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Context Enteroendocrine N cells secrete neurotensin (NTS). NTS reduces food intake in rodents and may increase insulin release. In humans, postprandial NTS responses increase following Roux-en-Y gastric bypass, associating the hormone with the glucose- and body weight-lowering effects of these procedures. Objective We looked at N cell density and mucosal messenger RNA (mRNA) expression profiles of NTS and NTS receptors in type 2 diabetes (T2D) patients and healthy controls. Methods Using double-balloon enteroscopy, 12 patients with T2D and 12 sex-, age-, and body mass index–matched healthy controls had mucosa biopsies taken from the entire length of the small intestine (at 30-cm intervals) and from 7 anatomically well-defined locations in the large intestine. Biopsies were analyzed using immunohistochemistry and mRNA sequencing. Results N cell density and NTS mRNA expression gradually increased from the duodenum to the ileum, while negligible NTS-positive cells and NTS mRNA expression were observed in the large intestine. NTS receptor 1 and 2 mRNA expression were not detected, but sortilin, a single-pass transmembrane neuropeptide receptor of which NTS also is a ligand, was uniformly expressed in the intestines. Patients with T2D exhibited lower levels of NTS-positive cells and mRNA expression than healthy controls, but this was not statistically significant after adjusting for multiple testing. Conclusion This unique intestinal mapping of N cell density and NTS expression shows increasing levels from the small intestine's proximal to distal end (without differences between patients with T2D and healthy controls), while negligible N-cells and NTS mRNA expression were observed in the large intestine. Sortilin was expressed throughout the intestines in both groups; no NTS receptor 1 or 2 mRNA expression were detected.

Context The mechanisms underlying Roux-en-Y gastric bypass (RYGB) surgery-induced weight loss and the immediate postoperative beneficial metabolic effects associated with the operation remain uncertain. Enteroendocrine cell (EEC) secretory function has been proposed as a key factor in the marked metabolic benefits from RYGB surgery. Objective To identify novel gut-derived peptides with therapeutic potential in obesity and/or diabetes by profiling EEC-specific molecular changes in obese patients following RYGB-induced weight loss. Subjects and Methods Genome-wide expression analysis was performed in isolated human small intestinal EECs obtained from 20 gut-biopsied obese subjects before and after RYGB. Targets of interest were profiled for preclinical and clinical metabolic effects. Results Roux-en-Y gastric bypass consistently increased expression levels of the inverse ghrelin receptor agonist, liver-expressed antimicrobial peptide 2 (LEAP2). A secreted endogenous LEAP2 fragment (LEAP238-47) demonstrated robust insulinotropic properties, stimulating insulin release in human pancreatic islets comparable to the gut hormone glucagon-like peptide-1. LEAP238-47 showed reciprocal effects on growth hormone secretagogue receptor (GHSR) activity, suggesting that the insulinotropic action of the peptide may be directly linked to attenuation of tonic GHSR activity. The fragment was infused in healthy human individuals (n = 10), but no glucoregulatory effect was observed in the chosen dose as compared to placebo. Conclusions Small intestinal LEAP2 expression was upregulated after RYGB. The corresponding circulating LEAP238-47 fragment demonstrated strong insulinotropic action in vitro but failed to elicit glucoregulatory effects in healthy human subjects.

OBJECTIVE: Changes in the secretion of gut-derived peptide hormones have been associated with the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. In this study, the effects of RYGB on anthropometrics, postprandial plasma hormone responses, and mRNA expression in small intestinal mucosa biopsy specimens before and after RYGB were evaluated.METHODS: In a cross-sectional study, 20 individuals with obesity undergoing RYGB underwent mixed meal tests and upper enteroscopy with retrieval of small intestinal mucosa biopsy specimens 3 months before and after surgery. Concentrations of circulating gut and pancreatic hormones during mixed meal tests as well as full mRNA sequencing of biopsy specimens were evaluated.RESULTS: RYGB-induced improvements of body weight and composition, insulin resistance, and circulating cholesterols were accompanied by significant changes in postprandial plasma responses of pancreatic and gut hormones. Global gene expression analysis of biopsy specimens identified 2,437 differentially expressed genes after RYGB, including changes in genes that encode prohormones and G protein-coupled receptors.CONCLUSIONS: RYGB affects the transcription of a wide range of genes, indicating that the observed beneficial metabolic effects of RYGB may rely on a changed expression of several genes in the gut. RYGB-induced changes in the expression of genes encoding signaling peptides and G protein-coupled receptors may disclose new gut-derived treatment targets against obesity and diabetes.

