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Background: In humans, intraduodenal infusion of L-tryptophan (Trp) increases plasma concentrations of gastrointestinal hormones and stimulates pyloric pressures, both key determinants of gastric emptying and associated with potent suppression of energy intake. The stimulation of gastrointestinal hormones by Trp has been shown, in preclinical studies, to be enhanced by extracellular calcium and mediated in part by the calcium-sensing receptor., Objectives: This study aim was to determine whether intraduodenal calcium can enhance the effects of Trp to stimulate gastrointestinal hormones and pyloric pressures and, if so, whether it is associated with greater suppression of energy intake, in healthy males., Methods: Fifteen males with normal weight (mean ± standard deviation; age: 26 ± 7 years; body mass index: 22 ± 2 kg/m 2 ), received on 3 separate occasions, 150-min intraduodenal infusions of 0, 500, or 1000 mg calcium (Ca), each combined with Trp (load: 0.1 kcal/min, with submaximal energy intake-suppressant effects) from t = 75-150 min, in a randomized, double-blind, crossover study. Plasma concentrations of GI hormones [gastrin, cholecystokinin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and peptide tyrosine-tyrosine (PYY)], and Trp and antropyloroduodenal pressures were measured throughout. Immediately postinfusions (t = 150-180 min), energy intake at a standardized buffet-style meal was quantified., Results: In response to calcium alone, both 500- and 1000-mg doses stimulated PYY, while only the 1000-mg dose stimulated GLP-1 and pyloric pressures (all P < 0.05). The 1000-mg dose also enhanced the effects of Trp to stimulate cholecystokinin and GLP-1, and both doses stimulated PYY but, surprisingly, reduced the stimulation of GIP (all P < 0.05). Both doses substantially and dose dependently enhanced the effects of Trp to suppress energy intake (Ca-0+Trp: 1108 ± 70 kcal; Ca-500+Trp: 961 ± 90 kcal; and Ca-1000+Trp: 922 ± 96 kcal; P < 0.05)., Conclusions: Intraduodenal administration of calcium enhances the effect of Trp to stimulate plasma cholecystokinin, GLP-1, and PYY and suppress energy intake in healthy males. These findings have potential implications for novel nutrient-based approaches to energy intake regulation in obesity. The trial was registered at the Australian New Zealand Clinical Trial Registry (www.anzctr.org.au) as ACTRN12620001294943)., Competing Interests: Conflict of interests The authors report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

This chapter attempts to provide an all-round picture of a dynamic and major branch of modern endocrinology, i.e. the gastrointestinal endocrinology. The advances during the last half century in our understanding of the dimensions and diversity of gut hormone biology - inside as well as outside the digestive tract - are astounding. Among major milestones are the dual brain-gut relationship, i.e. the comprehensive expression of gastrointestinal hormones as potent transmitters in central and peripheral neurons; the hormonal signaling from the enteroendocrine cells to the brain and other extraintestinal targets; the role of gut hormones as growth and fertility factors; and the new era of gut hormone-derived drugs. Accordingly, gastrointestinal hormones have pathogenetic roles in major metabolic disorders (diabetes mellitus and obesity); in tumor development (common cancers, sarcomas, and neuroendocrine tumors); and in cerebral diseases (anxiety, panic attacks, and probably eating disorders). Such clinical aspects require accurate pathogenetic and diagnostic measurements of gastrointestinal hormones - an obvious responsibility for clinical chemistry/biochemistry. In order to obtain a necessary insight into today's gastrointestinal endocrinology, the chapter will first describe the advances in gastrointestinal endocrinology in a historical context. The history provides a background for the subsequent description of the present biology of gastrointestinal hormones, and its biomedical consequences - not least for clinical chemistry/biochemistry with its specific responsibility for selection of appropriate assays and reliable measurements., (Copyright © 2024. Published by Elsevier Inc.)

Century old glucagon is a classic pancreatic hormone. But today we also know that the glucagon gene is expressed at high levels at extrapancreatic sites - particularly so in the gut. Major hormonal glucagon gene products in the digestive tract are the two glucagon-like peptides (GLP-1 and -2). Of these, truncated GLP-1 has in recent decades attracted massive interest due to its incretin effect, and the subsequent GLP-1 derived design of potent diabetes and obesity drugs. Truncated GLP-1 has consequently become an important contributor to gastrointestinal endocrinology. The gastrointestinal branch of endocrinology today includes more than 100 bioactive peptides encoded by some 30 different hormone genes. Therefore, the gut is the largest endocrine organ in the body. In addition to a general discussion of glucagon peptides in the hierarchy of gut hormones, this review also includes three short notes about glucagon studies from the 1970s. These studies dealt with reactive hypoglycemia, chronic liver disease, and the secretory response of pancreatic glucagon to gastrin/cholecystokinin stimulation. Considering today's possibilities in molecular endocrinology, revisits to the questions raised by these studies might be worthwhile., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Glucose induces the release of gastrointestinal (GI) satiation hormones, such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), in part via the activation of the gut sweet taste receptor (T1R2/T1R3)., Objectives: The primary objective was to investigate the importance of T1R2/T1R3 for the release of cholecystokinin (CCK), GLP-1, and PYY in response to D-allulose and erythritol by assessing the effect of the T1R2/T1R3 antagonist lactisole on these responses and as secondary objectives to study the effect of the T1R2/T1R3 blockade on gastric emptying, appetite-related sensations, and GI symptoms., Methods: In this randomized, controlled, double-blind, crossover study, 18 participants (5 men) with a mean ± SD BMI (in kg/m2) of 21.9 ± 1.7 and aged 24 ± 4 y received an intragastric administration of 25 g D-allulose, 50 g erythritol, or tap water, with or without 450 parts per million (ppm) lactisole, respectively, in 6 different sessions. 13C-sodium acetate was added to all solutions to determine gastric emptying. At fixed time intervals, blood and breath samples were collected, and appetite-related sensations and GI symptoms were assessed. Data were analyzed with linear mixed-model analysis., Results: D-allulose and erythritol induced a significant release of CCK, GLP-1, and PYY compared with tap water (all PHolm < 0.0001, dz >1). Lactisole did not affect the D-allulose- and erythritol-induced release of CCK, GLP-1, and PYY (all PHolm > 0.1). Erythritol significantly delayed gastric emptying, increased fullness, and decreased prospective food consumption compared with tap water (PHolm = 0.0002, dz = -1.05; PHolm = 0.0190, dz = 0.69; and PHolm = 0.0442, dz = -0.62, respectively)., Conclusions: D-allulose and erythritol stimulate the secretion of GI satiation hormones in humans. Lactisole had no effect on CCK, GLP-1, and PYY release, indicating that D-allulose- and erythritol-induced GI satiation hormone release is not mediated via T1R2/T1R3 in the gut., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Gastrointestinal hormones are peptides, and the gastrointestinal tract is the largest endocrine organ in the body for production of peptide hormones. As a premise for accurate measurement of gastrointestinal hormones, the present review provides first an overview over the complex biology of the hormones: The structures and structural homologies; biogenetic aspects; phenotype variabilities; and cellular expression in- and outside the digestive tract. Second, the different methodological principles for measurement are discussed: Bioassay, radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), mass-spectrometry (LC-MS/MS) and processing-independent analysis (PIA). Third, the variability of secretion patterns for some of the gut hormones is illustrated. Finally, the diagnostic value of gut hormone measurement is discussed. The review concludes that measurement of gastrointestinal peptide hormones is relevant not only for examination of digestive functions and diseases, but also for extra-intestinal functions. Moreover, it concludes that, so far, immunoassay technologies (RIA and ELISA) in modernized forms are still the most feasible for accurate measurements of gastrointestinal hormones in biological fluids. Mass-spectrometry technologies are promising, but still too insensitive and expensive., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To determine whether a dose-dependent effect in the stimulation of gut hormone release (plasma cholecystokinin [CCK], active glucagon-like peptide-1 [aGLP-1] and peptide tyrosine tyrosine [PYY]) is found for the natural sweetener erythritol., Materials and Methods: Twelve healthy, lean volunteers received solutions with 10, 25 or 50 g erythritol, or tap water enriched with 13 C-sodium acetate on four study days via a nasogastric tube in this randomized (active treatments), placebo-controlled, double-blind, cross-over trial. Blood samples and breath samples ( 13 C-sodium acetate method for measurement of gastric emptying [GE]) were taken at regular intervals, and sensations of appetite and gastrointestinal symptoms were rated., Results: We found (a) a dose-dependent stimulation of CCK, aGLP-1 and PYY, and slowing of GE, (b) no effect on blood glucose, insulin, motilin, glucagon or glucose-dependent insulinotropic polypeptide, (c) no effect on blood lipids and uric acid, and (d) no abdominal pain, nausea or vomiting., Conclusions: Solutions with 10 and 50 g of erythritol stimulated gut hormone release. Emptying of erythritol-containing solutions from the stomach was slower compared with placebo. There was no effect on plasma glucose, insulin, glucagon, blood lipids or uric acid. All doses were well tolerated., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.

