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The Metabolomic Effects of Tripeptide Gut Hormone Infusion Compared to Roux-en-Y Gastric Bypass and Caloric Restriction.
Jones, B, Sands, C, Alexiadou, K, Minnion, J, Tharakan, G, Behary, P, Ahmed, AR, Purkayastha, S, Lewis, MR, Bloom, S, et al
The Journal of clinical endocrinology and metabolism. 2022;(2):e767-e782
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Abstract
CONTEXT The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis and are thought to contribute to the glucose-lowering effects of bariatric surgery. OBJECTIVE To establish the metabolomic effects of a combined infusion of GLP-1, OXM, and PYY (tripeptide GOP) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). DESIGN AND SETTING Subanalysis of a single-blind, randomized, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. PATIENTS AND INTERVENTIONS Twenty-five obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n = 14) or 0.9% saline control (n = 11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. MAIN OUTCOME MEASURES Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modeling approaches to identify similarities and differences between the effects of each intervention. RESULTS Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. CONCLUSIONS Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.
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Associations between Postprandial Gut Hormones and Markers of Bone Remodeling.
Jensen, NW, Clemmensen, KKB, Jensen, MM, Pedersen, H, Færch, K, Diaz, LJ, Quist, JS, Størling, J
Nutrients. 2021;(9)
Abstract
Gut-derived hormones have been suggested to play a role in bone homeostasis following food intake, although the associations are highly complex and not fully understood. In a randomized, two-day cross-over study on 14 healthy individuals, we performed postprandial time-course studies to examine the associations of the bone remodeling markers carboxyl-terminal collagen type I crosslinks (CTX) and procollagen type 1 N-terminal propeptide (P1NP) with the gut hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) using two different meal types-a standardized mixed meal (498 kcal) or a granola bar (260 kcal). Plasma concentrations of total GIP, total GLP-1, total PYY, CTX, and P1NP were measured up to 240 min after meal intake, and the incremental area under the curve (iAUC) for each marker was calculated. The iAUC of CTX and P1NP were used to assess associations with the iAUC of GIP, GLP-1, and PYY in linear mixed effect models adjusted for meal type. CTX was positively associated with GIP and GLP-1, and it was inversely associated with PYY (all p < 0.001). No associations of P1NP with GIP or GLP-1 and PYY were found. In conclusion, the postprandial responses of the gut hormones GIP, GLP-1, and PYY are associated with the bone resorption marker CTX, supporting a link between gut hormones and bone homeostasis following food intake.
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The Postprandial Glycaemic and Hormonal Responses Following the Ingestion of a Novel, Ready-to-Drink Shot Containing a Low Dose of Whey Protein in Centrally Obese and Lean Adult Males: A Randomised Controlled Trial.
Smith, K, Taylor, GS, Allerton, DM, Brunsgaard, LH, Bowden Davies, KA, Stevenson, EJ, West, DJ
Frontiers in endocrinology. 2021;:696977
Abstract
PURPOSE Elevated postprandial glycaemia [PPG] increases the risk of cardiometabolic complications in insulin-resistant, centrally obese individuals. Therefore, strategies that improve PPG are of importance for this population. Consuming large doses of whey protein [WP] before meals reduces PPG by delaying gastric emptying and stimulating the secretion of the incretin peptides, glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide 1 [GLP-1]. It is unclear if these effects are observed after smaller amounts of WP and what impact central adiposity has on these gastrointestinal processes. METHODS In a randomised-crossover design, 12 lean and 12 centrally obese adult males performed two 240 min mixed-meal tests, ~5-10 d apart. After an overnight fast, participants consumed a novel, ready-to-drink WP shot (15 g) or volume-matched water (100 ml; PLA) 10 min before a mixed-nutrient meal. Gastric emptying was estimated by oral acetaminophen absorbance. Interval blood samples were collected to measure glucose, insulin, GIP, GLP-1, and acetaminophen. RESULTS WP reduced PPG area under the curve [AUC0-60] by 13 and 18.2% in the centrally obese and lean cohorts, respectively (both p <0.001). In both groups, the reduction in PPG was accompanied by a two-three-fold increase in GLP-1 and delayed gastric emptying. Despite similar GLP-1 responses during PLA, GLP-1 secretion during the WP trial was ~27% lower in centrally obese individuals compared to lean (p = 0.001). In lean participants, WP increased the GLP-1ACTIVE/TOTAL ratio comparative to PLA (p = 0.004), indicative of reduced GLP-1 degradation. Conversely, no treatment effects for GLP-1ACTIVE/TOTAL were seen in obese subjects. CONCLUSION Pre-meal ingestion of a novel, ready-to-drink WP shot containing just 15 g of dietary protein reduced PPG in lean and centrally obese males. However, an attenuated GLP-1 response to mealtime WP and increased incretin degradation might impact the efficacy of nutritional strategies utilising the actions of GLP-1 to regulate PPG in centrally obese populations. Whether these defects are caused by an individual's insulin resistance, their obese state, or other obesity-related ailments needs further investigation. CLINICAL TRIAL REGISTRATION ISRCTN.com, identifier [ISRCTN95281775]. https://www.isrctn.com/.
