A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice

1. Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone released postprandially that stimulates insulin secretion, suppresses glucagon secretion and delays gastric emptying. The insulinotropic action of GLP-1 is more potent under hyperglycaemic conditions. Several published studies have indicated the therapeutic potential of subcutaneous GLP-1 in non-insulin-dependent (Type 2) diabetes mellitus. 2. We investigated whether subcutaneous GLP-1, at a dose shown to improve glycaemic control in early Type 2 diabetes, is insulinotropic at normal fasting glucose concentrations. A double-blind, randomized, crossover study of 10 healthy subjects injected with GLP-1 or saline subcutaneously after a 16 h fast was performed. The effect on cardiovascular parameters was also examined. 3. GLP-1 caused a near 5-fold rise in plasma insulin concentration. After treatment with GLP-1, circulating plasma glucose concentrations fell below the normal range in all subjects. One subject had symptoms of hypoglycaemia after GLP-1. A rise in pulse rate was found which correlated with the fall in plasma glucose concentration. An increase in blood pressure occurred with GLP-1 injection which was seen at the same time as the rise in plasma GLP-1 concentrations. 4. This study indicates that subcutaneous GLP-1 can override the normal homoeostatic mechanism maintaining fasting plasma glucose in man, and is also associated with an increase in blood pressure.

Download Full-text

How glucagon-like peptide 1 receptor agonists work

Endocrine Connections ◽

10.1530/ec-21-0130 ◽

2021 ◽

Author(s):

Christine Rode Andreasen ◽

Andreas Andersen ◽

Filip Krag Knop ◽

Tina Vilsbøll

Keyword(s):

Body Weight ◽

Therapeutic Potential ◽

Clinical Effects ◽

Glucose Lowering ◽

Receptor Agonists ◽

Reduce Body Weight ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Clinical Utilisation

Recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of actions, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

Download Full-text

High-fat diet alters fluid intake without reducing sensitivity to glucagon-like peptide-1 receptor agonist effects

Physiology & Behavior ◽

10.1016/j.physbeh.2020.112910 ◽

2020 ◽

Vol 221 ◽

pp. 112910

Author(s):

K Linnea Volcko ◽

Quinn E Carroll ◽

Destiny J Brakey ◽

Derek Daniels

Keyword(s):

High Fat Diet ◽

Receptor Agonist ◽

Fluid Intake ◽

High Fat ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Download Full-text

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

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057114520971 ◽

2014 ◽

Vol 19 (6) ◽

pp. 847-858 ◽

Cited By ~ 9

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.

Download Full-text