Early but not late administration of glucagon-like peptide-2 following ileo-cecal resection augments putative intestinal stem cell expansion

Expansion of intestinal progenitors and putative stem cells (pISC) occurs early and transiently following ileo-cecal resection (ICR). The mechanism controlling this process is not defined. We hypothesized that glucagon-like peptide-2 (GLP-2) would augment jejunal pISC expansion only when administered to mice immediately after ICR. Since recent reports demonstrated increases in intestinal insulin-like growth factor (IGF)-I following GLP-2 administration, we further hypothesized that increased intestinal IGF-I expression would correlate with pISC expansion following ICR. To assess this, GLP-2 or vehicle was administered to mice either immediately after resection (early) or before tissue harvest 6 wk following ICR (late). Histological analysis quantified proliferation and intestinal morphometrics. Serum levels of GLP-2 were measured by ELISA and jejunal IGF-I mRNA by qRT-PCR. Expansion of jejunal pISC was assessed by fluorescent-activated cell sorting of side population cells, immunohistochemistry for phosphorylated β-catenin at serine 552 (a pISC marker), percent of crypt fission, and total numbers of crypts per jejunal circumference. We found that early but not late GLP-2 treatment after ICR significantly augmented pISC expansion. Increases in jejunal IGF-I mRNA correlated temporally with early pISC expansion and effects of GLP-2. Early GLP-2 increased crypt fission and accelerated adaptive increases in crypt number and intestinal caliber. GLP-2 increased proliferation and intestinal morphometrics in all groups. This study shows that, in mice, GLP-2 promotes jejunal pISC expansion only in the period immediately following ICR. This is associated with increased IGF-I and accelerated adaptive increases in mucosal mass. These data provide clinical rationale relevant to the optimal timing of GLP-2 in patients with intestinal failure.

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T1818 Early Administration of Glucagon-Like Peptide-2 (GLP-2) Following Ileocecal Resection Augments Insulin-Like Growth Factor-I (IGF-I) Signaling During Intestinal Stem Cell Expansion

Gastroenterology ◽

10.1016/s0016-5085(08)62659-1 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-569-A-570

Author(s):

Aaron P. Garrison ◽

Christopher M. Dekaney ◽

Doug C. von Allmen ◽

P. Kay Lund ◽

Susan J. Henning ◽

...

Keyword(s):

Stem Cell ◽

Growth Factor ◽

Cell Expansion ◽

Intestinal Stem Cell ◽

Ileocecal Resection ◽

Early Administration ◽

Stem Cell Expansion ◽

Factor I ◽

Igf I ◽

Glucagon Like Peptide

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Sustained glucagon-like peptide-2 infusion is required for intestinal adaptation, and cessation reverses increased cellularity in rats with intestinal failure

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00367.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. G1222-G1230 ◽

Cited By ~ 19

Author(s):

Matthew C. Koopmann ◽

Xueyan Chen ◽

Jens J. Holst ◽

Denise M. Ney

Keyword(s):

Rat Model ◽

Jugular Vein ◽

Body Weight Gain ◽

Intestinal Adaptation ◽

Intestinal Failure ◽

Dry Mass ◽

Sucrase Activity ◽

Short Bowel ◽

Crypt Fission ◽

Glucagon Like Peptide

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived hormone that is a proposed treatment for human short bowel syndrome (SBS). The objective was to determine how the timing, duration, and cessation of GLP-2 administration affect intestinal adaptation and enterocyte kinetics in a rat model of human SBS that results in intestinal failure requiring total parenteral nutrition (TPN). Rats underwent 60% jejunoileal resection plus cecectomy and jugular vein cannulation and were maintained exclusively with TPN for 18 days in these treatments: TPN control (no GLP-2); sustained GLP-2 (1–18 days); early GLP-2 (1–7 days, killed at 7 or 18 days); and delayed GLP-2 (12–18 days). Body weight gain was similar across groups, and plasma bioactive GLP-2 was significantly increased with coinfusion of GLP-2 (100 μg·kg−1·day−1) with TPN. GLP-2-treated rats showed significant increases in duodenum and jejunum mucosal dry mass, protein, DNA, and sucrase activity compared with TPN control. The increased jejunum cellularity reflected significantly decreased apoptosis and increased crypt mitosis and crypt fission due to GLP-2. When GLP-2 infusion stopped at 7 days, these effects were reversed at 18 days. Sustained GLP-2 infusion significantly increased duodenum length and decreased 18-day mortality to 0% from 37.5% deaths in TPN control ( P = 0.08). Colon proglucagon expression quantified by real-time RT-qPCR was increased in TPN controls and attenuated by GLP-2 infusion; jejunal expression of the GLP-2 receptor did not differ among groups. In summary, early, sustained GLP-2 infusion reduces mortality, induces crypt fission, and is required for intestinal adaptation, whereas cessation of GLP-2 reverses gains in mucosal cellularity in a rat model of intestinal failure.

