scholarly journals Equine glucagon-like peptide-1 receptor physiology

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4316 ◽  
Author(s):  
Murad H. Kheder ◽  
Simon R. Bailey ◽  
Kevin J. Dudley ◽  
Martin N. Sillence ◽  
Melody A. de Laat
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Response ◽  
Synthetic Analogue ◽  
Isolated Pancreatic Islets ◽  
Novel Approach ◽  
Insulin Dysregulation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background Equine metabolic syndrome (EMS) is associated with insulin dysregulation, which often manifests as post-prandial hyperinsulinemia. Circulating concentrations of the incretin hormone, glucagon-like peptide-1 (GLP-1) correlate with an increased insulin response to carbohydrate intake in animals with EMS. However, little is known about the equine GLP-1 receptor (eGLP-1R), or whether GLP-1 concentrations can be manipulated. The objectives were to determine (1) the tissue localisation of the eGLP-1R, (2) the GLP-1 secretory capacity of equine intestine in response to glucose and (3) whether GLP-1 stimulated insulin secretion from isolated pancreatic islets can be attenuated. Methods Archived and abattoir-sourced tissues from healthy horses were used. Reverse transcriptase PCR was used to determine the tissue distribution of the eGLP-1R gene, with immunohistochemical confirmation of its pancreatic location. The GLP-1 secretion from intestinal explants in response to 4 and 12 mM glucose was quantified in vitro. Pancreatic islets were freshly isolated to assess the insulin secretory response to GLP-1 agonism and antagonism in vitro, using concentration-response experiments. Results The eGLP-1R gene is widely distributed in horses (pancreas, heart, liver, kidney, duodenum, digital lamellae, tongue and gluteal skeletal muscle). Within the pancreas the eGLP-1R was immunolocalised to the pancreatic islets. Insulin secretion from pancreatic islets was concentration-dependent with human GLP-1, but not the synthetic analogue exendin-4. The GLP-1R antagonist exendin 9-39 (1 nM) reduced (P = 0.08) insulin secretion by 27%. Discussion The distribution of the eGLP-1R across a range of tissues indicates that it may have functions beyond insulin release. The ability to reduce insulin secretion, and therefore hyperinsulinemia, through eGLP-1R antagonism is a promising and novel approach to managing equine insulin dysregulation.

scholarly journals Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets

2019 ◽  
Vol 8 (5) ◽  
pp. 674 ◽  
Author(s):  
Rieko Goto ◽  
Tatsuya Kondo ◽  
Kaoru Ono ◽  
Sayaka Kitano ◽  
Nobukazu Miyakawa ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Glucose Homeostasis ◽  
Transcriptional Activation ◽  
Interleukin 6 ◽  
Primary Aldosteronism ◽  
Mineralocorticoid Receptor ◽  
Insulin Response ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in α-cells. In α-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in α-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic β-cells and improving glucose homeostasis.

Inhibition by rat diazepam-binding inhibitor/acyl-CoA-binding protein of glucose-induced insulin secretion in the rat

1994 ◽  
Vol 131 (2) ◽  
pp. 201-204 ◽  
Author(s):  
Claes-Göran Östenson ◽  
Bo Ahrén ◽  
Sven Karlsson ◽  
Jens Knudsen ◽  
Suad Efendic
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Binding Protein ◽  
Insulin Response ◽  
Isolated Islets ◽  
High Concentration ◽  
Isolated Pancreatic Islets ◽  
Rat Pancreas

Östenson C-G, Ahrén B, Karlsson S, Knudsen J, Efendic S. Inhibition by rat diazepam-binding inhibitor/ acyl-CoA-binding protein of glucose-induced insulin secretion in the rat. Eur J Endocrinol 1994;131:201–4. ISSN 0804–4643 Diazepam-binding inhibitor (DBI) has been localized immunohistochemically in many organs. In porcine and rat pancreas, DBI is present in non-B-cells of the pancreatic islets. Porcine peptide also has been shown to suppress insulin secretion from rat pancreas in vitro. Recently, acyl-CoA-binding protein (ACBP) was isolated from rat liver and shown to be identical structurally to DBI isolated from rat brain. Using this rat DBI/ACBP, we have studied its effects on glucose-stimulated insulin secretion in the rat, both in vivo and in isolated pancreatic islets. Infusion iv of rDBI/ACBP (25 pmol/min) during glucose stimulation induced a moderate and transient reduction of plasma insulin levels. Moreover, rDBI/ACBP suppressed insulin release from batch-incubated isolated islets, stimulated by 16.7 mmol/l glucose, by 24% at 10 nmol/l (p < 0.05) and by 40% at 100 nmol/l (p < 0.01). The peptide (100 nmol/l) also inhibited the insulin response to glucose (16.7 mmol/l) from perifused rat islets by 31% (p < 0.05), mainly by affecting the acute-phase response. Finally, incubation of isolated islets in the presence of rDBI/ACBP antiserum (diluted 1:100 and 1:300) augmented the insulin response to 16.7 mmol/l glucose (p < 0.05 or even less). We conclude that rDBI/ACBP, administered iv or added to the incubation media, suppresses insulin secretion in the rat but that the effect is moderate despite the high concentration used. It is therefore unlikely that the peptide modulates islet hormone release, acting as a classical hormone via the circulation. However, the occurrence of DBI/ACBP in the islets and the enhancing effect by the rDBI/ACBP antibodies on glucose-stimulated insulin release suggest that the peptide is a local modulator of insulin secretion. C-G Östenson, Department of Endocrinology, Karolinska Hospital, S-171 76 Stockholm, Sweden

scholarly journals Insulin secretion defects in liver cirrhosis can be reversed by glucagon-like peptide-1

