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.

scholarly journals GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action

2021 ◽  
Vol 12 ◽  
Author(s):  
Seunghun P. Lee ◽  
Jenson Qi ◽  
Guozhang Xu ◽  
Matthew M. Rankin ◽  
James Littrell ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
Dipeptidyl Peptidase 4 ◽  
Receptor Kinases ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Receptor Interacting Proteins ◽  
G Protein Coupled

The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.

scholarly journals Taspoglutide, an Analog of Human Glucagon-Like Peptide-1 with Enhanced Stability and in Vivo Potency

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2474-2482 ◽  
Author(s):  
Elena Sebokova ◽  
Andreas D. Christ ◽  
Haiyan Wang ◽  
Sabine Sewing ◽  
Jesse Z. Dong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Affinity Constant ◽  
Camp Production ◽  
Dipeptidyl Peptidase 4 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Taspoglutide is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide contains α-aminoisobutyric acid substitutions replacing Ala8 and Gly35 of hGLP-1(7-36)NH2. The binding affinity [radioligand binding assay using [125I]hGLP-1(7-36)NH2], potency (cAMP production in CHO cells stably overexpressing hGLP-1 receptor), and in vitro plasma stability of taspoglutide compared with hGLP-1(7-36)NH2 have been evaluated. Effects on basal and glucose-stimulated insulin secretion were determined in vitro in INS-1E cells and in vivo in normal rats. Taspoglutide has comparable affinity (affinity constant 1.1 ± 0.2 nm) to the natural ligand (affinity constant 1.5 ± 0.3 nm) for the hGLP-1 receptor and exhibits comparable potency in stimulating cAMP production (EC50 Taspo 0.06 nm and EC50 hGLP-1(7-36)NH2 0.08 nm). Taspoglutide exerts insulinotropic action in vitro and in vivo and retains the glucoincretin property of hGLP-1(7-36)NH2. Stimulation of insulin secretion is concentration dependent and evident in the presence of high-glucose concentrations (16.7 mm) with a taspoglutide concentration as low as 0.001 nm. Taspoglutide is fully resistant to dipeptidyl peptidase-4 cleavage (during 1 h incubation at room temperature with purified enzyme) and has an extended in vitro plasma half-life relative to hGLP-1(7-36)NH2 (9.8 h vs. 50 min). In vitro, taspoglutide does not inhibit dipeptidyl peptidase-4 activity. This study provides the biochemical and pharmacological basis for the sustained plasma drug levels and prolonged therapeutic activity seen in early clinical trials of taspoglutide. Excellent stability and potency with substantial glucoincretin effects position taspoglutide as a promising new agent for treatment of type 2 diabetes.

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

2019 ◽  
Vol 105 (4) ◽  
pp. e1549-e1560 ◽  
Author(s):  
Bénédicte Gaborit ◽  
Jean-Baptiste Julla ◽  
Samaher Besbes ◽  
Matthieu Proust ◽  
Clara Vincentelli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Fundus Photography ◽  
Endothelial Cell Proliferation ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Aims Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. Methods We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. Results In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. Conclusions The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

scholarly journals Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4171-4180 ◽  
Author(s):  
Takashi Nakakura ◽  
Chihiro Mogi ◽  
Masayuki Tobo ◽  
Hideaki Tomura ◽  
Koichi Sato ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Insulin Secretion ◽  
G Protein ◽  
Normal Glucose Tolerance ◽  
Extracellular Ph ◽  
G Protein Coupled Receptor ◽  
Glucose Stimulated Insulin Secretion ◽  
G Protein Coupled

Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of Gq/11 proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca2+ concentration. In conclusion, the OGR1/Gq/11 protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl.

scholarly journals Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes

2007 ◽  
Vol 192 (2) ◽  
pp. 371-380 ◽  
Author(s):  
Thomas H Claus ◽  
Clark Q Pan ◽  
Joanne M Buxton ◽  
Ling Yang ◽  
Jennifer C Reynolds ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Receptor Agonist ◽  
Antagonist Activity ◽  
Glucagon Receptor ◽  
Glucagon Receptor Antagonist ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9–39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.