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Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.
McGlone, ER, Malallah, K, Cuenco, J, Wewer Albrechtsen, NJ, Holst, JJ, Vincent, RP, Ling, C, Khan, OA, Verma, S, Ahmed, AR, et al
American journal of physiology. Endocrinology and metabolism. 2021;(4):E671-E679
Abstract
Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.
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Parenteral nutrition impairs plasma bile acid and gut hormone responses to mixed meal testing in lean healthy men.
Meessen, ECE, Bakker, GJ, Nieuwdorp, M, Dallinga-Thie, GM, Kemper, EM, Olde Damink, SW, Romijn, JA, Hartmann, B, Holst, JJ, Knop, FK, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(3):1013-1021
Abstract
BACKGROUND & AIMS To investigate the acute effects of intravenous vs enteral meal administration on circulating bile acid and gut hormone responses. METHODS In a randomized crossover design, we compared the effects of duodenal (via a nasoduodenal tube) vs parenteral (intravenous) administration over 180 min of identical mixed meals on circulating bile acid and gut hormone concentrations in eight healthy lean men. We analysed the bile acid and gut hormone responses in two periods: the intraprandial period from time point (T) 0 until T180 during meal administration and the postprandial period from T180 until T360, after discontinuation of meal administration. RESULTS Intravenous meal administration decreased the intraprandial (AUC (μmol/L∗min) duodenal 1469 ± 284 vs intravenous 240 ± 39, p < 0.01) and postprandial bile acid response (985 ± 240 vs 223 ± 5, p < 0.05) and was accompanied by decreased gut hormone responses including glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, glucagon-like peptide 2 and fibroblast growth factor 19. Furthermore, intravenous meal administration elicited greater glucose concentrations, but similar insulin concentrations compared to enteral administration. CONCLUSIONS Compared to enteral administration, parenteral nutrition results in lower postprandial bile acid and gut hormone responses in healthy lean men. This was accompanied by higher glucose concentrations in the face of similar insulin concentrations exposing a clear incretin effect of enteral mixed meal administration. The alterations in bile acid homeostasis were apparent after only one intravenous meal.
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Appetite, the enteroendocrine system, gastrointestinal disease and obesity.
Crooks, B, Stamataki, NS, McLaughlin, JT
The Proceedings of the Nutrition Society. 2021;(1):50-58
Abstract
The enteroendocrine system is located in the gastrointestinal (GI) tract, and makes up the largest endocrine system in the human body. Despite that, its roles and functions remain incompletely understood. Gut regulatory peptides are the main products of enteroendocrine cells, and play an integral role in the digestion and absorption of nutrients through their effect on intestinal secretions and gut motility. Several peptides, such as cholecystokinin, polypeptide YY and glucagon-like peptide-1, have traditionally been reported to suppress appetite following food intake, so-called satiety hormones. In this review, we propose that, in the healthy individual, this system to regulate appetite does not play a dominant role in normal food intake regulation, and that there is insufficient evidence to wholly link postprandial endogenous gut peptides with appetite-related behaviours. Instead, or additionally, top-down, hedonic drive and neurocognitive factors may have more of an impact on food intake. In GI disease however, supraphysiological levels of these hormones may have more of an impact on appetite regulation as well as contributing to other unpleasant abdominal symptoms, potentially as part of an innate response to injury. Further work is required to better understand the mechanisms involved in appetite control and unlock the therapeutic potential offered by the enteroendocrine system in GI disease and obesity.
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Emerging role of GIP and related gut hormones in fertility and PCOS.
Moffett, RC, Naughton, V
Peptides. 2020;:170233
Abstract
Gastric inhibitory polypeptide (GIP) is best known as an incretin hormone released by enteroendocrine K-cells in response to feeding and stimulates insulin release to regulate blood glucose and nutrient homeostasis. More recently GIP has been ascribed a positive role in lipid metabolism, bone strength, cardiovascular function and cognition. The present paper considers an emerging role of GIP and related gut hormones in fertility and especially polycystic ovarian syndrome (PCOS). Key evidence concerns restoration of fertility in women with gross obesity and PCOS following bariatric surgery. This is considered to reflect indirect effects mediated by alleviation of insulin resistance together with possible direct effects of surgically induced changes of GIP, GLP-1 and related peptide hormones on ovaries and the hypothalamic-pituitary-adrenal axis. Further studies are required to determine inter-relationships between the hormones and cellular mechanisms involved but these observations suggest that GIP and other gut may provide a novel therapeutic approach for PCOS and other reproductive disorders.
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The new place of enterohormones in intestinal failure.