Dietary carbohydrate restriction may improve the phenotype of Type 2 diabetes (T2D) patients. We aimed to investigate 6 wk of carbohydrate restriction on postprandial glucose metabolism, pancreatic α- and β-cell function, gut hormone secretion, and satiety in T2D patients. Methods In a crossover design, 28 T2D patients (mean HbA 1c : 60 mmol/mol) were randomized to 6 wk of carbohydrate-reduced high-protein (CRHP) diet and 6 wk of conventional diabetes (CD) diet (energy-percentage carbohydrate/protein/fat: 30/30/40 vs. 50/17/33). Twenty-four-hour continuous glucose monitoring (CGM) and mixed-meal tests were undertaken and fasting intact proinsulin (IP), 32,33 split proinsulin concentrations (SP), and postprandial insulin secretion rates (ISR), insulinogenic index (IGI), β-cell sensitivity to glucose ( B up ), glucagon, and gut hormones were measured. Gastric emptying was evaluated by postprandial paracetamol concentrations and satiety by visual analog scale ratings. A CRHP diet reduced postprandial glucose area under curve (net AUC) by 60% ( P < 0.001), 24 h glucose by 13% ( P < 0.001), fasting IP and SP concentrations (both absolute and relative to C-peptide, P < 0.05), and postprandial ISR (24%, P = 0.015), while IGI and B up improved by 31% and 45% (both P < 0.001). The CRHP diet increased postprandial glucagon net AUC by 235% ( P < 0.001), subjective satiety by 18% ( P = 0.03), delayed gastric emptying by 15 min ( P < 0.001), decreased gastric inhibitory polypeptide net AUC by 29% ( P < 0.001), but had no significant effect on glucagon-like-peptide-1, total peptide YY, and cholecystokinin responses. A CRHP diet reduced glucose excursions and improved β-cell function, including proinsulin processing, and increased subjective satiety in patients with T2D.

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.)

Dietary fat, and particularly fatty acids (FAs) from hydrolyzed triglycerides (TGs), reduces appetite, whereas paradoxically, a high-fat diet leads to excess calorie intake. We therefore hypothesized that the appetite-regulating effects of FAs are perturbed in obesity. Ten men with severe obesity [median body mass index (BMI) of 51.0 kg/m 2 (range of 47.9-69.0)] and 10 men without obesity [BMI of 24.6 kg/m 2 (range of 21.7-26.8)] were recruited for a double-blind randomized crossover study. On two occasions, participants were given isocaloric (2,660 kJ) and isovolemic (80 ml) loads of either oleic acid (long-chain FA) or olive oil (TG) containing radiolabeled lipid and water markers. Postload scintigraphy, blood sampling, and assessment of appetite were performed for 10 h, after which an ad libitum meal was served. Compared with olive oil, oleic acid slowed gastric mean emptying time (GMET) for lipids ( P < 0.001), accelerated orocoecal transit time (OCTT; P = 0.005), increased postload cholecystokinin section ( P < 0.001), and suppressed ad libitum energy intake ( P = 0.028) in men with severe obesity, and similar effects were seen in the nonobese group (no group × lipid interactions). However, independent of lipid loads, GMET and OCTT were slower (GMET lipid P = 0.046; GMET water P = 0.003; OCTT P = 0.001), and basal and postload secretion of glucagon-like peptide-1 (GLP-1) was attenuated ( P = 0.045 and P = 0.048, respectively) in men with severe obesity compared with men without obesity. We conclude that the more potent appetite-regulating effects of oleic acid versus olive oil are unimpaired in men with severe obesity. However, regardless of lipid formulations, severe obesity is associated with slowed gastrointestinal transit and attenuated GLP-1 secretion. NEW & NOTEWORTHY Orally ingested fatty acids more efficiently reduce appetite and energy intake than triglycerides also in men with severe obesity. Men with severe obesity have delayed gastrointestinal transit and attenuated early gut hormone responses after an oral lipid load compared with men without obesity.

Context: The mechanisms regulating the postprandial suppression of ghrelin secretion remain unclear, but recent observations in rats indicate that an increase in duodenal osmolarity is associated with a reduction in ghrelin levels. Several hormones have been implicated in the regulation of ghrelin., Objective: We hypothesized that intraduodenal infusion of a hyperosmolar solution would lower plasma ghrelin concentrations., Design, Setting, Participants, and Interventions: Eighteen healthy young men were studied after an overnight fast on two occasions in a randomized double-blinded fashion. A nasoduodenal catheter was positioned and isoosmolar (300 mOsm/L) or hyperosmolar (1500 mOsm/L) saline was infused intraduodenally (4 mL/min, t = 0 to 45 minutes). Venous blood was sampled at t = -45, -30, -15, 0, 15, 30, 45, 60, 75, 90, 120, and 180 minutes., Main Outcome Measures: Plasma concentrations of ghrelin, glucagonlike peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), neurotensin (NT), peptide YY (PYY), motilin, and glucose., Results: Ghrelin concentrations were suppressed with hyperosmolar when compared with isoosmolar saline, and remained lower until t = 180 minutes. CCK, NT, GLP-1, PYY, and glucagon all increased during hyperosmolar, but not isoosmolar, saline infusion (P < 0.01 for all), whereas GIP, PP, and motilin levels were not affected by either infusion., Conclusions: Plasma ghrelin concentrations are lowered, whereas CCK, GLP-1, PYY, NT, and glucagon concentrations are augmented, by hyperosmolar duodenal content in healthy individuals. These observations have implications for the evaluation of studies comparing the effects of different types and loads of nutrients and chemicals on gut hormone secretion.