AspireAssist® allows aspiration of ~30% of an ingested meal through a percutaneous gastrostomy tube, reducing caloric uptake. We evaluated the acute effects of gastric aspiration on postprandial glucose tolerance, responses of gluco-regulatory and appetite-regulating hormones, appetite sensations, and food intake.Seven AspireAssist®-treated individuals underwent two separate experimental days each involving a mixed meal test (MMT) with double-blinded aspiration and sham aspiration, respectively. Seven age and body mass index (BMI)-matched controls underwent one MMT. MMTs were followed by an ad libitum meal.Postprandial glucose tolerance was improved during aspiration vs. sham visits (median [interquartile range] baseline-subtracted area under the curve (bsAUC) 170 [88.4;356] vs. 388 [239;456] mmol/L × min, p = 0.025). Reduced responses (bsAUCs) of C-peptide (113 [28.4;224] vs. 302 [215;433] nmol/L × min, p = 0.014), cholecystokinin (223 [59.4;402] vs. 467 [416;546] pmol/L × min, p = 0.005), glucose-dependent insulinotropic polypeptide (4.63 [1.49;9.04] vs. 15.4 [9.59;18.9] nmol/L × min, p = 0.025), and glucagon-like peptide 1 (532.8 [274.5;1,278] vs. 1,296 [746.2;1,618] pmol/L × min, p = 0.032) were observed during aspiration vs. sham visits. Responses of glucagon, gastrin, ghrelin and peptide YY, appetite sensations, and ad libitum food intake were unaffected by aspiration. Responses of plasma glucose, gut hormones, appetite sensations, and food intake were similar during sham and control visits.Gastric aspiration improved postprandial glucose tolerance without causing compensatory increases in appetite or food intake, pointing to acute beneficial metabolic effects of aspiration therapy together with previously reported body weight-lowering effects.

Context After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1). Objective To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut. Design and Setting Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark. Participants Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes. Interventions Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB. Main Outcome Measures The 29–amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry–validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry. Results Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon. Conclusion Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB.

AspireAssist® allows aspiration of ~30% of an ingested meal through a percutaneous gastrostomy tube thereby reducing caloric uptake. We evaluated the acute effects of aspiration therapy on postprandial glucose tolerance, responses of gluco-regulatory and appetite-regulating gut hormones, appetite sensations and food intake. Seven AspireAssist®-treated persons without diabetes (median [IQR] age 52 [44;54] years; BMI 35.6 [31.5;40.5] kg/m2) underwent two mixed meal tests on separate days with double-blinded aspiration (aspiration visit) and sham aspiration (sham visit), respectively. Seven age and BMI-matched controls (age 43 [42;54]; BMI 34.1 [31.6;38.7] kg/m2) underwent one meal test (control visit). All mixed meal tests were followed by an ad libitum meal for evaluation of food intake. Compared to sham visits, postprandial glucose tolerance was improved on aspiration visits (median [IQR] baseline-subtracted area under the curve (bsAUC) 170 [88;356] vs. 388 [239;456] mmol/L × min, P = 0.025). Postprandial responses (bsAUCs) of C-peptide, cholecystokinin (CCK) and glucose-dependent insulinotropic polypeptide (GIP) were reduced during aspiration vs. sham visits (113 [28;224] vs. 302 [215;433] nmol/L × min, P = 0.014; 223 [59.4;402] vs. 467 [416;546] pmol/L × min, P = 0.005; and 4,634 [1,488;9,044] vs. 15,382 [9,588;18,850] pmol/L × min, P = 0.025). Glucagon, gastrin, ghrelin and peptide YY, respectively, were similar on aspiration and sham visits. Appetite sensations and ad libitum food intake were similar on aspiration and sham visits. Responses of plasma glucose, gut hormones, appetite sensations and food intake were similar on sham and control visits. In this study, aspiration therapy acutely improved postprandial glucose tolerance without causing a compensatory increase in appetite sensations or food intake at a subsequent ad libitum meal; pointing to acute beneficial metabolic effect of aspiration therapy in addition to the long-term bodyweight-lowering effect of this treatment. Disclosure I. Gether: None. M. M. Jensen: None. T. Jorsal: None. C. Nexøe-larsen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L. P. S. Naver: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Augustinus Fonden