2000 ◽  
Vol 164 (1) ◽  
pp. 13-19 ◽  
Author(s):  
EG Siegel ◽  
A Seidenstucker ◽  
B Gallwitz ◽  
F Schmitz ◽  
A Reinecke-Luthge ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Liver Cirrhosis ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Dependent Manner ◽  
Isolated Pancreatic Islets ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Liver cirrhosis is often accompanied by a disturbed carbohydrate metabolism similar to type 2 diabetes. To investigate the severity of the defect in insulin secretion in this form of diabetes, we measured insulin release from isolated pancreatic islets of rats with CCl(4)-phenobarbital-induced liver cirrhosis. Cirrhosis was confirmed by clinical signs, elevated liver enzymes and histology. Fasting venous plasma glucose concentrations were equal in rats with liver cirrhosis and in controls. Plasma insulin and glucagon concentrations were significantly greater (P<0.01) in cirrhotic rats than in control animals. Glucose (16.7 mM)-induced stimulation of insulin release from pancreatic islets revealed a twofold increase in control and cirrhotic rats. Basal and stimulated insulin secretion, however, were significantly lower in cirrhotic animals. The incretin hormone, glucagon-like peptide-1 (GLP-1), has therapeutic potential for the treatment of type 2 diabetes. Therefore, islets from control and cirrhotic animals were incubated with GLP-1 in concentrations from 10(-)(11) to 10(-)(6) M. GLP-1 stimulated insulin release in a concentration-dependent manner. In islets from cirrhotic rats, basal and stimulated insulin secretion was blunted compared with controls. These data show that the hyperinsulinemia observed in liver cirrhosis is not due to an increase of insulin secretion from islets, but could be explained by decreased hepatic clearance of insulin. GLP-1 may ameliorate diabetes in patients with liver cirrhosis.

scholarly journals The possible mechanisms by which phanoside stimulates insulin secretion from rat islets

2007 ◽  
Vol 192 (2) ◽  
pp. 389-394 ◽  
Author(s):  
Nguyen Khanh Hoa ◽  
Åke Norberg ◽  
Rannar Sillard ◽  
Dao Van Phan ◽  
Nguyen Duy Thuan ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
B Cells ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Pertussis Toxin ◽  
Insulin Response ◽  
Gk Rat ◽  
Isolated Pancreatic Islets ◽  
Gk Rats ◽  
Rat Islets

We recently showed that phanoside, a gypenoside isolated from the plant Gynostemma pentaphyllum, stimulates insulin secretion from rat pancreatic islets. To study the mechanisms by which phanoside stimulates insulin secretion. Isolated pancreatic islets of normal Wistar (W) rats and spontaneously diabetic Goto-Kakizaki (GK) rats were batch incubated or perifused. At both 3.3 and 16.7 mM glucose, phanoside stimulated insulin secretion several fold in both W and diabetic GK rat islets. In perifusion of W islets, phanoside (75 and 150 μM) dose dependently increased insulin secretion that returned to basal levels when phanoside was omitted. When W rat islets were incubated at 3.3 mM glucose with 150 μM phanoside and 0.25 mM diazoxide to keep K-ATP channels open, insulin secretion was similar to that in islets incubated in 150 μM phanoside alone. At 16.7 mM glucose, phanoside-stimulated insulin secretion was reduced in the presence of 0.25 mM diazoxide (P<0.01). In W islets depolarized by 50 mM KCl and with diazoxide, phanoside stimulated insulin release twofold at 3.3 mM glucose but did not further increase the release at 16.7 mM glucose. When using nimodipine to block L-type Ca2+ channels in B-cells, phanoside-induced insulin secretion was unaffected at 3.3 mM glucose but decreased at 16.7 mM glucose (P<0.01). Pretreatment of islets with pertussis toxin to inhibit exocytotic Ge-protein did not affect insulin response to 150 μM phanoside. Phanoside stimulated insulin secretion from Wand GK rat islets. This effect seems to be exerted distal to K-ATP channels and L-type Ca2+ channels, which is on the exocytotic machinery of the B-cells.

