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

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. 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. 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. 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.