Ghrelin Attenuates the Inhibitory Effects of Glucagon-Like Peptide-1 and Peptide YY(3-36) on Food Intake and Gastric Emptying in Rats

We investigated the effect of acarbose, an α-glucosidase and pancreatic α-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 ( r = 0.68 , P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.

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Glucagon Like Peptide 1 and Evidence Around Diabetes Specific Nutrition

World Nutrition ◽

10.26596/wn.201910264-75 ◽

2019 ◽

Vol 10 (2) ◽

pp. 64-75

Author(s):

ANSHU JOSHI ◽

SAMEER RAO ◽

GANESH KADHE

Keyword(s):

Fatty Acids ◽

Insulin Secretion ◽

Gastric Emptying ◽

Food Intake ◽

Diabetes Management ◽

Monounsaturated Fatty Acids ◽

Complex Carbohydrate ◽

Soluble Fibre ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

There has been significant research and development in pharmaco-therapeutic molecules for management of type 2 diabetes mellitus (T2DM). Diabetes specific nutrition intervention & newer incretin-based therapies have gained a lot of attention. Since incretins play an essential role in augmenting the post-prandial release of insulin, it is important to understand the science behind incretins and modulation of same by diabetic-specific nutrition (DSN). The purpose of this article is to summarize the available science around glucagon like peptide 1 (GLP-1) and the known role of nutrition, particularly diabetes specific nutrition. Literature published in PubMed, Google scholar and Embase were studied up to the end of August 2018. The key words of GLP-1, T2DM and Nutrients were used in different combinations. It was found that macronutrient aspects of DSN like complex carbohydrate, soluble fibre, proteins and high monounsaturated fatty acids augment GLP-1 secretion from intestinal L-cells. This may be attributed to insulin-trophic effects of DSN as well as its effects in causing deceleration in gastric emptying and reducing food intake. Hence, it was concluded that augmenting GLP-1 secretion in response to the intake of certain nutrients helps in modulating insulin secretion, metabolic homeostasis as well as decelerating gastric emptying and reducing food intake. DSN increases endogenous GLP-1 secretion which in turn improves insulin secretion and sensitivity. Thus, integrating DSN in mainstay diabetes management plans may result in better glycaemic and metabolic controls, particularly when GLP-1 based therapies are concurrently in use. Key Messages: DSN containing complex carbohydrate, soluble fibre, proteins and high monounsaturated fatty acids (MUFAs) augments GLP-1 secretion which in turn improves insulin secretion and sensitivity.

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The inhibitory effects of peripheral administration of peptide YY3–36 and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal–brainstem–hypothalamic pathway

Brain Research ◽

10.1016/j.brainres.2005.03.011 ◽

2005 ◽

Vol 1044 (1) ◽

pp. 127-131 ◽

Cited By ~ 390

Author(s):

Caroline R. Abbott ◽

Mariana Monteiro ◽

Caroline J. Small ◽

Arshia Sajedi ◽

Kirsty L. Smith ◽

...

Keyword(s):

Food Intake ◽

Inhibitory Effects ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Ghrelin Stimulates Gastric Emptying and Hunger in Normal-Weight Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-2638 ◽

2006 ◽

Vol 91 (9) ◽

pp. 3296-3302 ◽

Cited By ~ 170

Author(s):

F. Levin ◽

T. Edholm ◽

P. T. Schmidt ◽

P. Grybäck ◽

H. Jacobsson ◽

...

Keyword(s):

Gastric Emptying ◽

Peptide Yy ◽

Hormone Secretion ◽

Normal Weight ◽

Lag Phase ◽

Double Blind ◽

Gastric Emptying Rate ◽

Ghrelin Receptor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Context: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. Main Objective: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. Design: This was a randomized, double-blind, crossover study. Subjects: Subjects included normal human volunteers and patients with GH deficiency. Intervention: Intervention included saline or ghrelin (10 pmol/kg·min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. Main Outcome Measures: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. Results: The emptying rate was significantly faster for ghrelin (1.26 ± 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 ± 2.2 and 26.5 ± 3.8 min) and half-emptying time (49.4 ± 3.9 and 75.6 ± 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. Conclusion: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

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Mechanisms of gastric emptying disturbances in chronic and acute inflammation of the distal gastrointestinal tract

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00145.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. G861-G868 ◽

Cited By ~ 26

Author(s):

Jutta Keller ◽

Christoph Beglinger ◽

Jens Juul Holst ◽

Viola Andresen ◽

Peter Layer

Keyword(s):

Gastrointestinal Tract ◽

Gastric Emptying ◽

Plasma Glucose ◽

Peptide Yy ◽

Postprandial Plasma Glucose ◽

Patient Groups ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Upper Gastrointestinal ◽