Obesity is characterized by increased gut serotonin signaling, which has been shown to enhance hepatic gluconeogenesis favoring hyperglycemia and adipose tissue lipolysis promoting raised levels of free fatty acids and, thus, peripheral insulin resistance. Little is known about the potential involvement of the human gut serotonin system in the pathophysiology of type 2 diabetes. We investigated the transcriptional profile of key enzymes, receptors and transporters in the serotonin system in intestinal biopsies sampled using double-balloon enteroscopy from the duodenum, the jejunum, throughout the remaining small intestine with 30 cm intervals, the ileocecal region, the cecum, the four segments of the colon and the rectum in 12 individuals with type 2 diabetes and 12 gender, age and body mass index-matched healthy controls. Global gene expression analysis was performed on all biopsies, and intestinal expression profiles of genes involved in the serotonin system were mapped and compared between the two groups. We used false discovery rate adjustment to correct for multiple testing. Patients with type 2 diabetes exhibited 2-fold increased mRNA encoding the serotonin-synthesizing enzyme TPH1 in the sigmoid colon (P = 0.027) and the rectum (P < 0.001), and lower levels of mRNA encoding the transporter responsible for reuptake of serotonin in enterocytes, SERT (P = 0.038), and the serotonin-metabolizing enzymes MAOA (P = 0.001) in the distal small intestine and MAOB in the cecum (P = 0.013), the ascending colon (P = 0.020) and the transverse colon (P = 0.011). Our findings provide the first detailed transcriptional profile of key factors in the serotonin system along the entire intestinal tract in humans and lend support to previous animal and human studies suggesting that increased gut serotonin signaling may be involved in the development of dysmetabolic conditions including type 2 diabetes. Disclosure C. Legart: None. C. A. Hagemann: None. A. Ellegaard: None. D. Keating: None. T. Jorsal: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.

Background Cholecystokinin (CCK) is a gut hormone originally known for its effects on gallbladder contraction and release of digestive enzymes. CCK, however, also mediates satiety and stimulate insulin secretion. Knowledge of the distribution of CCK-producing enteroendocrine cells (I cells) in humans is sparse. The general notion, based on animal data, is that I cells are present mainly in the proximal small intestine. We examined the occurrence of I cells (immunohistochemically) and the expression of CCK messenger RNA (mRNA) as well as CCK1 and CCK2 receptor mRNA along the intestines in healthy individuals and patients with type 2 diabetes. Methods Mucosal biopsies collected with 30-cm intervals in the small intestine and from seven anatomical locations in the large intestine (using double-balloon enteroscopy) from 12 patients with type 2 diabetes and 12 gender-, age-, and body mass index–matched healthy individuals were analyzed using mRNA sequencing and immunohistochemical staining. Results We observed a gradual decrease in CCK mRNA expression and density of CCK-immunoreactive cells from duodenum to ileum. Very few CCK-immunoreactive cells and nearly undetectable CCK mRNA expression were found in the large intestine. No significant differences were seen between the groups. Expression of CCK receptors was observed in the duodenum of both groups. Conclusions Both density of CCK cells and expression of CCK mRNA decreased through the small intestine in both groups with low levels in the large intestine. Patients with type 2 diabetes did not have altered density of CCK cells or expression of CCK mRNA in intestinal mucosa.

