Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice.

Abstract

AIM:

Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies.

METHODS:

A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice.

RESULTS:

Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analogue teduglutide. Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analogue liraglutide. Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestinotrophic effect on mainly the small intestine volume and surface area was obtained. In contrast to GUB09-123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestinotrophic effect.

CONCLUSION:

Our data demonstrate that the GLP-1/GLP-2 co-agonists have effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area. Furthermore, effects on glucose tolerance and long-term glycemic control are evident. Effects on body weight and gastric emptying are also observed depending on the pharmacokinetic properties of the molecule. We suggest that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS.

• Authors: Pernille Wismann, Søren L Pedersen, Gitte Hansen, Karin Mannerstedt, Philip J Pedersen, Palle B Jeppesen, Niels Vrang, Keld Fosgerau, Jacob Jelsing
• Journal: Physiology & behavior (Physiol Behav) Vol. 192 Pg. 72-81 (08 01 2018) ISSN: 1873-507X [Electronic] United States
• PMID: 29540315 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Gastrointestinal Agents
• Glucagon-Like Peptide 2
• Hypoglycemic Agents
• Peptides
• teduglutide
• Liraglutide
• Glucagon-Like Peptide 1
• Glucose

Topics

• Animals
• Body Weight (drug effects, physiology)
• Diabetes Mellitus, Experimental (drug therapy, physiopathology)
• Dose-Response Relationship, Drug
• Eating (drug effects, physiology)
• Gastrointestinal Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Gastrointestinal Tract (drug effects, physiopathology)
• Glucagon-Like Peptide 1 (agonists, metabolism)
• Glucagon-Like Peptide 2 (agonists, metabolism)
• Glucose (metabolism)
• Homeostasis (drug effects, physiology)
• Hypoglycemic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Liraglutide (pharmacology)
• Male
• Mice, Inbred C57BL
• Peptides (chemical synthesis, pharmacokinetics, pharmacology)
• Random Allocation