Cck Release

It is unclear why patients with inflammation of the distal bowel complain of symptoms referable to the upper gastrointestinal tract, specifically to gastric emptying (GE) disturbances. Thus we aimed to determine occurrence and putative pathomechanisms of gastric motor disorders in such patients. Thirteen healthy subjects (CON), 13 patients with Crohn's disease (CD), 10 with ulcerative colitis (UC), and 7 with diverticulitis (DIV) underwent a standardized 13C-octanoic acid gastric emptying breath test. Plasma glucose, CCK, peptide YY, and glucagon-like peptide-1 (GLP-1) were measured periodically and correlated with GE parameters. Results were given in means ± SD. Compared with CON, GE half time (T) was prolonged by 50% in CD (115 ± 55 vs. 182 ± 95 min, P = 0.037). Six CD, 2 DIV, and 2 UC patients had pathological T (>200 min). Postprandial plasma glucose was increased in all patients but was highest in DIV and correlated with T ( r = 0.90, P = 0.006). In CD, mean postprandial CCK levels were increased threefold compared with CON (6.5 ± 6.7 vs. 2.1 ± 0.6 pmol/l, P = 0.027) and were correlated with T ( r = 0.60, P = 0.041). Compared with CON, GLP-1 levels were increased in UC (25.1 ± 5.2 vs. 33.5 ± 13.0 pmol/l, P = 0.046) but markedly decreased in DIV (9.6 ± 5.2 pmol/l, P < 0.0001). We concluded that a subset of patients with CD, UC, or DIV has delayed GE. GE disturbances are most pronounced in CD and might partly be caused by excessive CCK release. In DIV there might be a pathophysiological link between decreased GLP-1 release, postprandial hyperglycemia, and delayed GE. These explorative data encourage further studies in larger patient groups.

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The Glucagon-Like Peptide-1 Receptor Agonist Oxyntomodulin Enhances β-Cell Function but Does Not Inhibit Gastric Emptying in Mice

Endocrinology ◽

10.1210/en.2008-0336 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5670-5678 ◽

Cited By ~ 71

Author(s):

Adriano Maida ◽

Julie A. Lovshin ◽

Laurie L. Baggio ◽

Daniel J. Drucker

Keyword(s):

Blood Glucose ◽

Amino Acid ◽

Gastric Emptying ◽

Food Intake ◽

Oral Glucose ◽

Dependent Manner ◽

Glucose Administration ◽

Amino Acid Peptide ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The proglucagon gene gives rise to multiple peptides that play diverse roles in the control of energy intake, gut motility, and nutrient disposal. Glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide regulates glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. Oxyntomodulin (OXM) a 37-amino-acid peptide also derived from the proglucagon gene, binds to both the glucagon and GLP-1 receptor (GLP-1R); however, a separate OXM receptor has not yet been identified. Here we show that OXM, like other GLP-1R agonists, stimulates cAMP formation and lowers blood glucose after both oral and ip glucose administration, actions that require a functional GLP-1R. OXM also directly stimulates insulin secretion from murine islets and INS-1 cells in a glucose- and GLP-1R-dependent manner. Moreover, OXM ameliorates hyperglycemia and significantly reduces apoptosis in murine β-cells after streptozotocin administration and directly reduces apoptosis in thapsigargin-treated INS-1 cells. Unexpectedly, OXM, but not the GLP-1R agonist exendin-4, increased plasma levels of insulin after oral glucose administration. Moreover, OXM administered at doses that potently lower blood glucose had no effect on inhibition of gastric emptying but reduced food intake in WT mice. Taken together, these findings illustrate that although structurally distinct proglucagon-derived peptides such as GLP-1 and OXM engage the GLP-1R, OXM mimics some but not all of the actions of GLP-1R agonists in vivo. These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders.

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Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00029.2005 ◽

2005 ◽

Vol 289 (3) ◽

pp. R729-R737 ◽

Cited By ~ 61

Author(s):

Karine Proulx ◽

Daniela Cota ◽

Tamara R. Castañeda ◽

Matthias H. Tschöp ◽

David A. D'Alessio ◽

...

Keyword(s):

Food Intake ◽

Motor Activity ◽

Peptide Yy ◽

Metabolic Effects ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Apolipoprotein A ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Induced Changes

Oleoylethanolamide (OEA), a lipid synthesized in the intestine, reduces food intake and stimulates lipolysis through peroxisome proliferator-activated receptor-α. OEA also activates transient receptor potential vanilloid type 1 (TRPV1) in vitro. Because the anorexigenic effect of OEA is associated with delayed feeding onset and reduced locomotion, we examined whether intraperitoneal administration of OEA results in nonspecific behavioral effects that contribute to the anorexia in rats. Moreover, we determined whether circulating levels of other gut hormones are modulated by OEA and whether CCK is involved in OEA-induced anorexia. Our results indicate that OEA reduces food intake without causing a conditioned taste aversion or reducing sodium appetite. It also failed to induce a conditioned place aversion. However, OEA induced changes in posture and reduced spontaneous activity in the open field. This likely underlies the reduced heat expenditure and sodium consumption observed after OEA injection, which disappeared within 1 h. The effects of OEA on motor activity were similar to those of the TRPV1 agonist capsaicin and were also observed with the peroxisome proliferator-activated receptor-α agonist Wy-14643. Plasma levels of ghrelin, peptide YY, glucagon-like peptide 1, and apolipoprotein A-IV were not changed by OEA. Finally, antagonism of CCK-1 receptors did not affect OEA-induced anorexia. These results suggest that OEA suppresses feeding without causing visceral illness and that neither ghrelin, peptide YY, glucagon-like peptide 1, apolipoprotein A-IV, nor CCK plays a critical role in this effect. Despite that OEA-induced anorexia is unlikely to be due to impaired motor activity, our data raise a cautionary note in how specific behavioral and metabolic effects of OEA should be interpreted.

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