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Krieger JP, Daniels D, Lee S, Mastitskaya S, Langhans W. Glucagon-Like Peptide-1 Links Ingestion, Homeostasis, and the Heart. Compr Physiol 2025; 15:e7. [PMID: 39887844 PMCID: PMC11790259 DOI: 10.1002/cph4.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 02/01/2025]
Abstract
Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."
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Affiliation(s)
- Jean-Philippe Krieger
- Jean-Philippe Krieger, Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, Winterthurerstr. 260, 8057 Zurich
| | - Derek Daniels
- Department of Biological Sciences and the Center for Ingestive Behavior Research, University at Buffalo, the State University of New York, Buffalo NY 14260 USA
| | - Shin Lee
- Shin J. Lee, Neurimmune AG, Wagistrasse 18, 8952 Schlieren, Switzerland
| | - Svetlana Mastitskaya
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Dept. of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland
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Pedersen MGB, Lauritzen ES, Svart MV, Støy J, Søndergaard E, Thomsen HH, Kampmann U, Bjerre M, Jessen N, Møller N, Rittig N. Nutrient sensing: LEAP2 concentration in response to fasting, glucose, lactate, and β-hydroxybutyrate in healthy young males. Am J Clin Nutr 2023; 118:1091-1098. [PMID: 37844838 DOI: 10.1016/j.ajcnut.2023.10.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/03/2023] [Accepted: 10/11/2023] [Indexed: 10/18/2023] Open
Abstract
BACKGROUND The appetite-suppressing potential of liver-expressed antimicrobial peptide 2 (LEAP2), and its antagonistic effects on the hunger-inducing hormone ghrelin have attracted scientific interest. It is unclear how LEAP2 is influenced by fasting and how it responds to specific nutrients. OBJECTIVES The purpose of this investigation was to assess whether LEAP2 concentration 1) decreases after fasting, 2) increases postprandially, and 3) is regulated by nutrient sensing in the splanchnic bed. METHODS Plasma LEAP2 concentration was measured in blood samples from 5 clinical cross-over trials, following 1) 36 h of fasting (n = 8), 2) 10 h of fasting (n = 37, baseline data pooled from 4 of the clinical trials), 3) Oral and intravenous glucose administration (n = 11), 4) Oral and intravenous Na-lactate administration (n = 10), and 5) Oral and intravenous Na-β-hydroxybutyrate (BHB) administration (n = 8). All 5 trials included healthy males. RESULTS Compared with a 10-h fasting period, the median LEAP2 concentration was 38% lower following 36 h of fasting (P < 0.001). Oral administration of glucose elevated, whereas intravenous glucose administration lowered LEAP2 concentration (intervention x time, P = 0.001), resulting in a mean difference of 9 ng/mL (95% confidence interval [CI]: 1, 17) after 120 min. Oral lactate increased, and intravenous lactate decreased LEAP2 (intervention x time, P = 0.007), with a mean difference between interventions of 10 ng/mL (95% CI: 6, 15) after 120 min. In contrast, oral and intravenous administration of BHB reduced the LEAP2 concentration (main effect of time, P < 0.001). CONCLUSIONS Our investigations show that LEAP2 concentration was lower after a 36-h fast than an overnight fast and that oral delivery of glucose and lactate elevated LEAP2 concentration compared with intravenous administration, whereas LEAP2 concentrations decreased with both oral and intravenous BHB. This indicates that the LEAP2 concentration is sensitive to intestinal exposure to specific substrates, highlighting the need for future studies exploring the relationship between nutrients and LEAP2. This trial was registered at clinicaltrials.gov as NCT01840098, NCT03204877, NCT04299815, NCT03935841, and NCT01705782.