Postprandial responses to food are highly dependent on the macronutrient composition of the diet. We investigated the acute effects of transition from the recommended moderately high carbohydrate (HC) diet towards a carbohydrate-reduced high-protein (CRHP) diet on postprandial glycemia, insulinemia, lipemia, and appetite-regulating hormones in non-diabetic adults. Fourteen subjects, including five males (Mean ± SD: age 62 ± 6.5; BMI 32 ± 7.6 kg/m²; hemoglobin A 1c (HbA 1c ) 40 ± 3.0 mmol/mol; HOMA2-IR 2.1 ± 0.9) were included in this randomized, cross-over study. Iso-caloric diets were consumed for two consecutive days with a median wash-out period of 21 days (range 2⁻8 weeks) between diets (macronutrient energy composition: CRHP/HC; 31%/54% carbohydrate, 29%/16% protein, 40%/30% fat). Postprandial glucose, insulin secretion rate (ISR), triglycerides (TGs), non-esterified fatty acids (NEFAs), and satiety ratings were assessed after ingestion of breakfast (Br) and lunch (Lu), and gut hormones and glucagon were assessed after ingestion of Br. Compared with the HC diet, the CRHP diet reduced peak glucose concentrations (Br 11%, p = 0.024; Lu 11%, p < 0.001), glucose excursions (Br 80%, p = 0.20; Lu 85%, p < 0.001), and ISR (Br 31%; Lu 64%, both p < 0.001) whereas CRHP, as compared with HC, increased glucagon-like peptide-1 (Br 27%, p = 0.015) and glucagon values (Br 249%, p < 0.001). NEFA and TG levels increased in the CRHP diet as compared with the HC diet after Br, but no difference was found after Lu (NEFA Br 22%, p < 0.01; TG Br 42%, p = 0.012). Beta-cell glucose sensitivity, insulin clearance, cholecystokinin values, and subjective satiety ratings were unaffected. It is possible to achieve a reduction in postprandial glycemia and insulin without a deleterious effect on beta-cell glucose sensitivity by substituting part of dietary carbohydrate with iso-caloric protein and fat in subjects without type 2 diabetes mellitus (T2DM). The metabolic effects are more pronounced after the second meal.

Background: Activation of gastrointestinal (GI) sweet taste receptors by caloric sweeteners triggers secretion of anorexigenic and inhibition of orexigenic GI hormones to regulate food intake. The effect of noncaloric sweeteners on these mechanisms is controversial. We have recently shown that motilin-induced gastric phase III contractions signal hunger feelings, thereby identifying GI motility, and its regulatory hormone motilin, as novel players in food intake regulation., Objective: The objective of the present study was to determine the effect of caloric and noncaloric sweeteners on GI motility, GI hormone secretion, and hunger in humans., Design: The study was a randomized, double-blind, crossover trial. Twelve healthy volunteers underwent 4 gastroduodenal manometry recordings in which the occurrence of phase III contractions was followed by the intragastric (i.g.) administration of 250 mL tap water or equisweet caloric (1) 50 g glucose and 2) 25 g fructose) and noncaloric sweeteners [220 mg acesulfame-K (ace-K)] dissolved in 250 mL tap water. Measurement continued until ≥1 subsequent phase III. Blood samples were collected for the measurement of GI hormones. Visual analog scales were used to rate hunger and satiety feelings. Response curves were analyzed using (generalized) linear mixed models., Results: We found: 1) an inhibitory effect of the 2 caloric sweeteners on antral motility (P < 0.01), but no effect after ace-K, 2) an inhibitory effect of the 2 caloric sweeteners on motilin secretion (P < 0.01), but no effect after ace-K, 3) an early increase in cholecystokinin (CCK) secretion after the 2 caloric sweeteners (P < 0.01), but no effect after ace-K, and 4) an initial stronger decrease in hunger feelings and stronger increase in satiety after ace-K (P < 0.05), followed by a steeper return of hunger and decrease of satiety after ace-K (P < 0.05)., Conclusions: Our results demonstrate, for the first time to our knowledge, that the caloric sweeteners glucose and fructose, but not the noncaloric sweetener ace-K, inhibit motilin secretion and antral motility while increasing CCK secretion. This trial was registered at clinicaltrials.gov as NCT02891525.

A serious complication to the laparoscopic Roux-en-Y gastric bypass (RYGB) is internal hernia, which can lead to massive bowel necrosis that may result in short bowel syndrome. We determined postprandial enteropancreatic hormonal responses and metabolites in a 22-year-old nondiabetic woman with a history of RYGB experiencing severe internal herniation with widespread bowel necrosis. Extensive resections were performed leaving her with a saliva fistula from the pouch-enteric anastomosis, an intact duodenum, 15 cm of jejunum, 35 cm of ileum, and intact colon. Parenteral nutrition was initiated and 10 months after the bowel resection, intestinal continuity was re-established. After 6 weeks the patient reached parenteral nutrition independence. She underwent standardized liquid mixed meal tests before, 3 months after and 2 years after intestinal continuity was re-established. Gut hormone responses were completely restored postoperatively leading to very high concentrations in plasma. After 2 years, plasma concentrations had, however, decreased markedly, suggesting desensitization of the gut ostensibly in response to chronic hyperstimulation. There was no evidence of cephalic phase insulin secretion., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Gastrointestinal hormones are released from enteroendocrine cells in the digestive tract. More than 30 hormone genes are expressed, which make the gut the largest endocrine organ in the body. At present, it is feasible to conceive the hormones under 5 headings: the structural homology groups most hormones into 9 families, each of which is assumed to originate from a single gene. Today's hormone gene often has multiple phenotypes due to alternative splicing, tandem organization or differentiated maturation of the prohormone. By these mechanisms, more than 100 different hormonal peptides are released from the gut. Gut hormones are also widely expressed in extraintestinal cells. These cells may release different fragments of the same prohormone due to cell-specific processing pathways. Moreover, endocrine cells, immune cells, neurons, myocytes, kidney cells, sperm cells and cancer cells secrete gut peptides in different ways, so the same peptide may act for instance as a hormone, a neurotransmitter, a cytokine, a growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein coupled receptors that are expressed in the cell membrane all over the body. Thus, each gut hormone constitutes a regulatory system operating in the whole organism., (© 2017 S. Karger AG, Basel.)