RANTES (CCL5) reduces glucose-dependent secretion of glucagon-like peptides 1 and 2 and impairs glucose-induced insulin secretion in mice

2014 ◽  
Vol 307 (3) ◽  
pp. G330-G337 ◽  
Author(s):  
Ramona Pais ◽  
Tamara Zietek ◽  
Hans Hauner ◽  
Hannelore Daniel ◽  
Thomas Skurk
Keyword(s):  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Loss ◽  
Oral Glucose ◽  
Diabetes Therapy ◽  
Incretin Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Type 2 diabetes is associated with elevated circulating levels of the chemokine RANTES and with decreased plasma levels of the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 is a peptide secreted from intestinal L-cells upon nutrient ingestion. It enhances insulin secretion from pancreatic β-cells and protects from β-cell loss but also promotes satiety and weight loss. In search of chemokines that may reduce GLP-1 secretion we identified RANTES and show that it reduces glucose-stimulated GLP-1 secretion in the human enteroendocrine cell line NCI-H716, blocked by the antagonist Met-RANTES, and in vivo in mice. RANTES exposure to mouse intestinal tissues lowers transport function of the intestinal glucose transporter SGLT1, and administration in mice reduces plasma GLP-1 and GLP-2 levels after an oral glucose load and thereby impairs insulin secretion. These data show that RANTES is involved in altered secretion of glucagon-like peptide hormones most probably acting through SGLT1, and our study identifies the RANTES-receptor CCR1 as a potential target in diabetes therapy.

scholarly journals In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4–Fc fusion protein

RSC Advances ◽  
2017 ◽  
Vol 7 (85) ◽  
pp. 54178-54187 ◽  
Author(s):  
Lian Lu ◽  
Xiaoqing Su ◽  
Yantai Wang ◽  
Yi Luo ◽  
Jun Yang ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Antidiabetic Agent ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting ◽  
In Vivo Characterization

Exendin-4 (Ex-4), one of the important glucagon-like peptide-1 receptor (GLP-1R) agonists, has proven to be an effective antidiabetic agent for type 2 diabetes (T2D).

Glucagon and Glucagon-like Peptide-1 Receptors: Promising Therapeutic Targets for an Effective Management of Diabetes Mellitus

2020 ◽  
Vol 26 (4) ◽  
pp. 501-508
Author(s):  
Ghulam Abbas ◽  
Quazi M. I. Haq ◽  
Ahmad Hamaed ◽  
Mohammed Al-Sibani ◽  
Hidayat Hussain
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
G Protein ◽  
Treatment Modalities ◽  
Normal Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

: G-protein-coupled receptors (GPCRs) are membrane-bound proteins, which are responsible for the detection of extracellular stimuli and the origination of intracellular responses. Both glucagon and glucagon-like peptide-1 (GLP-1) receptors belong to G protein-coupled receptor (GPCR) superfamily. Along with insulin, glucagon and GLP-1 are critical hormones for maintaining normal serum glucose within the human body. Glucagon generally plays its role in the liver through cyclic adenosine monophosphate (cAMP), where it compensates for the action of insulin. GLP-1 is secreted by the L-cells of the small intestine to stimulate insulin secretion and inhibit glucagon action. Despite extensive research efforts and the multiple approaches adopted, the glycemic control in the case of type-2 diabetes mellitus remains a major challenge. Therefore, a deep understanding of the structure-function relationship of these receptors will have great implications for future therapies in order to maintain a normal glucose level for an extended period of time. The antagonists of glucagon receptors that can effectively block the hepatic glucose production, as a result of glucagon action, are highly desirable for the tuning of the hyperglycemic state in type 2 diabetes mellitus. In the same manner, GLP-1R agonists act as important treatment modalities, thanks to their multiple anti-diabetic actions to attain normal glucose levels. : In this review article, the structural diversity of glucagon and GLP-1 receptors along with their signaling pathways, site-directed mutations and significance in drug discovery against type-2 diabetes are illustrated. Moreover, the promising non-peptide antagonists of glucagon receptor and agonists of GLP-1 receptor, for the management of diabetes are presented with elaboration on the structure-activity relationship (SAR).

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