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Affiliation(s)
- Mette Glavind Bülow Pedersen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark; Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
| | | | - Mads Vandsted Svart
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark; Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Julie Støy
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark
| | - Esben Søndergaard
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark
| | - Henrik Holm Thomsen
- Department of Internal Medicine, Viborg Regional Hospital, Viborg, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark
| | - Ulla Kampmann
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark
| | - Mette Bjerre
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark; Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark
| | - Niels Møller
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark; Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Nikolaj Rittig
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark; Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
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Pedersen MGB, Søndergaard E, Nielsen CB, Johannsen M, Gormsen LC, Møller N, Jessen N, Rittig N. Oral lactate slows gastric emptying and suppresses appetite in young males. Clin Nutr 2022; 41:517-525. [PMID: 35016146 DOI: 10.1016/j.clnu.2021.12.032] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/09/2021] [Accepted: 12/20/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND Lactate serves as an alternative energy fuel but is also an important signaling metabolite. We aimed to investigate whether oral lactate administration affects appetite-regulating hormones, slows gastric emptying rate, and dampens appetite. METHODS Ten healthy male volunteers were investigated on two separate occasions: 1) following oral ingestion of D/L-Na-lactate and 2) following oral ingestion of isotonic iso-voluminous NaCl and intravenous iso-lactemic D/L-Na-lactate infusions. Appetite was evaluated by questionnaires and ad libitum meal tests were performed at the end of each study day. Gastric emptying rate was evaluated using the acetaminophen test. RESULTS Plasma concentrations of growth differential factor 15 (GDF15, primary outcome) increased following oral and iv administration of lactate (p < 0.001) with no detectable difference between interventions (p = 0.15). Oral lactate administration lowered plasma concentrations of acylated ghrelin (p = 0.02) and elevated glucagon like peptide-1 (GLP-1, p = 0.045), insulin (p < 0.001), and glucagon (p < 0.001) compared with iv administration. Oral lactate administration slowed gastric emptying (p < 0.001), increased the feeling of being "full" (p = 0.008) and lowered the "anticipated future food intake" (p = 0.007) compared with iv administration. Food intake during the ad libitum meal test did not differ between the two study days. CONCLUSION Oral lactate administration has a direct effect on the upper gastrointestinal tract, affecting gut hormone secretion, motility and appetite sensations which cannot be mediated through lactate in the systemic circulation alone. These data suggest that compounds rich in lactate may be useful in the treatment of metabolic disease. CLINICAL TRIAL REGISTRY NUMBER NCT0429981, https://clinicaltrials.gov/ct2/show/NCT04299815.
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Affiliation(s)
- Mette Glavind Bülow Pedersen
- Medical/Steno Aarhus Research Laboratory, Aarhus University, Aarhus University Hospital, Palle Juul-Jensens Blvd 165, 8200 Aarhus N, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Hedeager 3, 8200 Aarhus N, Denmark.
| | - Esben Søndergaard
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Hedeager 3, 8200 Aarhus N, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 165, 8200 Aarhus N, Denmark
| | - Camilla Bak Nielsen
- Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 43, 8200 Aarhus N, Denmark
| | - Mogens Johannsen
- Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 43, 8200 Aarhus N, Denmark
| | - Lars Christian Gormsen
- Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Palle Juul-Jensens Blvd. 165, 8200 Aarhus N, Denmark
| | - Niels Møller
- Medical/Steno Aarhus Research Laboratory, Aarhus University, Aarhus University Hospital, Palle Juul-Jensens Blvd 165, 8200 Aarhus N, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 165, 8200 Aarhus N, Denmark
| | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Hedeager 3, 8200 Aarhus N, Denmark
| | - Nikolaj Rittig
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Hedeager 3, 8200 Aarhus N, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 165, 8200 Aarhus N, Denmark
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Christiansen CB, Veedfald S, Hartmann B, Gauguin AM, Møller S, Moritz T, Madsbad S, Holst JJ. Colonic Lactulose Fermentation Has No Impact on Glucagon-like Peptide-1 and Peptide-YY Secretion in Healthy Young Men. J Clin Endocrinol Metab 2022; 107:77-87. [PMID: 34508600 DOI: 10.1210/clinem/dgab666] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Indexed: 01/14/2023]