Background and Aims: Roux-en-Y gastric bypass (RYGB) surgery significantly improves glucose metabolism independently of surgery-induced weight loss; partly due to the increased postprandial secretion of the insulinotropic gut hormone glucagon-like peptide 1 (GLP-1). Mouse studies have shown that intestinally derived ketone bodies inhibit GLP-1 secretion from enteroendocrine L cells, and it was recently suggested that RYGB-induced downregulation of intestinal ketogenesis contributes to the increased GLP-1 secretion after RYGB. We investigated the intestinal expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses before and after RYGB. Materials and Methods: Twenty obese individuals underwent mixed meal tests and anterograde enteroscopy with gut mucosal biopsy retrieval before and 3 months after RYGB. A global gene expression analysis was performed on the mucosal biopsies. Here, we report the expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses. Results: We observed a significant 7.6-fold downregulation of the gene encoding 3-hydroxy-3- methylglutaryl-CoA synthase 2 (HMGCS2) (the rate-determining enzyme in ketogenesis) in the alimentary limb after RYGB. The proglucagon gene encoding GLP-1 was significantly upregulated after surgery and postprandial plasma GLP-1 responses increased significantly after RYGB. Conclusions: RYGB-induced downregulation of intestinal HMGCS2 gene expression in obese individuals may indicate reduced intestinal ketogenesis; supporting the notion (originating from animal studies) that reduced ketone body-mediated inhibition of L cells constitute a contributor to postprandial hypersecretion of GLP-1 after RYGB. Disclosure C. Legart: None. T. Jorsal: None. C.A. Hagemann: Employee; Self; Gubra. D. Worm: None. C.B. Juhl: None. A.R. Andries: None. C. Zhang: Employee; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.

Background and Aims: Bile acids stimulate the secretion of gluco-regulatory and appetite-regulating gut hormones (including glucagon-like peptide 1 and fibroblast factor 19 (FGF19)) and increase energy expenditure. Changes in postprandial concentrations of circulating bile acids (primarily determined by the apical sodium-dependent bile acid transporter (ASBT) and organic solute transporter α/β (OSTα/β) in the terminal ileum) have been linked to type 2 diabetic pathophysiology. Methods: In a cross-sectional study, 12 persons with type 2 diabetes (T2D) (mean[range] age 51[34-63] years, BMI 26.8[23.7-31.5] kg/m2, HbA1c 48[36-85] mmol/mol) and 12 gender, age and BMI-matched nondiabetic controls (CTRLs) (age 50[41-67] years, BMI 27.1[20.3-30.8] kg/m2, HbA1c 34[29-43] mmol/mol) underwent upper and lower double-balloon enteroscopy with retrieval of mucosal biopsies from every 30 cm along the entire intestinal tract. The biopsies were subjected to full mRNA sequencing and here, the expression of ASBT, OSTα/β and FGF19 is reported. Results: For both groups, robust expression (reads per kilobase million (RPKM) ≥1) of ASBT and OSTα/β was evident in the duodenum and this increased along the small intestine, with highest expression of ASBT in the ileocecal region and highest expression of OSTα/β in terminal ileum. Compared to healthy controls, persons with T2D exhibited significantly lower ASBT and OSTα/β expression in the ileocecal region (P Conclusions: T2D is associated with reduced expression of ASBT, OSTα/β and FGF19 in the terminal ileum and the proximal colon. This may point to a link between dysfunctional enterohepatic circulation of bile acids and type 2 diabetic pathophysiology. Disclosure H.H. Nerild: Employee; Spouse/Partner; Novo Nordisk A/S. A. Brønden: None. A. El Haddouchi: None. T. Jorsal: None. D.P. Sonne: None. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.

Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants. In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age- and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine. Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine. Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants. NCT03044860.

We have previously shown that totally pancreatectomized patients (PX) and patients with type 2 diabetes (T2D) exhibit hypersecretion of glucagon in response to oral glucose stimulation whereas intravenous glucose suppresses plasma concentrations of glucagon. Here, we evaluated the expression of the gene encoding glucagon (GCG), glucagon peptide content and density of glucagon-positive cells in mucosal biopsies from the upper gastrointestinal tract of PX patients, patients with T2D and nondiabetic controls. Eight PX patients, eight patients with T2D and eight sex, age and BMI-matched healthy controls underwent upper enteroscopy with intestinal biopsy sampling followed by an intraluminal infusion of 100 ml 50% (w/v) glucose solution with frequent blood sampling. The mucosal biopsies were subjected to mRNA sequencing, immunohistochemistry using a new glucagon-directed C-terminal monoclonal antibody, peptide extraction and subsequent measurements of tissue concentrations of glucagon and other proglucagon-derived peptides. GCG expression in the small intestine was 3 to 4-fold higher in PX and T2D patients compared to controls (P Disclosure M. Baekdal: None. A.B. Lund: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J.I. Egholk: None. T. Jorsal: None. C.T. Juel: None. K.D. Galsgaard: None. J. Hunt: None. J.F. Rehfeld: None. K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. S.U. Friis: Stock/Shareholder; Self; Alk-Abello B, Bavarian Nordic, H. Lundbeck A/S, Lundbeck, Novo Nordisk A/S. C. Orskov: None. S.S. Poulsen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding European Foundation for the Study of Diabetes; Novo Nordisk Foundation; Aase og Ejnar Danielsens Foundation; A.P. Møller Foundation

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.