Objective: The gut microbiota has been designated as an active regulator of glucose metabolism and metabolic phenotype in a number of animal and human observational studies. We evaluated the effect of removing as many bacteria as possible by antibiotics on postprandial physiology in healthy humans., Methods: Meal tests with measurements of postprandial glucose tolerance and postprandial release of insulin and gut hormones were performed before, immediately after and 6 weeks after a 4-day, broad-spectrum, per oral antibiotic cocktail (vancomycin 500 mg, gentamycin 40 mg and meropenem 500 mg once-daily) in a group of 12 lean and glucose tolerant males. Faecal samples were collected for culture-based assessment of changes in gut microbiota composition., Results: Acute and dramatic reductions in the abundance of a representative set of gut bacteria was seen immediately following the antibiotic course, but no changes in postprandial glucose tolerance, insulin secretion or plasma lipid concentrations were found. Apart from an acute and reversible increase in peptide YY secretion, no changes were observed in postprandial gut hormone release., Conclusion: As evaluated by selective cultivation of gut bacteria, a broad-spectrum 4-day antibiotics course with vancomycin, gentamycin and meropenem induced shifts in gut microbiota composition that had no clinically relevant short or long-term effects on metabolic variables in healthy glucose-tolerant males., Trial Registration: clinicaltrials.gov NCT01633762.

Gastrointestinal hormones are peptides released from neuroendocrine cells in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gut, which makes it the largest hormone-producing organ in the body. Modern biology makes it feasible to conceive the hormones under five headings: The structural homology groups a majority of the hormones into nine families, each of which is assumed to originate from one ancestral gene. The individual hormone gene often has multiple phenotypes due to alternative splicing, tandem organization or differentiated posttranslational maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gut. Gut hormone genes are also widely expressed outside the gut, some only in extraintestinal endocrine cells and cerebral or peripheral neurons but others also in other cell types. The extraintestinal cells may release different bioactive fragments of the same prohormone due to cell-specific processing pathways. Moreover, endocrine cells, neurons, cancer cells and, for instance, spermatozoa secrete gut peptides in different ways, so the same peptide may act as a blood-borne hormone, a neurotransmitter, a local growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein-coupled receptors that are expressed in the cell membranes also outside the digestive tract. Thus, gut hormones not only regulate digestive functions, but also constitute regulatory systems operating in the whole organism. This overview of gut hormone biology is supplemented with an annotation on some Scandinavian contributions to gastrointestinal hormone research.

Gastrointestinal hormones are peptides released from endocrine cells and neurons in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gastrointestinal tract, which makes the gut the largest hormone producing organ in the body. Modern biology makes it feasible to conceive the hormones under five headings: The structural homology groups a majority of the hormones into nine families, each of which is assumed to originate from one ancestral gene. The individual hormone gene often has multiple phenotypes due to alternative splicing, tandem organization, or differentiated maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gut. Gut hormone genes are also widely expressed in cells outside the gut, some only in extraintestinal endocrine cells and neurons but others also in other cell types. The extraintestinal cells may synthesize different bioactive fragments of the same prohormone due to cell-specific processing pathways. Moreover, endocrine cells, neurons, cancer cells, and, for instance, spermatozoa release the peptides differentially (autocrine, endocrine, neurocrine, paracrine, spermiocrine secretion etc.), so the same peptide may act as a blood-borne hormone, a neurotransmitter, a local growth factor, or a fertility factor. The molecular targets of each bioactive peptide are specific G-protein coupled receptors expressed in the cell membranes of different target cells. Also the target cells of gut hormones occur widespread outside the digestive tract.

Background: Effects of protein intake on appetite-regulating hormones and their dynamics are unclear., Objectives: We investigated the satiating effects of meals with varying protein contents and whether there was an effect of dose on appetite-regulating hormones and appetite ratings., Design: Twenty-five men [mean ± SD age: 30.0 ± 8.7 y; body mass index (BMI; in kg/m(2)): 25.9 ± 4.7] participated in the 3-way, randomized, double-blind crossover study. Test meals were isocaloric with 30% of energy from fat and protein content adjusted at the expense of carbohydrate. Test meals were normal protein (NP; 14% of energy from protein), medium-high protein (MHP; 25% of energy from protein), and high protein (HP, 50% of energy from protein). Appetite ratings and blood samples were assessed every 0.5 h for 4 h. An ad libitum lunch was served 4 h after the meal., Results: Protein increased dose-dependently glucagon-like peptide-1 (GLP-1), peptide YY (PYY) 3-36, and glucagon; MHP produced 10%, 7%, and 47% greater responses, respectively; and HP produced 20%, 14%, and 116% greater responses, respectively, than did NP (P < 0.03). Compared with NP, HP increased insulin and cholecystokinin and decreased ghrelin and glucose-dependent insulinotropic polypeptide (P < 0.05). Satiety and fullness dose-dependently increased by 7% and 6% for MHP and 16% and 19% for HP compared with NP (P < 0.001). Hunger and prospective consumption dose-dependently decreased by 15% and 13% for MHP and by 25% and 26% for HP compared with NP (P < 0.0003). There was a combined effect of GLP-1 and PYY 3-36 (P = 0.03) next to the additive effect of GLP-1 (P = 0.006) on the composite appetite score. No difference was shown in ad libitum energy intake., Conclusion: Protein dose-dependently increased satiety and GLP-1, PYY 3-36, and glucagon, which may, at least in part, be responsible for the satiety-stimulating effect of protein. This trial was registered at clinicaltrials.gov as NCT01561235.

Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum bile acids were measured. We found similar basal glucose concentrations in the two groups, whereas cholecystectomized subjects had elevated postprandial glucose excursions. Cholecystectomized subjects had reduced postprandial concentrations of duodenal bile acids, but preserved postprandial plasma GLP-1 responses, compared with control subjects. Also, cholecystectomized patients exhibited augmented fasting glucagon. Basal plasma CCK concentrations were lower and peak concentrations were higher in cholecystectomized patients. The concentrations of GIP, GLP-2, and gastrin were similar in the two groups. In conclusion, cholecystectomized subjects had preserved postprandial GLP-1 responses in spite of decreased duodenal bile delivery, suggesting that gallbladder emptying is not a prerequisite for GLP-1 release. Cholecystectomized patients demonstrated a slight deterioration of postprandial glycemic control, probably because of metabolic changes unrelated to incretin secretion.