Abstract
CONTEXT The colon houses most of humans' gut microbiota, which ferments indigestible carbohydrates. The products of fermentation have been proposed to influence the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) from the many endocrine cells in the colonic epithelium. However, little is known about the colonic contribution to fasting or postprandial plasma levels of L-cell products. OBJECTIVE To determine the impact of colonic lactulose fermentation on gut peptide secretion and to evaluate whether colonic endocrine secretion contributes to gut hormone concentrations measurable in the fasting state. METHODS Ten healthy young men were studied on 3 occasions after an overnight fast. On 2 study days, lactulose (20 g) was given orally and compared to water intake on a third study day. For 1 of the lactulose visits, participants underwent a full colonic evacuation. Over a 6-h study protocol, lactulose fermentation was assessed by measuring exhaled hydrogen, and gut peptide secretion, paracetamol, and short-chain fatty acid levels were measured in plasma. RESULTS Colonic evacuation markedly reduced hydrogen exhalation after lactulose intake (P = 0.013). Our analysis suggests that the colon does not account for the measurable amounts of GLP-1 and PYY present in the circulation during fasting and that fermentation and peptide secretion are not acutely related. CONCLUSION Whether colonic luminal contents affect colonic L-cell secretion sufficiently to influence circulating concentrations requires further investigation. Colonic evacuation markedly reduced lactulose fermentation, but hormone releases were unchanged in the present study.
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Affiliation(s)
- Charlotte Bayer Christiansen
- Novo Nordic Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simon Veedfald
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Endocrinology, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
| | - Bolette Hartmann
- Novo Nordic Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Astrid Marie Gauguin
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Søren Møller
- Center for Functional and Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine 260, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Thomas Moritz
- Novo Nordic Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
| | - Jens Juul Holst
- Novo Nordic Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Veedfald S, Rehfeld JF, van Hall G, Svendsen LB, Holst JJ. Entero-Pancreatic Hormone Secretion, Gastric Emptying, and Glucose Absorption After Frequently Sampled Meal Tests. J Clin Endocrinol Metab 2022; 107:e188-e204. [PMID: 34479362 DOI: 10.1210/clinem/dgab610] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Entero-pancreatic hormone secretion has been reported during the pre-absorptive cephalic and gastric meal phases, but never with a blood sampling frequency providing a temporal resolution that allows close scrutiny and correlations with gastric emptying and glucose absorption. OBJECTIVE We hypothesized that entero-pancreatic hormone secretion after nutrient ingestion would be rapid and correlate with gastric emptying and glucose absorption. METHODS During 2 visits in a clinical research facility, 10 healthy young men ingested a 75-g glucose drink (OG) and a liquid mixed meal (LMM) (t = 0-2 minutes) on separate days. Acetaminophen and 3-O-methyl-D-glucopyranose (3-OMG) were added to the drinks to evaluate gastric emptying and glucose absorption, respectively. Arterialized venous blood was sampled (t = -30, -20, -18, -16, -14, -12, -10, -8, -6, -4, -2, 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30 minutes). Plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), gastrin, cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), 3-OMG, and glucose were measured, as were serum insulin, C-peptide, and acetaminophen. RESULTS Acetaminophen increased 8 minutes after OG (P < 0.001) and LMM (P < 0.05); 3-OMG, 8 minutes after LMM (P < 0.0001), 10 minutes after OG (P = 0.04); PP, 4 minutes after LMM (P < 0.03); gastrin, 6 minutes after LMM (P < 0.003) and OG (P < 0.003); CCK, 6 minutes after LMM (P = 0.0001); GIP, 8 minutes after OG (P < 0.05) and LMM (P < 0.03); glucose, 8 minutes after OG (P < 0.001); 12 minutes after LMM (P < 0.02); GLP-1, 12 minutes after OG (P < 0.01), 10 minutes after LMM (P < 0.01); insulin, 12 minutes after LMM (P = 0.02) and OG (P = 0.002); C-peptide, 12 minutes after OG (P = 0.002) and LMM (P = 0.04). CONCLUSION Early postprandial hormone responses show characteristic differences with regard to timing and amplitude but also great individual differences. This should be considered when interpreting mean responses and designing study protocols.