The Effect of Zinc-Crystallized Glucagon-Like Peptide-1 on Insulin Secretion of Macroencapsulated Pancreatic Islets

2001 ◽  
Vol 7 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Heather Gappa ◽  
Miroslav Baudyš ◽  
Jae Joon Koh ◽  
Sung Wan Kim ◽  
You Han Bae
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Transgenic Expression of Glucagon-Like Peptide-1 (GLP-1) and Activated Muscarinic Receptor (M3R) Significantly Improves Pig Islet Secretory Function

2017 ◽  
Vol 26 (5) ◽  
pp. 901-911 ◽  
Author(s):  
Nizar I. Mourad ◽  
Andrea Perota ◽  
Daela Xhema ◽  
Cesare Galli ◽  
Pierre Gianello
Keyword(s):  
Insulin Secretion ◽  
Muscarinic Receptor ◽  
Expression Vectors ◽  
Specific Expression ◽  
Transgenic Expression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Type 3

Porcine islets show notoriously low insulin secretion levels in response to glucose stimulation. While this is somehow expected in the case of immature islets isolated from fetal and neonatal pigs, disappointingly low secretory responses are frequently reported in studies using in vitro-maturated fetal and neonatal islets and even fully differentiated adult islets. Herein we show that β-cell-specific expression of a modified glucagon-like peptide-1 (GLP-1) and of a constitutively activated type 3 muscarinic receptor (M3R) efficiently amplifies glucose-stimulated insulin secretion (GSIS). Both adult and neonatal isolated pig islets were treated with adenoviral expression vectors carrying sequences encoding for GLP-1 and/or M3R. GSIS from transduced and control islets was evaluated during static incubation and dynamic perifusion assays. While expression of GLP-1 did not affect basal or stimulated insulin secretion, activated M3R produced a twofold increase in both first and second phases of GSIS. Coexpression of GLP-1 and M3R caused an even greater increase in the secretory response, which was amplified fourfold compared to controls. In conclusion, our work highlights pig islet insulin secretion deficiencies and proposes concomitant activation of cAMP-dependent and cholinergic pathways as a solution to ameliorate GSIS from pig islets used for transplantation.

scholarly journals Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1

2021 ◽  
Author(s):  
Amaara Marzook ◽  
Shiqian Chen ◽  
Phil Pickford ◽  
Maria Lucey ◽  
Yifan Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
G Protein ◽  
Early Endosomes ◽  
Important Regulator ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

AbstractThe glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.

Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice

2004 ◽  
Vol 286 (2) ◽  
pp. R269-R272 ◽  
Author(s):  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Direct Action ◽  
Insulin Response ◽  
Sensory Nerves ◽  
High Dose ◽  
Intravenous Glucose ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

It has been hypothesized that the potent insulinotropic action of the gut incretin hormone glucagon-like peptide-1 (GLP-1) is exerted not only through a direct action on the beta cells but may be partially dependent on sensory nerves. We therefore examined the influence of GLP-1 in mice rendered sensory denervated by neonatal administration of capsaicin performed at days 2 and 5 (50 mg/kg). Control mice were given vehicle. Results show that at 10-16 wk of age in control mice, intravenous GLP-1 at 0.1 or 10 nmol/kg augmented the insulin response to intravenous glucose (1 g/kg) in association with improved glucose elimination. In contrast, in capsaicin-pretreated mice, GLP-1 at 0.1 nmol/kg could not augment the insulin response to intravenous glucose and no effect on glucose elimination was observed. Nevertheless, at the high dose of 10 nmol/kg, GLP-1 augmented the insulin response to glucose in capsaicin-pretreated mice as efficiently as in control mice. The insulin response to GLP-1 from isolated islets was not affected by neonatal capsaicin, and, furthermore, the in vivo insulin response to glucose was augmented whereas that to arginine was not affected by capsaicin. It is concluded that GLP-1-induced insulin secretion at a low dose in mice is dependent on intact sensory nerves and therefore indirectly mediated and that this distinguishes GLP-1 from other examined insulin secretagogues.

Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes

2004 ◽  
Vol 286 (6) ◽  
pp. E882-E890 ◽  
Author(s):  
David A. D'Alessio ◽  
Torsten P. Vahl
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Cell Mass ◽  
Insulin Response ◽  
Gastrointestinal Hormones ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Treatment Of Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) is a product of proglucagon that is secreted by specialized intestinal endocrine cells after meals. GLP-1 is insulinotropic and plays a role in the incretin effect, the augmented insulin response observed when glucose is absorbed through the gut. GLP-1 also appears to regulate a number of processes that reduce fluctuations in blood glucose, such as gastric emptying, glucagon secretion, food intake, and possibly glucose production and glucose uptake. These effects, in addition to the stimulation of insulin secretion, suggest a broad role for GLP-1 as a mediator of postprandial glucose homeostasis. Consistent with this role, the most prominent effect of experimental blockade of GLP-1 signaling is an increase in blood glucose. Recent data also suggest that GLP-1 is involved in the regulation of β-cell mass. Whereas other insulinotropic gastrointestinal hormones are relatively ineffective in stimulating insulin secretion in persons with type 2 diabetes, GLP-1 retains this action and is very effective in lowering blood glucose levels in these patients. There are currently a number of products in development that utilize the GLP-1-signaling system as a mechanism for the treatment of diabetes. These compounds, GLP-1 receptor agonists and agents that retard the metabolism of native GLP-1, have shown promising results in clinical trials. The application of GLP-1 to clinical use fulfills a long-standing interest in adapting endogenous insulinotropic hormones to the treatment of diabetes.

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