The gut is the largest endocrine organ in the body. Gut hormones share some characteristics: Their structure groups hormones into families, each of which originate from a single gene. A hormone gene is often expressed in multiple peptides due to tandem genes, alternative splicing or differentiated posttranslational processing. By these mechanisms, more than 100 different hormonally active peptides are produced in the gastrointestinal tract. In addition, gut hormones are widely expressed outside the gut. The different cell types often express different products of the same gene and release the peptides in different ways. Consequently, the same peptide may act as a hormone, a local growth factor, or a neurotransmitter. This new biology suggests that gastrointestinal hormones should be conceived as intercellular messengers of major general impact. The following short review is a vignette on steps in the history of gastrointestinal endocrinology from classic studies of digestive juice secretion over peptide chemistry, immunochemistry, and molecular genetics to modern receptor pharmacology and drug development. From shadowy beginnings, gastrointestinal endocrinology has emerged as a central discipline in the understanding of multicellular life and its diseases., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cholecystokinin (CCK) is a peptide hormone discovered in the small intestine. Together with secretin and gastrin, CCK constitutes the classical gut hormone triad. In addition to gallbladder contraction, CCK also regulates pancreatic enzyme secretion and growth, intestinal motility, satiety signalling and the inhibition of gastric acid secretion. CCK is, however, also a transmitter in central and intestinal neurons. Notably, CCK is the most abundant neuropeptide in the human brain. Owing to difficulties in developing accurate assays, knowledge about CCK secretion in disease is limited. Available data indicate, however, that proCCK is expressed in certain neuroendocrine tumours and sarcomas, whereas the secretion of CCK is impaired in celiac disease and bulimia nervosa. Stimulation with exogenous CCK has proved useful in diagnostic tests of gallbladder and pancreatic diseases, as well as medullary thyroid carcinomas.

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. [ABSTRACT FROM AUTHOR]

Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic hypophysiotropic factors, and to the isolation and cloning of multiple brain neuropeptides. These discoveries were followed by the discovery of G‐protein‐coupled and other membrane receptors for these peptides. Subsequently, the systems physiology associated with some of these multiple regulatory peptides and receptors has been comprehensively elucidated and has led to improved therapeutics and diagnostics and their approval by the US Food and Drug Administration. In light of this wealth of information and further potential, it is truly a time of renaissance for regulatory peptides. In this perspective, we review what we have learned from the pioneers in exemplified fields of gut peptides, such as cholecystokinin, enterochromaffin‐like‐cell peptides, and glucagon, from the trailblazing studies on the key stress hormone, corticotropin‐releasing factor, as well as from more recently characterized relaxin‐family peptides and receptors. The historical viewpoints are based on our understanding of these topics in light of the earliest phases of research and on subsequent studies and the evolution of knowledge, aiming to sharpen our vision of the current state‐of‐the‐art and those studies that should be prioritized in the future. [ABSTRACT FROM AUTHOR]

Aim: Liraglutide treatment is associated with gallbladder‐related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon‐like peptide 2 (GLP‐2), are known to regulate gallbladder motility and may be implicated in gallbladder‐related disorders associated with liraglutide treatment. Materials and Methods: In a double‐blind, 12‐week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4 kg/m2 (mean ± standard deviation)] with obesity were randomized 1:1 to once‐daily subcutaneous liraglutide (escalated from 0.6 mg to 3.0 mg once‐daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP‐2. Results: Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC)0‐240 min 24.8 vs. 48.0 min × ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC0‐240 min 33.7 vs. 48.5 ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP‐2 responses (AUC0‐240 min 3650 vs. 4894 min × pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC0‐240 min 3760 vs. 4882 min × pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC0‐240 min 762 vs. 670 min × pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC0‐240 min 873 vs. 628 min × pmol/L; TR 1.39 (1.12; 1.73)]. Conclusion: Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP‐2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide. [ABSTRACT FROM AUTHOR]

Aim: Postprandial secretion of the appetite‐inhibiting hormones, glucagon‐like peptide‐1 (GLP‐1), and peptide YY are reduced with obesity. It is unclear if the reduced secretion persists following weight loss (WL), if other appetite‐inhibiting hormones are also reduced, and if so whether reduced secretion results from intrinsic changes in the gut. Methods: To address whether WL may restore secretion of GLP‐1 and other appetite‐inhibiting hormones, we performed a gut perfusion study of the small intestine in diet‐induced obese (DIO) rats after WL. A 20% weight loss (means ± SEM (g): 916 ± 53 vs. 703 ± 35, p < 0.01, n = 7) was induced by calorie restriction, and maintained stable for ≥7 days prior to gut perfusion to allow for complete renewal of enteroendocrine cells. Age‐matched DIO rats were used as comparator. Several gut hormones were analyzed from the venous effluent, and gene expression was performed on gut tissue along the entire length of the intestine. Results: Secretion of cholecystokinin, gastrin, glucose‐dependent insulinotropic peptide, GLP‐1, neurotensin, and somatostatin was not affected by WL during basal conditions (p ≥ 0.25) or in response to macronutrients and bile acids (p ≥ 0.14). Glucose absorption was indistinguishable following WL. The expression of genes encoding the studied peptides, macronutrient transporters (glucose, fructose, and di‐/tripeptides) and bile acid receptors did also not differ between DIO and WL groups. Conclusions: These data suggest that the attenuated postprandial responses of GLP‐1, as well as reduced responses of other appetite‐inhibiting gut hormones, in people living with obesity may persist after weight loss and may contribute to their susceptibility for weight regain. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine whether the degree of ketosis, measured as plasma β-hydroxybutyrate (βHB) in fasting, was associated with changes in appetite feelings and plasma concentration of appetite-related hormones after weight loss.Methods: A total of 87 individuals with obesity (BMI: 36.5 ± 4.0 kg/m2 ; age: 42.4 ± 9.7 years; 39 males) underwent 8 weeks of a very low-energy diet. Body weight/composition, plasma concentration of βHB, and appetite-related hormones (active ghrelin, active glucagon-like peptide 1 [GLP-1], total peptide YY, cholecystokinin [CCK], and insulin) and subjective appetite feelings were measured at baseline and week 9.Results: Participants lost 17.7 ± 4.1 kg and were ketotic (βHB: 1.24 ± 0.82 mmol/L in fasting) at week 9. A negative association was found between βHB in fasting at week 9 and changes in basal (r = -0.315, P = 0.003) and postprandial ghrelin concentration (r = -0.286, P = 0.008), and a positive association was found with the change in postprandial GLP-1 (r = 0.244, P = 0.025) and CCK (r = 0.228, P = 0.035). No association was seen between βHB in fasting and changes in peptide YY or subjective feelings of appetite.Conclusions: βHB plasma concentration in fasting is associated with lower concentrations of the hunger hormone ghrelin and increased concentrations of the satiety hormones GLP-1 and CCK. Future studies should explore the molecular mechanisms by which βHB modulates the secretion of gut hormones. [ABSTRACT FROM AUTHOR]

Human studies have demonstrated that physiologically relevant changes in circulating glucagon‐like peptide‐1 (GLP‐1) elicit a rapid increase in renal sodium excretion when combined with expansion of the extracellular fluid volume. Other studies support the involvement of various gastrointestinal hormones, e.g., gastrin and cholecystokinin (CCK) in a gut‐kidney axis, responsible for a rapid‐acting feed‐forward natriuretic mechanism. This study was designed to investigate the hypothesis that the postprandial GLP‐1 plasma concentration is sensitive to the sodium content in the meal. Under fixed sodium intake for 4 days prior to each experimental day, 10 lean healthy male participants were examined twice in random order after a 12‐hr fasting period. Arterial blood samples were collected at 10–20‐min intervals for 140 min after 75 grams of oral glucose + 6 grams of oral sodium chloride (NaCl) load versus 75 grams of glucose alone. Twenty‐four‐hour baseline urinary sodium excretions were similar between study days. Arterial GLP‐1 levels increased during both oral glucose loads and were significantly higher at the 40–80 min period during glucose + NaCl compared to glucose alone. The postprandial arterial responses of CCK, gastrin, and glucose‐dependent insulinotropic polypeptide as well as glucose, insulin, and C‐peptide did not differ between the two study days. Arterial renin, aldosterone, and natriuretic peptides levels did not change within subjects or between study days. Angiotensin II levels were significantly lower at the time GLP‐1 was higher (60–80 min) during glucose + NaCl. Sodium intake in addition to a glucose load selectively amplifies the postprandial GLP‐1 plasma concentration. Thus, GLP‐1 may be part of an acute feed‐forward mechanism for natriuresis. [ABSTRACT FROM AUTHOR]

