. Cummings B.P. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice.Gut. 2017; 66: 226-234Google Scholar) (Figure S1). As expected, the VSG group lost more weight during the first week after surgery than the sham controls, associated with reduced food intake. OGTTs triggered higher plasma GLP-1 and insulin levels and lower glucose excursions in VSG than in sham control groups. This lean VSG model was used to examine the effect of an antagonistic anti-GLP1R antibody, providing long-lasting blockade of GLP1R (Biggs et al., 2018Biggs E.K. Liang L. Naylor J. Madalli S. Collier R. Coghlan M.P. Baker D.J. Hornigold D.C. Ravn P. Reimann F. Gribble F.M. Development and characterisation of a novel glucagon like peptide-1 receptor antibody.Diabetologia. 2018; 61: 711-721Google Scholar). Mice were injected weekly with anti-GLP1R or isotype control antibody for 12 weeks, beginning 1 day before VSG or sham surgery. After surgery, all groups received 4 weeks of liquid diet, followed by 4 weeks of high-fat diet (HFD) and then 12 days of the control low-fat diet (LFD), to assess whether the response to surgery was diet dependent. Peak and trough antibody titers are shown in Figure S2A. Weight loss in the post-operative period was higher in VSG than in sham mice, and liquid food intake was correspondingly reduced, but no differences were observed between the control and the active antibody groups (Figures 2A, 2B, 2D, and 2E ). When transferred to HFD, by contrast, the VSG group on anti-GLP1R antibody (Ab) paradoxically ate significantly more than VSG mice given isotype control and showed a trend toward additional weight gain (p = 0.08 versus VSG controls) (Figures 2A, 2B, 2C, and 2F), suggesting that endogenous GLP-1 suppressed intake of HFD despite having little effect on ingestion of the liquid diet. OGTTs (1 g/kg) were performed one day after antibody injection at weeks 2, 4, and 10 after surgery (Figures 2G–2I; Figures S2C–S2K). Post-GTT plasma glucose concentrations were higher in mice given GLP1R than control antibody in both sham and VSG groups. Corresponding 5 min insulin levels were reduced in the anti-GLP1R-Ab VSG group compared with VSG isotype controls, whereas the anti-GLP1R antibody did not affect insulin levels in the sham group. We investigated whether altered plasma gut hormone profiles observed after gastrectomy can be explained by changes in peptide biosynthesis in the gut. In lean human gastrectomy patients, we compared biopsies taken from the jejunum at the time of surgery, with biopsies taken by endoscopy after surgery from the same anatomic region, just distal to the site of anastomosis with the esophagus. Biopsies were examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), enabling the identification and quantification of 22 candidate secretory peptides. Principal-component analysis (PCA) of the samples across all measured peptides did not differentiate pre- and post-operative samples (Figure 3A), and no differences were detected when individual peptides were examined by multi-factorial ANOVA (Figures 3B and 3C). From the proglucagon peptide, we detected GLP-1(7-36amide), GLP-2, glicentin-related peptide (GRPP), and oxyntomodulin (OXM), but not pancreatic-type glucagon. GLP-1(7-36amide), PYY1-36, and PYY3-36 were not increased in the post-surgical intestinal biopsies, despite the raised plasma levels of total immunoreactive GLP-1 and PYY detected after an OGTT in post-gastrectomy patients. Because it was not possible to examine other regions of the post-surgical human gut, we performed a similar study in mice after VSG or sham surgery. Samples were taken from the stomach to the rectum and analyzed by LC-MS/MS, as they were for the human jejunum. By PCA, we observed longitudinal gradients in hormone production in both sham and VSG mice but no substantial differences between the surgical groups (Figures 3D and 3E). The similarity between sham and VSG samples was also evident at the level of individual peptide profiles (Figures 3F–3K). In the cohort of VSG and sham mice treated with GLP1R or control antibodies, we performed a similar LC-MS/MS analysis of pancreatic homogenates at