Ghrelin Does Not Directly Stimulate Secretion of Glucagon-like Peptide-1

Abstract Context The gastrointestinal hormone ghrelin stimulates growth hormone secretion and appetite, but recent studies indicate that ghrelin also stimulates the secretion of the appetite-inhibiting and insulinotropic hormone glucagon-like peptide-1 (GLP-1). Objective To investigate the putative effect of ghrelin on GLP-1 secretion in vivo and in vitro. Subjects and Methods A randomized placebo-controlled crossover study was performed in eight hypopituitary subjects. Ghrelin or saline was infused intravenously (1 pmol/min × kg) after collection of baseline sample (0 min), and blood was subsequently collected at time 30, 60, 90, and 120 minutes. Mouse small intestine was perfused (n = 6) and GLP-1 output from perfused mouse small intestine was investigated in response to vascular ghrelin administration in the presence and absence of a simultaneous luminal glucose stimulus. Ghrelin receptor expression was quantified in human (n = 11) and mouse L-cells (n = 3) by RNA sequencing and RT-qPCR, respectively. Results Ghrelin did not affect GLP-1 secretion in humans (area under the curve [AUC; 0–120 min]: ghrelin infusion = 1.37 ± 0.05 min × nmol vs. saline infusion = 1.40 ± 0.06 min × nmol [P = 0.63]), but induced peripheral insulin resistance. Likewise, ghrelin did not stimulate GLP-1 secretion from the perfused mouse small intestine model (mean outputs during baseline/ghrelin infusion = 19.3 ± 1.6/25.5 ± 2.0 fmol/min, n = 6, P = 0.16), whereas glucose-dependent insulinotropic polypeptide administration, used as a positive control, doubled GLP-1 secretion (P < 0.001). Intraluminal glucose increased GLP-1 secretion by 4-fold (P < 0.001), which was not potentiated by ghrelin. Finally, gene expression of the ghrelin receptor was undetectable in mouse L-cells and marginal in human L-cells. Conclusions Ghrelin does not interact directly with the L-cell and does not directly affect GLP-1 secretion.

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GLP-1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90635.2008 ◽

2009 ◽

Vol 297 (4) ◽

pp. G663-G671 ◽

Cited By ~ 62

Author(s):

Tohru Hira ◽

Taisuke Mochida ◽

Kyoko Miyashita ◽

Hiroshi Hara

Keyword(s):

Small Intestine ◽

Sampling Method ◽

Rat Intestine ◽

Mesenteric Vein ◽

L Cells ◽

Corn Protein ◽

Before And After ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Dose Dependent

Glucagon-like peptide-1 (GLP-1) is released from enteroendocrine cells (L cells) in response to food ingestion. The mechanism by which dietary peptides stimulate GLP-1 secretion in the gut is unknown. In the present study, we found that a hydrolysate prepared from zein, a major corn protein [zein hydrolysate (ZeinH)], strongly stimulates GLP-1 secretion in enteroendocrine GLUTag cells. Stimulatory mechanisms of GLP-1 secretion induced by ZeinH were investigated in the rat small intestine under anesthesia. Blood was collected through a portal catheter before and after ZeinH administration into different sites of the small intestine. The duodenal, jejunal, and ileal administration of ZeinH induced dose-dependent increases in portal GLP-1 concentration. GLP-1 secretion in response to the ileal administration of ZeinH was higher than that in the duodenal or jejunal administration. Capsaicin treatment on esophageal vagal trunks abolished the GLP-1 secretion induced by duodenal ZeinH but did not affect the secretion induced by jejunal or ileal ZeinH. These results suggest that ZeinH in the jejunum or ileum directly stimulates GLP-1 secretion but duodenal ZeinH indirectly stimulates GLP-1 secretion via the vagal afferent nerve. A direct blood sampling method from the duodenal vein and ileal mesenteric vein revealed that ZeinH administered into the ligated duodenal loop enhanced GLP-1 concentration in the ileal mesenteric vein but not in the duodenal vein. This confirmed that ZeinH in the duodenum induces GLP-1 secretion from L cells located in the ileum by an indirect mechanism. These results indicate that a potent GLP-1-releasing peptide, ZeinH, induces GLP-1 secretion by direct and indirect mechanisms in the rat intestine.

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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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Effect of intravenous administration of glucagon-like peptide 1 on growth hormone secretion in sheep

Journal of Animal and Feed Sciences ◽

10.22358/jafs/73958/2004 ◽

2004 ◽

Vol 13 (Suppl. 1) ◽

pp. 433-435

Author(s):

Y. Kurose ◽

A. Kuwahara ◽

Y. Oshiba ◽

H. Takahashi ◽

Y. Watanabe ◽

...

Keyword(s):

Growth Hormone ◽

Intravenous Administration ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Failure of the Brain Glucagon-Like Peptide-1-Mediated Control of Intestinal Redox Homeostasis in a Rat Model of Sporadic Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox10071118 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1118

Author(s):

Jan Homolak ◽

Ana Babic Perhoc ◽

Ana Knezovic ◽

Jelena Osmanovic Barilar ◽

Melita Salkovic-Petrisic

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rat Model ◽

Redox Homeostasis ◽

Brain State ◽

Gastrointestinal Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The Brain

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer’s disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore (i) gastrointestinal homeostasis in the STZ-icv model (ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and (iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and low molecular weight thiols (LMWT), protein sulfhydryls (SH), and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that (i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, (ii) brain GLP-1R signaling is involved in systemic redox regulation, (iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.

