Glucagon-like peptide-2 acutely increases proximal small intestinal blood flow in TPN-fed neonatal piglets

Stephens, John; Stoll, Barbara J.; Cottrell, Jeremy J.; Chang, Xiaoyan; Helmrath, Michael A.; Burrin, Douglas G.

doi:10.1152/ajpregu.00588.2005

Cited by 58 publications

(53 citation statements)

References 37 publications

(49 reference statements)

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“…However, it is unknown how rapidly these cell signaling events are activated or how quickly the TPN-induced mucosal atrophy is reversed after GLP-2 treatment in vivo. We hypothesized that GLP-2 infusion in TPN-fed piglets would lead to rapid activation of cell signaling based on evidence that intestinal blood flow is significantly increased within 15 min of infusion (14,40). Our results indicate that GLP-2 infusion rapidly (1-4 h) induced intestinal PKA phosphorylation and putative downstream signals associated with increased cell survival, including PKB/ GSK-3/Bcl-2.…”

Section: Discussionmentioning

confidence: 86%

“…However, despite the recent evidence from cell culture studies, there are no in vivo studies confirming whether GLP-2 activates intestinal ERK1/2 signaling and whether this is associated with changes in crypt cell proliferation. Thus the aim of the current study was to further establish the physiological relevance of these signaling pathways in vivo by quantifying their temporal activation in piglets treated with GLP-2 for 1, 4, and 48 h. We were especially interested in the early activation of these two apparently divergent pathways and their association with intestinal epithelial cell survival and proliferation because previous evidence showed that GLP-2 maximally increases small intestinal blood flow within 30 min after infusion in neonatal piglets (14,15,40). .…”

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confidence: 99%

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GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets

Burrin

Stoll²,

Guan³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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We previously demonstrated the dose-dependent glucagon-like peptide (GLP)-2 activation of intracellular signals associated with increased epithelial cell survival and proliferation in the neonatal intestine. Our current aim was to quantify the acute, temporal GLP-2 activation of these key intracellular signals and relate this to changes in epithelial cell survival and proliferation in the neonatal intestine. We studied 29 total parenteral nutrition-fed neonatal piglets infused intravenously with either saline (control) or human GLP-2 (420 μmol·kg−1·h−1) for 1, 4, or 48 h. GLP-2 infusion increased small intestinal weight, DNA and protein content, and villus height at 48 h, but not at 1 or 4 h. Intestinal crypt and villus apoptosis decreased and crypt cell proliferation and protein synthesis increased linearly with duration of GLP-2 infusion, but were statistically different from controls only after 48 h. Before the morphological and cellular kinetic changes, GLP-2 rapidly activated putative GLP-2 receptor downstream signals within 1–4 h, including phosphorylation of protein kinase A, protein kinase B, extracellular signal-regulated kinase 1/2, and the transcription factors cAMP response element-binding protein and c-Fos. GLP-2 rapidly suppressed caspase-3 activation and upregulated Bcl-2 abundance within 1 h, whereas there was an increase in apoptosis inhibitors X-linked inhibitor of apoptosis at 1 h and cellular inhibitor of apoptosis-2 at 4 and 48 h. We also show that the increased c-Fos and reduced active caspase-3 immunostaining after GLP-2 infusion was localized in epithelial cells. We conclude that GLP-2-induced activation of intracellular signals involved in both cell survival and proliferation occurs rapidly and precedes the trophic cellular kinetic effects that occur later in intestinal epithelial cells.

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets

Burrin

Stoll²,

Guan³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…The integrative GI responses to GLP-2 are mediated via the GLP-2 receptor, a member of the glucagon/secretin G protein-coupled receptor superfamily that is located on enteric (Bjerknes and Cheng, 2001) and vagal (Nelson et al, 2007) nerves, subepithelial myofibroblasts (Orskov et al, 2005), and a subset of intestinal epithelial cells . Activation of GLP-2 receptors regulates epithelial cell growth (Bjerknes and Cheng, 2001), reduces intestinal permeability (Estall and Drucker, 2006), increases mesenteric blood flow (Guan et al, 2006;Stephens et al, 2006), and promotes nutrient absorption (Nelson et al, 2007).…”

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confidence: 99%

GLP-2 Receptor Agonism Ameliorates Inflammation and Gastrointestinal Stasis in Murine Postoperative Ileus

Moore¹,

Peffer²,

Pirone³

et al. 2010

J Pharmacol Exp Ther

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Glucagon-like peptide 2 (GLP-2) is a pleiotropic intestinotrophic hormone that we hypothesized could lessen gastrointestinal inflammation associated with postoperative ileus (POI). To test this idea, the prophylactic timing and dose of a long-acting variant of human GLP-2 linked to the Fc portion of murine immunoglobulin G (IgG) (GLP-2/IgG) was optimized in a murine model of POI. Surgically treated mice received a single dose of GLP-2/IgG, IgG isotype control, or phosphate-buffered saline 1 to 48 h before small bowel surgical manipulation. The distribution of orally fed fluorescein isothiocyanate-dextran and histological analyses of myeloperoxidase-positive immune cells were determined 24 and 48 h postoperatively. TaqMan quantitative polymerase chain reaction was used to determine early changes in mRNA expression in the muscularis or mucosa. In

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“…GLP-2 analogs (Teduglutide, NPS Pharmaceuticals, Bedminster, NJ) have been the subject of clinical trials that have shown safety and efficacy in the promotion of intestinal growth in SBS patients (19,20). GLP-2 has subsequently been demonstrated to increase blood flow to the superior mesenteric artery (21)(22)(23) and portal vein (24). Increased blood flow is necessary during growth of the small bowel; however, the mechanism by which GLP-2 affects blood flow is unknown.…”

Section: Introductionmentioning

confidence: 99%

Glucagon-Like Peptide 2 Increases Efficacy of Distraction Enterogenesis

Ryo

Ralls

Feng

et al. 2013

Journal of Surgical Research

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Glucagon-like peptide-2 acutely increases proximal small intestinal blood flow in TPN-fed neonatal piglets

Abstract: . Glucagon-like peptide-2 acutely increases proximal small intestinal blood flow in TPN-fed neonatal piglets.

Cited by 58 publications

References 37 publications

GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets

GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets

GLP-2 Receptor Agonism Ameliorates Inflammation and Gastrointestinal Stasis in Murine Postoperative Ileus

Glucagon-Like Peptide 2 Increases Efficacy of Distraction Enterogenesis

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