the end of the protocol (samples taken ∼7 min after an Ensure gavage meal, as described later). Pancreatic levels of peptides derived from insulin, GCG, IAPP (islet amyloid polypeptide), PPY (pancreatic polypeptide), and PYY were similar across all groups; from the proglucagon peptide, we detected glucagon, GRPP, OXM, and GLP-1(1-37), but not GLP-1(7-37) or GLP-1(7-36amide) (Figures S3G–S3I). We next investigated whether the increased plasma GLP-1 and PYY levels after surgery were associated with transcriptomic adaptations in intestinal EECs, which could potentially change their responsiveness to food ingestion. In humans, we fluorescence-activated cell sorting (FACS)-purified EECs from the jejunum of peri-operative patients (collected during gastrectomy surgery) and from the same anatomic site in post-operative patients (collected by endoscopy) and performed transcriptomic analysis by RNA sequencing. EEC purity estimated from the FACS profiles ranged from 10% to 50%, compared with ∼0.1% in the starting cell populations, so to prevent bias introduced from non-EECs, we restricted the analysis to genes known to be differentially expressed and enriched in human EECs (Roberts et al., 2018aRoberts G. Larraufie P. Richards P. Kay R. Galvin S. Miedzybrodzka E. Leiter A. Li J. Glass L. Ma M. et al.Comparison of Human and Murine Enteroendocrine Cells by Transcriptomic and Peptidomic Profiling. Bioarchives, 2018Google Scholar). By PCA, the pre- and post-surgical samples did not show any distinct clustering (Figure 4A), and the relatively few EEC genes that did exhibit significant differential expression between pre- and post-operative samples (Figure 4B) were not suggestive of major functional differences between the groups. Interrogation of the dataset for expression patterns of peptides, G-protein coupled receptors (GPCRs) (Figures 4E and 4F), transcription factors, and ion channels (Figures S4K and S4L) also revealed no segregation between pre- and post-operative groups. We performed a similar study in the mouse VSG model using lean NeuroD1-cre/YFP mice (Li et al., 2012Li H.J. Kapoor A. Giel-Moloney M. Rindi G. Leiter A.B. Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestine.Dev. Biol. 2012; 371: 156-169Google Scholar) fed chow diet after surgery. FACS-purified NeuroD1-positive cells from the top 5 cm or bottom 15 cm of the small intestine and the combined colon and rectum were analyzed from VSG, sham, and weight-matched sham animals by RNA sequencing. No differences in the percentages of sorted EECs were found among the groups (Figure S4B). PCA of the top 500 differentially expressed genes revealed that EECs differed according to the intestinal site from which they were collected, but not by treatment group (Figures 4C and 4D). The top 25 variable genes across all samples annotated as hormones, transcription factors, GPCRs, and ion channels are represented as heatmaps in Figures 4G, 4H, S4I, and S4J, revealing that genes involved in EEC function were distinct among different intestinal regions but not altered by surgery. Further clustering analyses examining samples from each region separately also did not reveal clustering by treatment based on the top 100 variable genes (Figures S4C–S4H). An alternative explanation for the increased plasma GLP-1 and PYY concentrations seen following an OGTT in humans and mice after gastrectomy is that ingested nutrients transit more quickly through the upper gut after surgery and penetrate to more distal regions of the gut before they are absorbed, thus targeting a larger and more distal pool of EECs. To test this hypothesis in the VSG model, mice were gavaged with a mixture of Ensure and fluorescein isothiocyanate (FITC) dextran and killed ∼7 min later to coincide with peak GLP-1 levels measured after OGTT for collection of the luminal contents, intestinal tissue, and plasma. The FITC contents of sequential segments of the stomach and intestines were measured by fluorescence, revealing that FITC dextran penetrated farther down the gut in VSG compared with sham mice, represented by a higher intestinal transit (IT) score (Figures 5A and 5B ). The study was performed