This review describes the premises for accurate measurement of the gut hormone and satiety factor cholecystokinin (CCK) in circulation. Such a description is useful for nutrition and obesity research in which CCK in its satiety role has evoked considerable interest during the last decades. The background for the review is two sorts of considerations or concerns. First, CCK is a complex peptide system that in several ways challenges plasma measurements because the concentrations in plasma are very low (in the femtomolar to low picomolar range), and the bioactive CCK circulates in different molecular forms (CCK-58, -33, -22, and -8). Furthermore, there are major specificity problems because the structurally similar gastrin hormone circulates in 10- to 20-fold higher concentrations, and in addition, plasma proteins may, due to their high concentration, interfere in an unspecific way with immunoassay measurements. The second concern is that several obesity studies in recent decades have been based on commercial CCK kits with often inadequate documentation of the reliability in plasma measurement. Consequently, many plasma CCK results in today's obesity studies are difficult to compare. Moreover, the use of even fairly reliable commercial CCK kits has recently suffered from sudden discontinuation of the kit production, which has endangered several projects in nutrition and obesity research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Recent randomized and controlled trials of drugs derived from the gut hormone glucagonlike peptide-1 (GLP-1) show that the most frequent adverse symptoms are gastrointestinal, including gallbladder-related side effects such as cholithiasis and cholecystitis. Since the gut hormone cholecystokinin (CCK) stimulates bile secretion and regulates gallbladder motility and emptying, we examined the effect of GLP-1 on the secretion of CCK in normal subjects and patients with type 1 diabetes mellitus. Materials and methods: Plasma was sampled from 10 healthy subjects and 10 patients with diabetes. With plasma glucose concentrations clamped between 6 and 9 nmol/l, GLP-1 or saline was infused for 240 min during and after a meal. The plasma concentrations of CCK were measured with a highly specific radioimmunoassay. Results: Basal plasma concentrations of CCK were similar in the normal subjects and in the diabetes patients. During the meal, the CCK concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of CCK significantly in both normal subjects and in the diabetes patients. Conclusions: The results show that GLP-1 suppresses the secretion of CCK after a meal in normal and diabetic subjects. The suppression attenuates the gallbladder contractility. Our data, therefore, offer an explanation for the increased risk of adverse gallbladder events during treatment with GLP-1- derived drugs. [ABSTRACT FROM AUTHOR]

Gastrointestinal hormones that stimulate insulin secretion at physiological concentrations are incretins. This concept has recently attracted considerable attention in the wake of drugs developed from the gut hormone GLP-1 (glucagon-like peptide-1) for diabetes therapy. But the renewed enthusiasm has also restricted the concept to just two hormones, GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). The purpose of the present overview is two-fold: First to tell that the incretin concept is far from new. It has a more than a century long history full of ups and downs. Second, that the incretin concept may now have become too narrow. Thus, it is likely that incretin comprises additional gastrointestinal hormones, which interact with GIP and GLP-1 during normal meals containing protein, fat and complex carbohydrates (and not just pure glucose). Such broader incretin concept may stimulate development of novel gut hormone-derived drugs. [ABSTRACT FROM AUTHOR]

Cholecystokinin (CCK) was discovered in 1928 in jejunal extracts as a gallbladder contraction factor. It was later shown to be member of a peptide family, which are all ligands for the CCK1 and CCK2 receptors. CCK peptides are known to be synthetized in small intestinal endocrine I-cells and cerebral neurons. But in addition, CCK is expressed in several endocrine glands (pituitary cells, thyroid C-cells, pancreatic islets, the adrenals, and the testes); in peripheral nerves; in cortical and medullary kidney cells; in cardial myocytes; and in cells of the immune system. CCK peptides stimulate pancreatic enzyme secretion and growth, gallbladder contraction, and gut motility, satiety and inhibit acid secretion from the stomach. Moreover, they are major neurotransmitters in the brain and the periphery. CCK peptides also stimulate calcitonin, insulin, and glucagon secretion, and they may act as natriuretic peptides in the kidneys. CCK peptides are derived from proCCK with a C-terminal bioactive YMGWMDFamide sequence, in which the Y-residue is partly O-sulfated. The plasma forms are CCK-58, -33, -22, and -8, whereas the small CCK-8 and -5 are potent neurotransmitters. Over the last decades, CCK expression has also been encountered in tumors (neuroendocrine tumors, cerebral astrocytomas, gliomas, acoustic neuromas, and specific pediatric tumors). Recently, a metastastic islet cell tumor was found to cause a specific CCKoma syndrome, suggesting that circulating CCK may be a useful tumor marker. [ABSTRACT FROM AUTHOR]

Background & Aims: Patients with Zollinger–Ellison syndrome (ZES) are treated by proton pump inhibitors (PPIs) to protect them from severe and potentially lethal peptic complications related to massive gastric acid hypersecretion. We report here on the dangerous consequences of interrupting PPI therapy. Methods: We describe 2 ZES patients in whom interruption of PPI treatment for diagnostic evaluation generated severe health complications. Results: Less than 48 hours after stopping PPIs, patient 1 developed multiple strictures of the esophagus caused by massive vomiting of gastric acid, and patient 2 presented with severe abdominal pain with intestinal microperforation from duodenal ulcers. Because of persistent gastrin stimulatory drive and because of the abolition of reflex protective defense mechanisms against gastric acid hypersecretion during PPI treatment, patients with ZES under PPI therapy are exposed to severe peptic complications when facing rebound acid secretion at the interruption of their antisecretory treatment. Conclusions: PPI treatment interruption has dangerous consequences, and PPI therapy always should be maintained in patients known or suspected of ZES. Diagnostic evaluations should be performed under PPI protection. [ABSTRACT FROM AUTHOR]

