Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice
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Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice. / Wismann, Pernille; Pedersen, Søren L; Hansen, Gitte; Mannerstedt, Karin; Pedersen, Philip J; Jeppesen, Palle B; Vrang, Niels; Fosgerau, Keld; Jelsing, Jacob.
I: Physiology & Behavior, Bind 192, 2018, s. 72-81.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice
AU - Wismann, Pernille
AU - Pedersen, Søren L
AU - Hansen, Gitte
AU - Mannerstedt, Karin
AU - Pedersen, Philip J
AU - Jeppesen, Palle B
AU - Vrang, Niels
AU - Fosgerau, Keld
AU - Jelsing, Jacob
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1016/j.physbeh.2018.03.004
DO - 10.1016/j.physbeh.2018.03.004
M3 - Journal article
C2 - 29540315
VL - 192
SP - 72
EP - 81
JO - Physiology & Behavior
JF - Physiology & Behavior
SN - 0031-9384
ER -
ID: 216567040