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

Physiol Behav. 2018 Aug 1:192:72-81. doi: 10.1016/j.physbeh.2018.03.004. Epub 2018 Mar 11.

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.

Keywords: Co-agonist; Diabetes; GLP-1; GLP-2; Glucose homeostasis; Intestinal growth; Obesity; Short bowel syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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