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Affiliation(s)
- Simon Veedfald
- Department of Surgical Gastroenterology, Rigshospitalet, Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Gerrit van Hall
- Clinical Metabolic Core Facility, Rigshospitalet, Copenhagen, Denmark
| | - Lars B Svendsen
- Department of Surgical Gastroenterology, Rigshospitalet, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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Nunez-Salces M, Li H, Young RL, Page AJ. The secretion of total and acyl ghrelin from the mouse gastric mucosa: Role of nutrients and the lipid chemosensors FFAR4 and CD36. Peptides 2021; 146:170673. [PMID: 34627956 DOI: 10.1016/j.peptides.2021.170673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 10/20/2022]
Abstract
AIMS This study investigated the nutrient-mediated modulation of total ghrelin (TG) and acyl ghrelin (AG) secretion from the mouse gastric mucosa, and the role of long-chain fatty acid chemosensors, FFAR4 and CD36, in lipid-mediated modulation of TG and AG release. METHODS Ex-vivo experiments were conducted using mouse gastric mucosa to examine the effects of nutrients (D-glucose, L-phenylalanine, peptone (mixture of oligopeptides & single amino acids), D-mannitol, α-linolenic acid and fat emulsion (intralipid)) on TG and AG secretion. Additionally, inhibition of FFAR4 and CD36 on α-linolenic acid and intralipid-mediated regulation of TG and AG secretion was assessed. RESULTS TG and AG secretion were unaffected by glucose and D-mannitol. Peptone stimulated the release of TG and AG. In contrast, L-phenylalanine reduced AG secretion only. Intralipid reduced TG secretion and stimulated AG secretion, and α-linolenic acid reduced AG release, without affecting TG mobilisation. Modulation of ghrelin secretion by lipids occurred in an FFAR4 and CD36-independent manner. CONCLUSION Ghrelin secretion is modulated in a nutrient-specific manner by proteins and lipids, with TG and AG displaying independent responses to the same stimuli. In addition, FFAR4 and CD36 do not participate in modulation of TG and AG secretion by α-linolenic acid and intralipid.
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Affiliation(s)
- Maria Nunez-Salces
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Hui Li
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Richard L Young
- Intestinal Nutrient Sensing Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Amanda J Page
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia.
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Wölnerhanssen BK, Drewe J, Verbeure W, le Roux CW, Dellatorre‐Teixeira L, Rehfeld JF, Holst JJ, Hartmann B, Tack J, Peterli R, Beglinger C, Meyer‐Gerspach AC. Gastric emptying of solutions containing the natural sweetener erythritol and effects on gut hormone secretion in humans: A pilot dose-ranging study. Diabetes Obes Metab 2021; 23:1311-1321. [PMID: 33565706 PMCID: PMC8247993 DOI: 10.1111/dom.14342] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/28/2021] [Accepted: 02/04/2021] [Indexed: 12/25/2022]
Abstract
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.