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Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00010.2019 ◽

2019 ◽

Vol 316 (5) ◽

pp. G574-G584 ◽

Cited By ~ 9

Author(s):

Charlotte Bayer Christiansen ◽

Samuel Addison Jack Trammell ◽

Nicolai Jacob Wewer Albrechtsen ◽

Kristina Schoonjans ◽

Reidar Albrechtsen ◽

...

Keyword(s):

Bile Acids ◽

G Protein ◽

Peptide Yy ◽

Whole Body ◽

Rat Colon ◽

G Protein Coupled Receptor ◽

L Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled

A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrate that BAs represent a major physiological stimulus for colonic L-cell secretion.NEW & NOTEWORTHY By the use of isolated perfused rodent colon preparations we show that bile acids are potent and direct promoters of colonic glucagon-like-peptide 1 and peptide-YY secretion. The study provides convincing evidence that basolateral Takeda-G protein-coupled-receptor 5 activation is mediating the effects of bile acids in the colon and thus add to the existing literature described for L cells in the ileum.

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Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment

Acta Histochemica ◽

10.1016/j.acthis.2014.12.007 ◽

2015 ◽

Vol 117 (2) ◽

pp. 205-210 ◽

Cited By ~ 9

Author(s):

Yang Cao ◽

Xun Cao ◽

Xiao-Min Liu

Keyword(s):

L Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Stimulation Of

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Evaluation of glucagon-like peptide-1 receptor expression in non-diabetic and diabetic atherosclerotic mice using PET tracer 68Ga-NODAGA-exendin-4

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00465.2020 ◽

2021 ◽

Author(s):

Mia Ståhle ◽

Sanna Hellberg ◽

Jenni Virta ◽

Heidi Liljenbäck ◽

Olli Metsälä ◽

...

Keyword(s):

Vessel Wall ◽

Vascular Inflammation ◽

Tracer Uptake ◽

Receptor Expression ◽

Atherosclerotic Lesions ◽

Pet Tracer ◽

Positron Emission ◽

Healthy Control ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling attenuates development of atherosclerosis and vascular inflammation. However, the expression of GLP-1R in atherosclerotic arteries remains uncertain. We evaluated whether a positron emission tomography (PET) tracer 68Ga-NODAGA-exendin-4 enables detection and imaging of GLP-1R expression in the mouse atherosclerotic aorta. Hypercholesterolemic (LDLR-/-ApoB100/100), hypercholesterolemic and diabetic (IGF-II/LDLR-/-ApoB100/100) as well as healthy control (C57BL/6N) mice were utilized in the study. The uptake of 68Ga-NODAGA-exendin-4 in atherosclerotic lesions was studied by autoradiography of tissue sections followed by immunofluorescence evaluation of inflammatory and vascular cell markers and GLP-1R. A subset of mice was imaged with 68Ga-NODAGA-exendin-4 PET/computed tomography (CT). The aortas of both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice contained prominent, macrophage-rich atherosclerotic lesions. Diabetic mice demonstrated hyperglycemia and glucose intolerance. We found that by autoradiography, 68Ga-NODAGA-exendin-4 uptake was focally increased in macrophage-rich lesion areas compared with corresponding healthy vessel wall (lesion-to-wall ratio 1.6 ± 0.10, p<0.0001) in both non-diabetic and diabetic hypercholesterolemic mice. Pre-injection of unlabeled exendin-4 peptide significantly reduced cellular uptake of 68Ga-NODAGA-exendin-4. Furthermore, PET/CT imaging showed 68Ga-NODAGA-exendin-4 accumulation in the atherosclerotic aorta. Immunofluorescence stainings demonstrated co-localization of GLP-1R with macrophage-rich areas in atherosclerotic lesions. Tracer uptake was low in the healthy vessel wall of C57BL/6N mice coupled with negative GLP-1R staining. In conclusion, 68Ga-NODAGA-exendin-4 detects GLP-1R expression in atherosclerotic lesions in both non-diabetic and diabetic hypercholesterolemic mice. These results provide evidence that GLP-1R expression is mainly localized in macrophage-rich area in atherosclerotic lesions and may have implications for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.

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Glucagon-like peptide-1 receptor expression after myocardial infarction: Imaging study using 68Ga-NODAGA-exendin-4 positron emission tomography

Journal of Nuclear Cardiology ◽

10.1007/s12350-018-01547-1 ◽

2018 ◽

Vol 27 (6) ◽

pp. 2386-2397 ◽

Cited By ~ 4

Author(s):

Mia Ståhle ◽

Ville Kytö ◽

Max Kiugel ◽

Heidi Liljenbäck ◽

Olli Metsälä ◽

...

Keyword(s):

Myocardial Infarction ◽

Positron Emission Tomography ◽

Smooth Muscle Actin ◽

Receptor Expression ◽

Emission Tomography ◽

Sham Operation ◽

Alpha Smooth Muscle Actin ◽

Positron Emission ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Background Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats. Methods and Results Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68Ga-NODAGA-exendin-4 uptake. By autoradiography, 68Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium. Conclusions 68Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.

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