Background: Salatrim is modified triacylglycerol that is rich in short-chain fatty acids and stearic acid. It is used as a lower-calorie fat replacer. In addition, it has been hypothesized that salatrim's reduced absorption in the small intestinemaylead to greater amounts of fat in the gastrointestinal tract, which may decrease appetite and energy intake through the release of appetite-regulating gastrointestinal hormones. Objective: We aimed to compare the effects of salatrim and traditional fat on appetite, ad libitum energy intake, and gastrointestinal hormones. Design: Twenty-two healthy, young, normal-weight men participated in a randomized, double-blind, crossover study. Test meals were a traditional fat meal and a salatrim meal with a mixture of traditional fat and salatrim. Visual analogue scales were used to record appetite and well-being every 30 min, and blood was sampled frequently. An ad libitum lunch was served 4.5 h after the test meal. Results: The salatrim meal increased fullness (P = 0.04) and decreased hunger (P=0.06) significantly more than did the traditional fat meal. The traditional fat meal increased well-being (P = 0.02). There was no significant difference in ad libitum energy intake or overall energy intake between the 2 test days. No significant differences in blood glucose, insulin, triacylglycerol, ghrelin, cholecystokinin, glucagon-like peptide-1, or peptideYYconcentrations were found. A significantly (P=0.01) smaller increase in free fatty acids was observed after the salatrim meal than after the traditional fat meal. Conclusions: Salatrim had a modestly more suppressive effect on appetite than did a traditional fat. Gastrointestinal hormones did not seem to be involved. [ABSTRACT FROM AUTHOR]

The homologous brain-gut propeptides, procholecystokinin (proCCK) and progastrin, both undergo extensive posttranslational maturation in specific neuroendocrine cells. The process comprises multiple endoproteolytic cleavages at mono- and dibasic sites, in addition to exoproteolytic trimmings and amino acid derivatizations. Knockout of prohormone convertases (PCs) in mice and studies in cell lines indicate that PC1, PC2 and, to a minor extent, PC5, are responsible for most of the endoproteolytic cleavages of both prohormones. Progastrin in antral G-cells is cleaved by PC1 at two di-Arg sites, R36R37 and R73R74, whereas, PC2 only cleaves at the single di-Lys site, K53K54. Pituitary corticotrophs and intestinal TG-cells, both of which express gastrin, do not cleave K53K54 due to lack of PC2. In proCCK five monobasic (R25, R44, R50, K61 and R75) as well as a single dibasic site (R85R86) can all be cleaved by both PC1 and PC2. But the cleavage differs in a cell-specific manner in that PC1 is responsible for the entire endoproteolytic cleavage in intestinal endocrine I-cells, except for perhaps the K61 site. In contrast PC2 is responsible for most endoproteolysis of proCCK in the cerebral CCK-neurons, which do not express PC1 in significant amounts. Moreover, PC5 appears to contribute to a minor extent to the neuronal proCCK and to the antral progastrin processing. This review emphasizes that prohormone convertases play a decisive but substrate and cell-specific role in the biosynthetic maturation of gastrin and CCK. [ABSTRACT FROM AUTHOR]

Objective. Epidemiological studies have shown that Helicobacter pylori infection with associated chronic gastritis is the main risk factor for development of gastric cancer. The aim of this study was to investigate the long-term development of H. pylori -induced gastritis in Mongolian gerbils in terms of morphology, gastrin secretion, epithelial proliferation and gene expression of pro-inflammatory cytokines. Material and methods. A total of 133 gerbils were inoculated with H. pylori and 62 served as controls. The gerbils were killed at different time-points between 6 and 94 weeks after inoculation. Serum concentrations of anti- H. pylori IgG and gastrin were determined by enzyme-linked immunoabsorbent assay (ELISA) and radioimmunoassay (RIA), respectively. Epithelial proliferation was evaluated immunohistochemically after labeling with 5-bromo-2′-deoxy-uridine. Gene expression of beta-actin, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Histological parameters of gastritis were assessed semiquantitatively and expressed as a “gastritis score”. Results. Serum concentrations of anti- H. pylori IgG and gastrin increased over time. Epithelial proliferation in the antrum was increased 6 weeks after inoculation, followed by increased proliferation in the corpus 32 weeks after inoculation. Gene expression of IL-1beta and TNF-alpha were increased in H. pylori -infected gerbils. Beta-actin was not a reliable endogenous control for RT-PCR. With time, gastritis expanded from the antrum to the corpus and the gastritis score increased to reach a peak 32 weeks after inoculation. Pseudopyloric metaplasia (loss of specialized cells) was a characteristic feature in the corpus mucosa. Gastric ulcers, but neither dysplasia nor carcinoma, were observed during 94 weeks of infection. Conclusions. Long-term H. pylori infection in Mongolian gerbils led to progressive gastritis, glandular atrophy, hypergastrinemia, increased epithelial proliferation and elevated gene expression of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Explains that gastrin-17 specific antibodies are too specific for gastrinoma diagnosis but stain G-cells. Secretion of gastrin increases permanently in diseases such as achlorhydria and gastrinomas; Biosynthesis of gastrin is complex; Carboxyamidated gastrin-17; Gastrin-34; Serum contains progastrin and processing-intermediates. .

Aims The duodenal-jejunal bypass sleeve (( DJBS) or EndoBarrier Gastrointestinal Liner) induces weight loss in obese subjects and may improve glucose homeostasis in patients with type 2 diabetes ( T2D). To explore the underlying mechanisms, we evaluated postprandial physiology including glucose metabolism, gut hormone secretion, gallbladder emptying, appetite and food intake in patients undergoing DJBS treatment. Material and methods A total of 10 normal glucose-tolerant ( NGT) obese subjects and 9 age-, body weight- and body mass index-matched metformin-treated T2D patients underwent a liquid mixed meal test and a subsequent ad libitum meal test before implantation with DJBS and 1 week (1w) and 26 weeks (26w) after implantation. Results At 26w, both groups had achieved a weight loss of 6 to 7 kg. Postprandial glucagon-like peptide-1 ( GLP-1) and peptide YY responses increased at 1w and 26w, but only in T2D subjects. In contrast, glucose-dependent insulinotropic polypeptide responses were reduced only by DJBS in the NGT group. Postprandial glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin responses were unaffected by DJBS in both groups. Satiety and fullness sensations were stronger and food intake was reduced at 1w in NGT subjects; no changes in appetite measures or food intake were observed in the T2D group. No effect of DJBS on postprandial gallbladder emptying was observed, and gastric emptying was not delayed. Conclusions DJBS-induced weight loss was associated with only marginal changes in postprandial physiology, which may explain the absence of effect on postprandial glucose metabolism. [ABSTRACT FROM AUTHOR]

The article discusses the gastrin vaccination against gastrointestinal and pancreatic cancer. The gastrointestinal hormone, gastrin, is a well-established growth factor for mucosal cells in the stomach. The gastrin gene is expressed in colorectal, gastric and pancreatic carninomas. The gastrin is a heterogeneous and consists of several bioactive peptides. Furthermore, the removal of gastrin in cancer patients requires that both gastrin in circulation and the locally synthesized gastrin in the carcinomas are neutralized.