as a terminal step in the mice that had received either GLP1R antibody or isotype control for 12 weeks, but no difference in intestinal transit score was observed between those treated with the active and those treated with the control antibody. Across sham and VSG mice, plasma GLP-1, PYY, and GIP levels triggered by the Ensure liquid meal correlated with the intestinal transit score (Figures 5C–5E). Lean patients who have undergone gastrectomy with RYGB, and mice after VSG, provide models to assess the metabolic responses to intestinal rearrangements without the confounding effects of profound weight loss seen in obese bariatric patients. Gastrectomy patients exhibit very high GLP-1, PYY, and insulin levels after an OGTT, mimicking the enteroendocrine physiology of bariatric surgery (Miholic et al., 1991Miholic J. Orskov C. Holst J.J. Kotzerke J. Meyer H.J. Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy.Dig. Dis. Sci. 1991; 36: 1361-1370Google Scholar, Roberts et al., 2018bRoberts G.P. Kay R.G. Howard J. Hardwick R.H. Reimann F. Gribble F.M. Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery.Surg. Obes. Relat. Dis. 2018; 14: 562-568Google Scholar). The results of the Exendin-9 infusion in humans and anti-GLP1R antibody administration in mice demonstrate that elevated GLP-1 levels after glucose ingestion in these surgical groups are a strong driver of hyperinsulinemia. Peak insulin concentrations in gastrectomy patients were approximately 2-fold higher than in control subjects and were restored to normal levels by Exendin-9. Although other studies in obese humans have similarly concluded that GLP-1 plays an important role in driving insulin secretion after bariatric surgery (Jørgensen et al., 2013Jørgensen N.B. Dirksen C. Bojsen-Møller K.N. Jacobsen S.H. Worm D. Hansen D.L. Kristiansen V.B. Naver L. Madsbad S. Holst J.J. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes.Diabetes. 2013; 62: 3044-3052Google Scholar, Salehi et al., 2014Salehi M. Gastaldelli A. D’Alessio D.A. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass.Gastroenterology. 2014; 146: 669-680Abstract Full Text Full Text PDF Scopus (175) Google Scholar), studies in mice have yielded conflicting results, with some groups arguing in favor (Garibay et al., 2016Garibay D. McGavigan A.K. Lee S.A. Ficorilli J.V. Cox A.L. Michael M.D. Sloop K.W. Cummings B.P. β-cell glucagon-like peptide-1 receptor contributes to improved glucose tolerance after vertical sleeve gastrectomy.Endocrinology. 2016; 157: 3405-3409Scopus (36) Google Scholar) and others against (Douros et al., 2018Douros J.D. Lewis A.G. Smith E.P. Niu J. Capozzi M. Wittmann A. Campbell J. Tong J. Wagner C. Mahbod P. et al.Enhanced glucose control following vertical sleeve gastrectomy does not require a β-cell glucagon-like peptide 1 receptor.Diabetes. 2018; 67: 1504-1511Google Scholar, Wilson-Pérez et al., 2013Wilson-Pérez H.E. Chambers A.P. Ryan K.K. Li B. Sandoval D.A. Stoffers D. Drucker D.J. Pérez-Tilve D. Seeley R.J. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide 1 receptor deficiency.Diabetes. 2013; 62: 2380-2385Google Scholar) this idea (Hutch and Sandoval, 2017Hutch C.R. Sandoval D. The role of GLP-1 in the metabolic success of bariatric surgery.Endocrinology. 2017; 158: 4139-4151Google Scholar, Smith et al., 2018Smith E.P. Polanco G. Yaqub A. Salehi M. Altered glucose metabolism after bariatric surgery: what’s GLP-1 got to do with it?.Metabolism. 2018; 83: 159-166Google Scholar). Additional improved glucose tolerance arising from concomitant weight loss and improved insulin sensitivity makes the interpretation of these types of study in mice particularly challenging. In practice, the elevated insulin secretion after bariatric surgery likely arises because of the combined rapid elevations of plasma glucose and GLP-1 occurring after glucose ingestion. Glucose concentrations rise faster after gastrectomy because the absence of a gastri" @default.
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• W2912094716 title "Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery" @default.
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