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Affiliation(s)
| | - Jürgen Drewe
- Department of Clinical Pharmacology and ToxicologyUniversity Hospital of BaselBaselSwitzerland
| | - Wout Verbeure
- Translational Research Center for Gastrointestinal DisordersCatholic University of LeuvenLeuvenBelgium
| | - Carel W. le Roux
- Diabetes Complications Research CentreConway Institute University College DublinDublinIreland
| | | | - Jens F. Rehfeld
- Department of Clinical Biochemistry, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
| | - Jens J. Holst
- Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Bolette Hartmann
- Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Jan Tack
- Translational Research Center for Gastrointestinal DisordersCatholic University of LeuvenLeuvenBelgium
| | - Ralph Peterli
- Clarunis, Department of Surgery, St. ClaraspitalBaselSwitzerland
| | - Christoph Beglinger
- St. Clara Research Ltd at St. ClaraspitalBaselSwitzerland
- University of BaselBaselSwitzerland
| | - Anne C. Meyer‐Gerspach
- St. Clara Research Ltd at St. ClaraspitalBaselSwitzerland
- University of BaselBaselSwitzerland
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8
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Nunez‐Salces M, Li H, Feinle‐Bisset C, Young RL, Page AJ. The regulation of gastric ghrelin secretion. Acta Physiol (Oxf) 2021; 231:e13588. [PMID: 33249751 DOI: 10.1111/apha.13588] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022]
Abstract
Ghrelin is a gastric hormone with multiple physiological functions, including the stimulation of food intake and adiposity. It is well established that circulating ghrelin levels are closely associated with feeding patterns, rising strongly before a meal and lowering upon food intake. However, the mechanisms underlying the modulation of ghrelin secretion are not fully understood. The purpose of this review is to discuss current knowledge on the circadian oscillation of circulating ghrelin levels, the neural mechanisms stimulating fasting ghrelin levels and peripheral mechanisms modulating postprandial ghrelin levels. Furthermore, the therapeutic potential of targeting the ghrelin pathway is discussed in the context of the treatment of various metabolic disorders, including obesity, type 2 diabetes, diabetic gastroparesis and Prader-Willi syndrome. Moreover, eating disorders including anorexia nervosa, bulimia nervosa and binge-eating disorder are also discussed.
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Affiliation(s)
- Maria Nunez‐Salces
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
| | - Hui Li
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
| | - Christine Feinle‐Bisset
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
| | - Richard L. Young
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
- Intestinal Nutrient Sensing Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
| | - Amanda J. Page
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
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Effect of the Natural Sweetener Xylitol on Gut Hormone Secretion and Gastric Emptying in Humans: A Pilot Dose-Ranging Study. Nutrients 2021; 13:nu13010174. [PMID: 33429977 PMCID: PMC7828005 DOI: 10.3390/nu13010174] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 12/29/2020] [Accepted: 12/31/2020] [Indexed: 01/27/2023] Open
Abstract
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.
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10
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Appetite Control across the Lifecourse: The Acute Impact of Breakfast Drink Quantity and Protein Content. The Full4Health Project. Nutrients 2020; 12:nu12123710. [PMID: 33266325 PMCID: PMC7759987 DOI: 10.3390/nu12123710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/25/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Understanding the mechanisms of hunger, satiety and how nutrients affect appetite control is important for successful weight management across the lifecourse. The primary aim of this study was to describe acute appetite control across the lifecourse, comparing age groups (children, adolescents, adults, elderly), weight categories, genders and European sites (Scotland and Greece). Participants (n = 391) consumed four test drinks, varying in composition (15% (normal protein, NP) and 30% (high protein, HP) of energy from protein) and quantity (based on 100% basal metabolic rate (BMR) and 140% BMR), on four separate days in a double-blind randomized controlled study. Ad libitum energy intake (EI), subjective appetite and biomarkers of appetite and metabolism (adults and elderly only) were measured. The adults' appetite was significantly greater than that of the elderly across all drink types (p < 0.004) and in response to drink quantities (p < 0.001). There were no significant differences in EI between age groups, weight categories, genders or sites. Concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) were significantly greater in the elderly than the adults (p < 0.001). Ghrelin and fasting leptin concentrations differed significantly between weight categories, genders and sites (p < 0.05), while GLP-1 and PYY concentrations differed significantly between genders only (p < 0.05). Compared to NP drinks, HP drinks significantly increased postprandial GLP-1 and PYY (p < 0.001). Advanced age was concomitant with reduced appetite and elevated anorectic hormone release, which may contribute to the development of malnutrition. In addition, appetite hormone concentrations differed between weight categories, genders and geographical locations.
