Porcine glucagon-like peptide-2: Structure, signaling, metabolism and effects

Pedersen, Nis Borbye; Hjøllund, Karina Rahr; Johnsen, Anders H.; Ørskov, Cathrine; Hartmann, Bolette; Holst, Jens J.

doi:10.1016/j.regpep.2007.11.003

Cited by 28 publications

(18 citation statements)

References 36 publications

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“…In fact, Thulesen et al (45) have reported positive accumulation of GLP-2 in rat liver but were not able to define whether this detection represented a specific receptor binding or a nonspecific metabolic fate. Moreover, Pedersen et al (36) have detected through mass spectrometry a positive extraction for the inactive metabolite of GLP-2 in pigs' liver and pointed to the existence of a hepatic uptake mechanism for GLP-2. In this work, we showed that the proliferative functions of GLP-2 are not restricted to the intestinal compartment but rather extend to a major role in liver regeneration.…”

Section: Discussionmentioning

confidence: 99%

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

El-Jamal

Erdual

Neunlist

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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The glucagon-like peptide 2 (GLP-2) is an intestinotrophic hormone with growth promoting and anti-inflammatory actions. However, the full biological functions of GLP-2 and the localization of its receptor (GLP-2R) remain controversial. Among cell lines tested, the expression of GLP-2R transcript was detected in human colonic myofibroblasts (CCD-18Co) and in primary culture of rat enteric nervous system but not in intestinal epithelial cell lines, lymphocytes, monocytes, or endothelial cells. Surprisingly, GLP-2R was expressed in murine (GLUTag), but not human (NCI-H716) enteroendocrine cells. The screening of GLP-2R mRNA in mice organs revealed an increasing gradient of GLP-2R toward the distal gut. An unexpected expression was detected in the mesenteric fat, mesenteric lymph nodes, bladder, spleen, and liver, particularly in hepatocytes. In two mice models of trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis, the colonic expression of GLP-2R mRNA was decreased by 60% compared with control mice. Also, GLP-2R mRNA was significantly downregulated in intestinal tissues of inflammatory bowel disease patients. Therapeutically, GLP-2 showed a weak restorative effect on intestinal inflammation during TNBS-induced colitis as assessed by macroscopic score and inflammatory markers. Finally, GLP-2 treatment accelerated mouse liver regeneration following partial hepatectomy as assessed by histological and molecular analyses. In conclusion, the limited therapeutic effect of GLP-2 on colonic inflammation dampens its utility in the management of severe inflammatory intestinal disorders. However, the role of GLP-2 in liver regeneration is a novelty that might introduce GLP-2 into the management of liver diseases and emphasizes on the importance of elucidating other extraintestinal functions of GLP-2.

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Section: Discussionmentioning

confidence: 99%

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

El-Jamal

Erdual

Neunlist

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, the short half-life (t 1/2 = 8.4 ± 0.9 min) of intact porcine GLP-2 (pGLP-2) caused by the cleavage of dipeptidyl peptidase-IV (DPP-IV) (Pedersen et al, 2008) requires frequent high-dosage administration in clinical applications. This shortage limits the development of pGLP-2 for the treatment of intestinal diseases of weaning piglets because frequent injection induces stress.…”

Section: Introductionmentioning

confidence: 99%

PEGylated porcine glucagon-like peptide-2 improved the intestinal digestive function and prevented inflammation of weaning piglets challenged with LPS