Summary: Background & aims: In lean subjects, free fatty acid (FFA) promotes gut hormone release, delays gastric emptying, and reduces appetite and energy intake more than an isocaloric load of triglyceride (TG). In obesity, the gastrointestinal sensitivity to lipids may be reduced. Therefore, we compared the effects of the FFA oleic acid and the TG olive oil on gut hormone secretion, gastric emptying, appetite, and energy intake in lean and overweight/obese subjects. Methods: In a double-blind, randomized cross-over study, 8 lean and 13 overweight/obese healthy subjects were examined at two occasions to evaluate the effect of intragastric isocaloric loads of radiolabelled oleic acid or olive oil on gastric emptying, plasma CCK, PYY, and GLP-1 concentrations, appetite, and energy intake. Results: In comparison to olive oil, oleic acid caused a slower gastric emptying (p < 0.001), a higher plasma concentration of CCK (p < 0.05) and PYY (p < 0.05), and a lower subsequent energy intake (p < 0.05) whereas no difference was observed in GLP-1 concentrations. No significant differences were observed between lean and overweight/obese subjects. Conclusion: An intragastric load of FFA is followed by slower gastric emptying, increased CCK and PYY secretion, and a lesser subsequent energy intake than an isocaloric load of TG in both lean and overweight/obese healthy subjects. [ABSTRACT FROM AUTHOR]

Abstract: Cephalic effects on appetite are mediated by vagal tone and altered gastrointestinal hormones. The objective of this study is to explore the relationship between appetite and levels of gastrointestinal hormones after smelling chocolate and after melt-and-swallow 30g chocolate (1.059oz, 85% cocoa, 12.5g of sugar per 100g product). Twelve female residents (BMI between 18 and 25kg/m2) all participated in two 60-minute study sessions. In the first session, all 12 women ate chocolate; for the second session, they were randomized either to smell chocolate (n =6) or to serve as a control (no eating or smelling; n =6). At the start of the sessions, levels of insulin, glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK), but not glucose, correlated with appetite scored on a visual analogue scale (VAS). In contrast, ghrelin levels correlated inversely with scored appetite. Chocolate eating and smelling both induced a similar appetite suppression with a disappearance of correlations between VAS scores and insulin, GLP-1 and CCK levels. However, while the correlation between VAS score and ghrelin disappeared completely after chocolate eating, it reversed after chocolate smelling, that is, olfactory stimulation with dark chocolate (85%) resulted in a satiation response that correlated inversely with ghrelin levels. [Copyright &y& Elsevier]

Abstract: Objectives: In addition to the acid-stimulatory gastrins, progastrin also release N-terminal fragments. In order to examine the cellular content, secretion and peripheral metabolism of these fragments, we developed an immunoassay specific for the N-terminal sequence of human progastrin. Results: The concentration of N-terminal progastrin fragments in human antral tissue was 6.7 nmol/g tissue (n =5), which was only half of that of acid-stimulatory gastrins (12 nmol/g tissue). Gel chromatography of antral extracts showed that the progastrin fragment 1–35 and 1–19 constitute the major part of the N-terminal progastrin fragments. The basal concentration of N-terminal fragments in normal human plasma was almost 30-fold higher than that of the amidated, acid-stimulatory gastrins (286 pmol/l versus 9.8 pmol/l, n =26, P < 0.001). In contrast, the concentration of N-terminal fragments in hypergastrinemic plasma was only 2.7-fold higher than the concentration of amidated gastrins (540 pmol vs. 198 pmol/l, P =0.02). During meal stimulation, the plasma concentrations of N-terminal progastrin fragments and amidated gastrins increased in a correlated manner (r =0.97, P =0.005). The half life for progastrin 1–35 in circulation was 30 min, and a pig model revealed the kidneys and the vasculature to the head as the primary sites of degradation. Conclusion: The cellular and circulatory concentration profiles of N-terminal progastrin fragments differ markedly from those of the acid-stimulatory gastrins. The high basal plasma concentrations of N-terminal progastrin fragments cannot be explained by differences in elimination. [Copyright &y& Elsevier]

Bioactivation of prohormones occurs in the granules of the regulated secretory pathway of endocrine cells, which release hormones in response to external stimulation. How secretory granules are formed and how the cargo is selected is still unclear, but it has been shown for several prohormones and processing enzymes that domains within the prohormone structure can act as "sorting signals" for this pathway. The domains mediate interactions with other proteins or with the membrane or facilitate aggregation of the (pro)peptides. We have now searched for domains in progastrin that are active in sorting the prohormone into secretory granules. Truncation studies showed that the N-terminal 30 residues of progastrin are dispensable, whereas the last 49 residues are sufficient for correct biosynthesis of bioactive gastrin. Thus, further N-terminal truncation abolished gastrin expression. C-terminal truncation of 8 residues resulted in an increase in basal secretion as did point mutations in the dibasic processing sites of progastrin. These mutants, however, still responded to secretagogues, suggesting a residual sorting capacity to the regulated pathway. Amino acid substitutions in an acidic, polyglutamate motif within gastrin-17, the main bioactive, cellular gastrin form, did not alter secretion per se, but when these residues were substituted in Cterminally truncated mutants, double mutants increased in basal secretion and did not respond to secretagogue stimulation. This implies that the mutants are constitutively secreted. Our data suggest that the dibasic processing sites constitute the most important sorting domain of progastrin, and these sites act in synergy with the acidic domain. [ABSTRACT FROM AUTHOR]

Abstract: Prohormones mature to biologically active peptide hormones through posttranslational modifications, which include endoproteolytic cleavages. Cleavages at mono- and dibasic sites are well characterized, and several of the responsible prohormone convertases have been identified. There is, however, evidence that endoproteolytic maturation occurs also at other sites. Among these, post-Phe cleavage occurs in the maturation of chicken progastrin, where the processing to gastrin-30 has been examined in detail. In this study we have characterized an endoprotease of the aspartic acid protease family in chicken and human tissue capable of cleaving at the Phe site. Enzymatic activity was monitored by radioimmunoassays using antibodies specific for the N- and C-termini exposed after cleavage. Analysis showed that only pepstatin, a specific inhibitor of aspartic proteases, inhibited the enzyme. The pH optimum of the enzyme ranged from pH 2 to pH 5. Amino acid substitution from Phe to Ala in the substrate completely abolished enzyme activity. The endoproteolytic activity was identified in chicken antrum and pectoral muscle as well as human cardiac and prostate extracts, suggesting that the enzyme has widespread biological functions. Experiments using recombinant cathepsin D and E indicated that neither is responsible for the endoproteolytic cleavage of chicken progastrin at post-Phe bonds. [Copyright &y& Elsevier]

Investigates the effect of acarbose, an alpha-glucosidase and pancreatic alpha-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Effect on blood glucose and serum insulin; Carbohydrate-free meal after sucrose ingestion.

This article presents the case of a 61-year-old man who was admitted with a two-year history of diarrhea and episodes of epigastric pain but no weight loss. Before this admission the patient had undergone a series of tests but no abnormalities had been found and treatment had no effect. Further testing suggested celiac disease and the patient was put on a gluten-free diet. The diet did not change his diarrhea and the patient was readmitted and started on parenteral nutrition. A secretin-injection test was performed and the findings led to the diagnosis of gastrinoma. An endoscopic ultrasonography with a mechanical sector scanner found a tumor in the submucosal layer of the anterior wall of the duodenal bulb which had been missed on five previous endoscopies.