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11
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Sorrentino ZA, Smith G, Palm L, Motwani K, Butterfield J, Archer C, Henderson R, Heldermon C, Gautam S, Brantly ML. An Erythritol-Sweetened Beverage Induces Satiety and Suppresses Ghrelin Compared to Aspartame in Healthy Non-Obese Subjects: A Pilot Study. Cureus 2020; 12:e11409. [PMID: 33194505 PMCID: PMC7657312 DOI: 10.7759/cureus.11409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 11/09/2020] [Indexed: 11/28/2022] Open
Abstract
Despite the reduced caloric content of artificially sweetened beverages (ASBs) relative to those sweetened with sucrose, consumption of ASBs fail to consistently decrease the risk of obesity and associated diseases. This failure may be due to the inability of ASBs to effectively reduce appetite and hence overall caloric intake. A variety of non-nutritive sweeteners (NNS), however, remain to be screened for effectiveness in promoting satiety and reducing calorie consumption. Erythritol is well-tolerated, low-calorie sugar alcohol widely used as a sugar substitute. It is unique among NNS due to its low sweetness index relative to glucose, meaning that it is typically served at much higher concentrations than other common NNS. Animal and human studies have noted correlations between osmolarity, satiety, and levels of satiety hormones, independent of the effects of sweetness or nutritive value. We hypothesized that consumption of a beverage sweetened with erythritol to the sweetness and osmolarity of a common soft drink will improve self-reported satiety and more strongly affect the magnitude of changes in the hormone ghrelin than would an iso sweet beverage sweetened only with aspartame, a sweetener with a high sweetness index relative to glucose. Using a randomized double-blind crossover trial, we found that serum ghrelin was significantly decreased after consumption of an erythritol-sweetened beverage compared to aspartame. Likewise, consumption of the erythritol-sweetened beverage increased various measures of satiety in volunteers. Knowledge gained from this project demonstrates that high-osmolarity NNS may be useful in formulating ASBs that are satiating and low in calories.
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Affiliation(s)
| | - Garrett Smith
- Medicine, University of Florida College of Medicine, Gainesville, USA
| | - Lindsey Palm
- Medicine, University of Florida College of Medicine, Gainesville, USA
| | - Kartik Motwani
- Medicine, University of Florida College of Medicine, Gainesville, USA
| | - John Butterfield
- Medicine, University of Florida College of Medicine, Gainesville, USA
| | - Christian Archer
- Medicine, University of Florida College of Medicine, Gainesville, USA
| | - Rebecca Henderson
- Medicine, University of Florida College of Medicine, Gainesville, USA
| | - Coy Heldermon
- Medicine, University of Florida College of Medicine, Gainesville, USA
| | - Shiva Gautam
- Medicine, University of Florida College of Medicine, Jacksonville, USA
| | - Mark L Brantly
- Medicine, University of Florida College of Medicine, Gainesville, USA
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12
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Asmar A, Cramon PK, Asmar M, Simonsen L, Sorensen CM, Madsbad S, Moro C, Hartmann B, Rehfeld JF, Holst JJ, Hovind P, Jensen BL, Bülow J. Increased oral sodium chloride intake in humans amplifies selectively postprandial GLP-1 but not GIP, CCK, and gastrin in plasma. Physiol Rep 2020; 8:e14519. [PMID: 32770661 PMCID: PMC7413881 DOI: 10.14814/phy2.14519] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/03/2020] [Accepted: 07/03/2020] [Indexed: 12/24/2022] Open
Abstract
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.