Daoud, DC, Joly, F
Current opinion in clinical nutrition and metabolic care. 2020;(5):344-349
Abstract
PURPOSE OF REVIEW Since the approval of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, for the treatment of patients with short bowel syndrome (SBS) associated with intestinal failure, enterohormone therapy has received significant interest and is becoming the first choice of treatment in selected patients. As such, it is paramount to assess and understand the new place of hormonal therapy in the algorithm of treatments in SBS-intestinal failure. RECENT FINDINGS Specialized intestinal failure units have recently reported their outcomes with teduglutide to evaluate if they are consistent with the phase III trials results. SBS-intestinal failure patients are very heterogenous including their response to this treatment, hence the importance of real-life studies beyond the context of clinical trials. Moreover, it is essential to find a consensus on criteria identifying candidate patients for teduglutide. In addition, the impact of teduglutide on quality of life and its cost-effectiveness are emerging as well as new enterohormone treatments are being studied whether it is long action GLP-2 analog or other ileocolonic break hormones like glucagon-like peptide-1 analog. SUMMARY Hormonotherapy is currently modifying the natural history of patients with SBS-intestinal failure by decreasing their need for parenteral support and possibly even complications associated with long-term parenteral support. Enterohormone treatment is now the cornerstone in SBS-intestinal failure and should be offered as a first-line therapy to selected patients.
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Effects of Age on Acute Appetite-Related Responses to Whey-Protein Drinks, Including Energy Intake, Gastric Emptying, Blood Glucose, and Plasma Gut Hormone Concentrations-A Randomized Controlled Trial.
Giezenaar, C, Lange, K, Hausken, T, Jones, KL, Horowitz, M, Chapman, I, Soenen, S
Nutrients. 2020;(4)
Abstract
Protein-rich supplements are used commonly to increase energy intake in undernourished older people. This study aimed to establish age effects on energy intake, appetite, gastric emptying, blood glucose, and gut hormones in response to protein-rich drinks. In a randomized double-blind, order, 13 older men (age: 75 ± 2 yrs, body mass index (BMI): 26 ± 1 kg/m2) and 13 younger (23 ± 1 yrs, 24 ± 1 kg/m2) men consumed (i) a control drink (~2 kcal) or drinks (450 mL) containing protein/fat/carbohydrate: (ii) 70 g/0 g/0 g (280 kcal/'P280'), (iii) 14 g/12.4 g/28 g (280 kcal/'M280'), (iv) 70 g/12.4 g/28 g (504 kcal/'M504'), on four separate days. Appetite (visual analog scales), gastric emptying (3D ultrasonography), blood glucose, plasma insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) concentrations (0-180 min), and ad-libitum energy intake (180-210 min) were determined. Older men, compared to younger men, had higher fasting glucose and CCK concentrations and lower fasting GLP-1 concentrations (all p < 0.05). Energy intake by P280 compared to control was less suppressed in older men (increase: 49 ± 42 kcal) than it was in younger men (suppression: 100 ± 54 kcal, p = 0.038). After the caloric drinks, the suppression of hunger and the desire to eat, and the stimulation of fullness was less (p < 0.05), and the stimulation of plasma GLP-1 was higher (p < 0.05) in older men compared to younger men. Gastric emptying, glucose, insulin, ghrelin, and CCK responses were similar between age groups. In conclusion, ageing reduces the responses of caloric drinks on hunger, the desire to eat, fullness, and energy intake, and protein-rich nutrition supplements may be an effective strategy to increase energy intake in undernourished older people.
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The Implication of Gut Hormones in the Regulation of Energy Homeostasis and Their Role in the Pathophysiology of Obesity.
Koliaki, C, Liatis, S, Dalamaga, M, Kokkinos, A
Current obesity reports. 2020;(3):255-271
Abstract
PURPOSE OF REVIEW This review provides an update on the role of gut hormones and their interactions in the regulation of energy homeostasis, describes gut hormone adaptations in obesity and in response to weight loss, and summarizes the current evidence on the role of gut hormone-based therapies for obesity treatment. RECENT FINDINGS Gut hormones play a key role in regulating eating behaviour, energy and glucose homeostasis. Dysregulated gut hormone responses have been proposed to be pathogenetically involved in the development and perpetuation of obesity. Summarizing the major gut hormone changes in obesity, obese individuals are characterized by blunted postprandial ghrelin suppression, loss of premeal ghrelin peaks, impaired diurnal ghrelin variability and reduced fasting and postprandial levels of anorexigenic peptides. Adaptive alterations of gut hormone levels are implicated in weight regain, thus complicating hypocaloric dietary interventions, and can further explain the profound weight loss and metabolic improvement following bariatric surgery. A plethora of compounds mimicking gut hormone changes after bariatric surgery are currently under investigation, introducing a new era in the pharmacotherapy of obesity. The current trend is to combine different gut hormone receptor agonists and target multiple systems simultaneously, in order to replicate as closely as possible the gut hormone milieu after bariatric surgery and circumvent the counter-regulatory adaptive changes associated with dietary energy restriction. An increasing number of preclinical and early-phase clinical trials reveal the additive benefits obtained with dual or triple gut peptide receptor agonists in reducing body weight and improving glycaemia. Gut hormones act as potent regulators of energy and glucose homeostasis. Therapeutic strategies targeting their levels or receptors emerge as a promising approach to treat patients with obesity and hyperglycaemia.