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Associations between prenatal serum levels of leptin, IGF-I, and estradiol and adolescent mothers’ height gain during and after pregnancy

PLoS ONE ◽

10.1371/journal.pone.0228706 ◽

2020 ◽

Vol 15 (2) ◽

pp. e0228706

Author(s):

Reyna Sámano ◽

Hugo Martínez-Rojano ◽

Gabriela Chico-Barba ◽

María Hernández-Trejo ◽

Raymundo Guzmán ◽

...

Keyword(s):

Adolescent Mothers ◽

Serum Levels ◽

Igf I ◽

Height Gain

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Combination of quantification and observation methods for study of “Side Population” cells in their “in vitro” microenvironment

Cytometry Part A ◽

10.1002/cyto.a.20367 ◽

2007 ◽

Vol 71A (4) ◽

pp. 251-257 ◽

Cited By ~ 8

Author(s):

Rachid Benchaouir ◽

Julien Picot ◽

Nicolas Greppo ◽

Philippe Rameau ◽

Daniel Stockholm ◽

...

Keyword(s):

Side Population ◽

Side Population Cells ◽

Observation Methods

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Glucagon-Like Peptide-2 Activates β-Catenin Signaling in the Mouse Intestinal Crypt: Role of Insulin-Like Growth Factor-I

Endocrinology ◽

10.1210/en.2007-0561 ◽

2007 ◽

Vol 149 (1) ◽

pp. 291-301 ◽

Cited By ~ 56

Author(s):

Philip E. Dubé ◽

Katherine J. Rowland ◽

Patricia L. Brubaker

Keyword(s):

Cell Proliferation ◽

Nuclear Translocation ◽

Glycogen Synthase ◽

Crypt Cell ◽

Acute Administration ◽

Intestinal Crypt ◽

Crypt Cell Proliferation ◽

Igf I ◽

Glucagon Like Peptide ◽

Crypt Cells

Chronic administration of glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism requiring IGF-I. However, the intracellular pathways through which IGF-I mediates GLP-2-induced epithelial tropic signaling remain undefined. Because β-catenin and Akt are important regulators of crypt cell proliferation, we hypothesized that GLP-2 activates these signaling pathways through an IGF-I-dependent mechanism. In this study, fasted mice were administered Gly2-GLP-2 or LR3-IGF-I (positive control) for 0.5–4 h. Nuclear translocation of β-catenin in non-Paneth crypt cells was assessed by immunohistochemistry and expression of its downstream proliferative markers, c-myc and Sox9, by quantitative RT-PCR. Akt phosphorylation and activation of its targets, glycogen synthase kinase-3β and caspase-3, were determined by Western blot. IGF-I receptor (IGF-IR) and IGF-I signaling were blocked by preadministration of NVP-AEW541 and through the use of IGF-I knockout mice, respectively. We found that GLP-2 increased β-catenin nuclear translocation in non-Paneth crypt cells by 72 ± 17% (P < 0.05) and increased mucosal c-myc and Sox9 mRNA expression by 90 ± 20 and 376 ± 170%, respectively (P < 0.05–0.01), with similar results observed with IGF-I. This effect of GLP-2 was prevented by blocking the IGF-IR as well as ablation of IGF-I signaling. GLP-2 also produced a time- and dose-dependent activation of Akt in the intestinal mucosa (P < 0.01), most notably in the epithelium. This action was reduced by IGF-IR inhibition but not IGF-I knockout. We concluded that acute administration of GLP-2 activates β-catenin and proliferative signaling in non-Paneth murine intestinal crypt cells as well as Akt signaling in the mucosa. However, IGF-I is required only for the GLP-2-induced alterations in β-catenin.

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