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Affiliation(s)
- Ali Asmar
- Department of Clinical Physiology, Nuclear Medicine and PET, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
- Department of Clinical Physiology and Nuclear MedicineBispebjerg and Frederiksberg HospitalUniversity Hospital of CopenhagenCopenhagenDenmark
| | - Per K. Cramon
- Department of Clinical Physiology and Nuclear MedicineBispebjerg and Frederiksberg HospitalUniversity Hospital of CopenhagenCopenhagenDenmark
| | - Meena Asmar
- Department of Clinical Physiology and Nuclear MedicineBispebjerg and Frederiksberg HospitalUniversity Hospital of CopenhagenCopenhagenDenmark
- Department of EndocrinologyOdense University HospitalOdenseDenmark
| | - Lene Simonsen
- Department of Clinical Physiology and Nuclear MedicineBispebjerg and Frederiksberg HospitalUniversity Hospital of CopenhagenCopenhagenDenmark
| | | | - Sten Madsbad
- Department of EndocrinologyHvidovre HospitalUniversity Hospital of CopenhagenCopenhagenDenmark
| | - Cedric Moro
- Institut National de la Santé et de la Recherche Médicale (Inserm) UMR 1048Institute of Metabolic and Cardiovascular DiseasesPaul Sabatier UniversityToulouseFrance
| | - Bolette Hartmann
- Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| | - Jens F. Rehfeld
- Department of Clinical Biochemistry, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
| | - Jens J. Holst
- Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| | - Peter Hovind
- Department of Clinical Physiology, Nuclear Medicine and PET, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
- Department of Clinical Physiology and Nuclear MedicineBispebjerg and Frederiksberg HospitalUniversity Hospital of CopenhagenCopenhagenDenmark
| | - Boye L. Jensen
- Department of Cardiovascular and Renal ResearchUniversity of Southern DenmarkOdenseDenmark
| | - Jens Bülow
- Department of Clinical Physiology and Nuclear MedicineBispebjerg and Frederiksberg HospitalUniversity Hospital of CopenhagenCopenhagenDenmark
- Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
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13
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Huang WK, Xie C, Young RL, Zhao JB, Ebendorff-Heidepriem H, Jones KL, Rayner CK, Wu TZ. Development of innovative tools for investigation of nutrient-gut interaction. World J Gastroenterol 2020; 26:3562-3576. [PMID: 32742126 PMCID: PMC7366065 DOI: 10.3748/wjg.v26.i25.3562] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 05/29/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract is the key interface between the ingesta and the human body. There is wide recognition that the gastrointestinal response to nutrients or bioactive compounds, particularly the secretion of numerous hormones, is critical to the regulation of appetite, body weight and blood glucose. This concept has led to an increasing focus on "gut-based" strategies for the management of metabolic disorders, including type 2 diabetes and obesity. Understanding the underlying mechanisms and downstream effects of nutrient-gut interactions is fundamental to effective translation of this knowledge to clinical practice. To this end, an array of research tools and platforms have been developed to better understand the mechanisms of gut hormone secretion from enteroendocrine cells. This review discusses the evolution of in vitro and in vivo models and the integration of innovative techniques that will ultimately enable the development of novel therapies for metabolic diseases.
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Affiliation(s)
- Wei-Kun Huang
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Cong Xie
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Richard L Young
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Diabetes, Nutrition and Gut Health, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, SA 5005, Australia
| | - Jiang-Bo Zhao
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Heike Ebendorff-Heidepriem
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Karen L Jones
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Christopher K Rayner
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Tong-Zhi Wu
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
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14
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Effect of bolus enteral tube feeding on body weight in ambulatory adults with obesity and type 2 diabetes: a feasibility pilot randomized trial. Nutr Diabetes 2020; 10:22. [PMID: 32555148 PMCID: PMC7298641 DOI: 10.1038/s41387-020-0125-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 05/27/2020] [Accepted: 06/02/2020] [Indexed: 11/16/2022] Open
Abstract
Background/objectives To ascertain the effect on body weight of 14 days of bolus enteral feeding with mixed meal (MM) and electrolyte solution (ES) in ambulatory adults with type 2 diabetes and obesity, and also the safety and feasibility of using a modified, intraorally anchored enteral feeding tube for this purpose. Subjects/methods We conducted a randomized, crossover pilot trial with 16 participants. A 140 cm, 8-French feeding tube was placed in the jejunum under electromagnetic guidance and anchored intraorally. Participants were randomized to self-administer 120 mL 523 kJ (125 kcal) MM, or 50 kJ (12 kcal) ES four times/day for 14 days. After ≥14 days without the tube, participants crossed over to the other treatment. The primary outcome compared weight change between treatments. Thereafter, participants could elect to undergo additional MM cycles. Participants were encouraged to continue with all usual activities including eating ad lib throughout the study. Results Ten participants withdrew prior to completing two randomized 14-day cycles (4 social, 3 intolerant of anchor, and 3 intolerant of tube). Six participants were assessed for the primary outcome and showed no significant difference in weight loss between MM and ES (p = 0.082). For the secondary outcome of within-group weight loss, average weight loss from baseline was significant for MM but not for ES: −2.40 kg (95% CI: −3.78, −1.02; p = 0.008) vs. −0.64 kg (95% CI: −2.01, 0.74; p = 0.27). A total of 23 2-week cycles were completed (12 paired, 2 unpaired, and 9 additional), with no significant adverse events for 334 days of tube use. Conclusions Repeated bolus nutrient administration via enteral feeding tube is associated with weight loss in adults with obesity and type 2 diabetes, with no significant difference seen between MM and ES feeds. The prototype device was safe, but requires development for further investigation into the effect of bolus jejunal feeding on weight and to improve acceptability.
