scholarly journals Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice

Diabetes ◽  
2009 ◽  
Vol 58 (10) ◽  
pp. 2258-2266 ◽  
Author(s):  
A. Pocai ◽  
P. E. Carrington ◽  
J. R. Adams ◽  
M. Wright ◽  
G. Eiermann ◽  
...  
Keyword(s):  
Glucagon Receptor ◽  
Obesity In Mice ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors

2014 ◽  
Vol 19 (6) ◽  
pp. 847-858 ◽  
Author(s):  
Lindsey C. Morris ◽  
Emily L. Days ◽  
Maxine Turney ◽  
Dehui Mi ◽  
Craig W. Lindsley ◽  
...  
Keyword(s):  
High Throughput ◽  
Allosteric Modulators ◽  
High Throughput Screen ◽  
Glucagon Receptor ◽  
Three Phase ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Orally Bioavailable ◽  
Glucagon Receptors

Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.

scholarly journals A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice

Hepatology ◽  
2017 ◽  
Vol 65 (3) ◽  
pp. 950-968 ◽  
Author(s):  
M. Pilar Valdecantos ◽  
Virginia Pardo ◽  
Laura Ruiz ◽  
Luis Castro-Sánchez ◽  
Borja Lanzón ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Glucagon Receptor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Dual Agonist

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.

scholarly journals Glucagon receptor family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Dominique Bataille ◽  
Susan L. Chan ◽  
Philippe Delagrange ◽  
Daniel J. Drucker ◽  
Burkhard Göke ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Gastric Inhibitory Polypeptide ◽  
Current Understanding ◽  
Glucagon Receptor ◽  
Endogenous Peptide ◽  
Common Precursor ◽  
Signaling Events ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Receptor Family

The glucagon family of receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [159]) are activated by the endogenous peptide (27-44 aa) hormones glucagon, glucagon-like peptide 1, glucagon-like peptide 2, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide), GHRH and secretin. One common precursor (GCG) generates glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 peptides [116]. For a recent review on review the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [87].

Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists

2017 ◽  
Vol 60 (10) ◽  
pp. 4293-4303 ◽  
Author(s):  
Andreas Evers ◽  
Torsten Haack ◽  
Martin Lorenz ◽  
Martin Bossart ◽  
Ralf Elvert ◽  
...  
Keyword(s):  
Glucagon Receptor ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1
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