Deng

et al. 2015

Animal

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This study was conducted to determine the effects on intestinal function, anti-inflammatory role and possible mechanism of polyethylene glycosylated (PEGylated) porcine glucagon-like peptide-2 (pGLP-2), a long-acting form of pGLP-2, in weaning piglets challenged with Escherichia coli lipopolysaccharide (LPS). We divided 18 weaned piglets on day 21 into three groups (control, LPS and LPS + PEG-pGLP-2; n = 6). The piglets from the LPS + PEG-pGLP-2 group were injected with PEG-pGLP-2 at 10 nmol/kg BW from 5 to 7 days of the trials daily. On 8 th day, the piglets in the LPS and LPS + PEG-pGLP-2 groups were intraperitoneally administered with 100 µg LPS/kg. The control group was administered with the same volume of saline solution. The piglets were then sacrificed on day 28. Afterwards, serum, duodenum, jejunum and ileum samples were collected for analysis of structural and functional endpoints. LPS + PEG-pGLP-2 treatment increased ( P < 0.05) lactase activities in the duodenum and the jejunum compared with LPS treatment. LPS + PEG-pGLP-2 treatment also significantly increased sucrase activity in the jejunum compared with LPS treatment. Furthermore, LPS treatment increased ( P < 0.05) the mRNA expression levels of interleukin (IL)-8, tumour necrosis factor-α (TNF-α) and IL-10 in the ileum compared with the control treatment. By contrast, LPS + PEG-pGLP-2 treatment decreased ( P < 0.05) the mRNA expression levels of IL-8, IL-10 and TNF-α in the ileum compared with the LPS treatment. LPS treatment also increased ( P < 0.05) the mRNA expression level of GLP-2 receptor (GLP-2R) and the percentage of GLP-2R-positive cells in the ileum; by comparison, these results were ( P < 0.05) reduced by LPS + PEG-pGLP-2 treatment. Moreover, LPS + PEGpGLP-2 treatment increased ( P < 0.05) the content of serum keratinocyte growth factor compared with the control group and the LPS group. The protective effects of PEG-pGLP-2 on intestinal digestive function were associated with the release of GLP-2R mediator (keratinocyte growth factor) and the decrease in the expressions of intestinal pro-inflammatory cytokines.

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“…To provide references for the intestinal injury of weaned pigs by PEG–p[Gly 2 ]GLP-2, the pharmacokinetics of PEG–p[Gly 2 ]GLP-2 was conducted. The results showed that the half-life of p[Gly 2 ]GLP-2 and PEG–p[Gly 2 ]GLP-2 is 49 and 202 min in rat, respectively, which is longer than the half-life of intact pGLP-2 (8.4 min) [1]. PEGylated p[Gly 2 ]GLP-2 significantly improves the pharmacological profiles; increases half-time, peak time and mean residence time; decreases reduce clearance rate; and improves bioavailability [7].…”

Section: Discussionmentioning

confidence: 99%

“…Frequent injection of porcine glucagon-like peptide-2 (pGLP-2) because of the rapid degradation of pGLP-2 by the enzyme dipeptidyl peptidase-IV (DPP-IV) is the main impediment of pGLP-2 as a potential therapeutic agent for intestinal dysfunction and damage in weaning piglets [1]. For the first time, our team designed and purified polyethylene glycosylated (PEGylated) pGLP-2 (PEG-pGLP-2), whose half-life (t 1/2 ) is 16-fold longer than that of pGLP-2 in DPP-IV in vitro [2].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of different doses of polyethylene glycosylated porcine glucagon-like peptide-2 on ulcerative colitis in male rats

et al. 2017

BMC Gastroenterol

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Background: Polyethylene glycosylated (PEGylated) porcine glucagon-like peptide-2 (pGLP-2) considerably increases half-life and stability compared with the native pGLP-2, but the effective dose for intestinal damage is still unclear. This study aims to evaluate the available dose of polyethylene glycosylated porcine glucagon-like peptide-2 (PEG-pGLP-2), a modified, long-acting form of pGLP-2 in an experimental rat model of ulcerative colitis. Methods: Thirty-five male rats were randomly assigned into five groups: control, dextran sodium sulphate (DSS), DSS + PEG-pGLP-2(L), DSS + PEG-pGLP-2(M) and DSS + PEG-pGLP-2(H). Rats in control group received only water; other rats were fed with 5% (w/v) DSS and intraperitoneally administered with 12.5, 25 and 100 nmol/kg PEG-pGLP-2 daily for 6 days.

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Porcine glucagon-like peptide-2: Structure, signaling, metabolism and effects

Cited by 28 publications

References 36 publications

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

PEGylated porcine glucagon-like peptide-2 improved the intestinal digestive function and prevented inflammation of weaning piglets challenged with LPS

Therapeutic effects of different doses of polyethylene glycosylated porcine glucagon-like peptide-2 on ulcerative colitis in male rats

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