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 Unraveling oxyntomodulin, GLP1's enigmatic brother

2012 ◽  
Vol 215 (3) ◽  
pp. 335-346 ◽  
Author(s):  
Alessandro Pocai
Keyword(s):  
Weight Loss ◽  
Glycemic Control ◽  
Glucose Tolerance ◽  
Obese Mice ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Diabetes And Obesity ◽  
Dual Agonist

Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.

667-P: IBI362 (LY3305677), a Weekly-Dose Glucagon-Like Peptide-1/Glucagon Receptor Dual Agonist, in Subjects with Overweight or Obesity

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 667-P
Author(s):  
HONGWEI JIANG ◽  
PEI AN ◽  
HELENA DENG ◽  
LI LI ◽  
LIQI FENG ◽  
...  
Keyword(s):  
Weekly Dose ◽  
Glucagon Receptor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Dual Agonist ◽  
Overweight Or Obesity

A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects

2017 ◽  
Vol 138 ◽  
pp. 1158-1169 ◽  
Author(s):  
Jie Zhou ◽  
Xingguang Cai ◽  
Xun Huang ◽  
Yuxuan Dai ◽  
Lidan Sun ◽  
...  
Keyword(s):  
Protective Effects ◽  
Glucagon Receptor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Dual Agonist

scholarly journals Fibroblast Growth Factor 21 (FGF21) and Glucagon-Like Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor-Deficient Mice

Diabetes ◽  
2013 ◽  
Vol 63 (1) ◽  
pp. 101-110 ◽  
Author(s):  
B. A. Omar ◽  
B. Andersen ◽  
J. Hald ◽  
K. Raun ◽  
E. Nishimura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Glucagon Receptor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Deficient Mice

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 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 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.

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