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15
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Lanng AR, Gasbjerg LS, Bergmann NC, Bergmann S, Helsted MM, Gillum MP, Hartmann B, Holst JJ, Vilsbøll T, Knop FK. Gluco-metabolic effects of oral and intravenous alcohol administration in men. Endocr Connect 2019; 8:1372-1382. [PMID: 31518994 PMCID: PMC6790903 DOI: 10.1530/ec-19-0317] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 09/13/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ingestion of the calorically dense compound alcohol may cause metabolic disturbances including hypoglycaemia, hepatic steatosis and insulin resistance, but the underlying mechanisms are uncertain. The gastrointestinal tract is well recognised as a major influencer on glucose, protein and lipid metabolism, but its role in alcohol metabolism remains unclear. OBJECTIVE To examine the effects of oral and intravenous alcohol, respectively, on plasma concentrations of several gluco-regulatory hormones including serum/plasma insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21). DESIGN AND METHODS In a double-blinded, randomised, crossover design, we subjected 12 healthy men to intragastric ethanol infusion (IGEI) and an isoethanolaemic intravenous ethanol infusion (IVEI) (0.7 g alcohol per kg body weight), respectively, on two separate experimental days. RESULTS Isoethanolaemia during the two alcohol administration forms was obtained (P = 0.38). During both interventions, plasma glucose peaked after ~30 min and thereafter fell below baseline concentrations. GIP and GLP-1 concentrations were unaffected by the two interventions. Insulin concentrations were unaffected by IGEI but decreased during IVEI. C-peptide, insulin secretion rate and glucagon concentrations were lowered similarly during IGEI and IVEI. FGF21 concentrations increased dramatically (nine-fold) and similarly during IGEI and IVEI. CONCLUSIONS Alcohol does not seem to affect the secretion of incretin hormones but decreased insulin and glucagon secretion independently of gut-derived factors. IGEI as well as IVEI potently stimulate FGF21 secretion indicating a gut-independent effect of alcohol on FGF21 secretion in humans.
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Affiliation(s)
- Amalie R Lanng
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Sigrid Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Matthew P Gillum
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Correspondence should be addressed to F K Knop:
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16
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Zhang X, Young RL, Bound M, Hu S, Jones KL, Horowitz M, Rayner CK, Wu T. Comparative Effects of Proximal and Distal Small Intestinal Glucose Exposure on Glycemia, Incretin Hormone Secretion, and the Incretin Effect in Health and Type 2 Diabetes. Diabetes Care 2019; 42:520-528. [PMID: 30765429 DOI: 10.2337/dc18-2156] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/16/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-O-methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic clamp studies were performed on the other two days. Blood glucose, serum 3-O-methylglucose, and plasma hormones were evaluated over 180 min. RESULTS In both groups, blood glucose and serum 3-O-methylglucose concentrations were higher after proximal than distal glucose infusion (all P < 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P < 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P ≤ 0.009). CONCLUSIONS The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM.
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Affiliation(s)
- Xiang Zhang
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Richard L Young
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Michelle Bound
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia
| | - Sanyuan Hu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Karen L Jones
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- Institute of Diabetes, School of Medicine, Southeast University, Nanjing, Jiangsu, China
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