Aspiration therapy with AspireAssist is a novel endoscopic obesity treatment. Patients aspirate approximately 30% of an ingested meal through a draining system connected to a percutanous endoscopic gastrostomy tube. AspireAssist was recently approved by the US Food and Drug Administration, and it induces weight loss comparable to the weight loss observed after bariatric surgery, but with a lower risk of complications. Few clinical studies about the efficacy and safety of AspireAssist have been carried out and published. Thus, further intervention studies evaluating acute as well as long-term effects are warranted.

Summary Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion., Graphical Abstract, Highlights • PG 1-61 is a glucagon-like peptide in humans • Hyperglucagonemia may include PG 1-61, as well as glucagon • PG 1-61 stimulates insulin secretion and activates human hepatocytes • PG 1-61 may be a surrogate marker of alpha cell dysfunction, Wewer Albrechtsen et al. identify a glucagon-like molecule, PG 1-61, in humans using mass-spectrometry-based proteomics. PG 1-61 activates the glucagon receptor, stimulates insulin secretion, and activates key gluconeogenic enzymes. In dysmetabolic conditions, PG 1-61 is upregulated and may therefore serve as a marker of alpha cell stress.

Intracranial germ cell tumours (icGCTs) represent 3-15% of primary paediatric intracranial neoplasms with a considerable geographical variation in incidence. Ninety percent of patients diagnosed with icGCTs are under 20 years of age.Histologic characteristics and investigation of the tumour markers β-human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) help define the different categories of icGCTs. The tumours are divided into two major groups called germinomas and non-germinomatous GCTs (NGGCTs).The clinical symptoms depend on the size and location of tumour in the brain, which is most commonly in the pineal or suprasellar region. Pineal GCTs often present with neurological symptoms because of their tendency to cause increased intracranial pressure. Suprasellar GCTs are often accompanied by endocrine abnormalities such as diabetes insipidus (DI), growth retardation and precocious or delayed puberty.A combination of clinical findings, endocrine and tumour marker evaluation, spinal fluid cytology, magnetic resonance imaging (MRI) and biopsy helps verifying the diagnosis of an icGCT. A summary of published data (n = 97) revealed that90% of patients at diagnosis had at least one endocrine abnormality, DI being the most common (80%).Classification of tumour is important for choice of treatment and for prognosis. A combination of chemotherapy and radiotherapy is often used, since most icGCTs have a great sensitivity to these treatment modalities.Endocrine symptoms are very frequently appearing in patients with icGCTs and they can present long before neuroimaging verification of tumour is possible. It is of the outmost importance to have the diagnosis of icGCTs in mind when children, adolescents and young adults are presenting with endocrine irregularities, because most icGCTs are very sensitive to radiotherapy and chemotherapy, and early onset of treatment is important in order to minimize morbidity and mortality.

For decades, extensive research has aimed to clarify the role of pancreas and gut-derived peptide hormones in the regulation of glucose homeostasis and feeding behavior. Among these are the beta-cell hormone amylin and the intestinal L cell hormone glucagon-like peptide-1 (GLP-1). They exhibit distinct and yet several similar physiological actions including suppression of food intake, postprandial glucagon secretion, and gastric emptying-altogether lowering plasma glucose and body weight. These actions have been clinically exploited by the development of amylin and GLP-1 hormone analogs now used for treatment of diabetes and obesity. This review will outline the physiology and pharmacological potential of amylin and GLP-1, respectively, and focus on innovative peptide drug development leading to drugs acting on two or more distinct receptors, such as an amylin and GLP-1 peptide hybrid, potentially producing a more effective treatment strategy to combat the rapidly increasing global obesity.