Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice

Murali, Sangita G.; Brinkman, Adam S.; Solverson, Patrick; Pun, Wing; Pintar, John E.; Ney, Denise M.

doi:10.1152/ajpgi.00372.2011

Cited by 17 publications

(9 citation statements)

References 42 publications

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“…Evidence suggests that IGFBP-5 can potentiate the intestinotrophic action of IGF-I by increasing the availability of IGF-I to bind the IGF receptor (2,17) and that IGF-I action is dependent on expression of IGFBP-5 (43). Interestingly, we observed that the increased jejunal and systemic growth noted in groups provided PN ϩ EN ϩ GLP-2 was associated with increased jejunal expression of both IGF-I and IGFBP-5.…”

Section: Discussionmentioning

confidence: 53%

“…The mucosa was separated from the muscularis propria and serosa by having a single surgeon incise the segment of intestine longitudinally and carefully scrape the mucosa with a glass slide as previously reported (43). The first 2 cm (0 -2 cm) distal to the ligament of Treitz were used for measuring wet and dry intestinal mass, and the following 4 cm (2-6 cm) were used for RNA extraction and real-time quantitative PCR.…”

Section: Intestinal Composition Histology Enzyme Analysismentioning

confidence: 99%

“…Jejunal expression of IGFBP-5 was measured to explore the relationship between jejunal growth and expression of IGF-I given its modulation of IGF-I bioactivity (43). Treatment with TPN alone reduced IGFBP-5 expression to nearly undetectable levels compared with the oral reference group (Fig.…”

Section: Body Weight and Energy Intakementioning

confidence: 99%

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Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

Brinkman

Murali

Hitt

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that shows promise for the treatment of short bowel syndrome (SBS). Our objective was to investigate how combination GLP-2 + enteral nutrients (EN) affects intestinal adaption in a rat model that mimics severe human SBS and requires parenteral nutrition (PN). Male Sprague-Dawley rats were assigned to one of five groups and maintained with PN for 18 days: total parenteral nutrition (TPN) alone, TPN + GLP-2 (100 μg·kg(-1)·day(-1)), PN + EN + GLP-2(7 days), PN + EN + GLP-2(18 days), and a nonsurgical oral reference group. Animals underwent massive distal bowel resection followed by jejunocolic anastomosis and placement of jugular catheters. Starting on postoperative day 4, rats in the EN groups were allowed ad libitum access to EN. Groups provided PN + EN + GLP-2 had their rate of PN reduced by 0.25 ml/day starting on postoperative day 6. Groups provided PN + EN + GLP-2 demonstrated significantly greater body weight gain with similar energy intake and a safe 80% reduction in PN compared with TPN ± GLP-2. Groups provided PN + EN + GLP-2 for 7 or 18 days showed similar body weight gain, residual jejunal length, and digestive capacity. Groups provided PN + EN + GLP-2 showed increased jejunal GLP-2 receptor (GLP-2R), insulin-like growth factor-I (IGF-I), and IGF-binding protein-5 (IGFBP-5) expression. Treatment with TPN + GLP-2 demonstrated increased jejunal expression of epidermal growth factor. Cessation of GLP-2 after 7 days with continued EN sustained the majority of intestinal adaption and significantly increased expression of colonic proglucagon compared with PN + EN + GLP-2 for 18 days, and increased plasma GLP-2 concentrations compared with TPN alone. In summary, EN potentiate the intestinotrophic actions of GLP-2 by improving body weight gain allowing for a safe 80% reduction in PN with increased jejunal expression of GLP-2R, IGF-I, and IGFBP-5 following distal bowel resection in the rat.

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Section: Discussionmentioning

confidence: 53%

Section: Intestinal Composition Histology Enzyme Analysismentioning

confidence: 99%

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Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

Brinkman

Murali

Hitt

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…A strong case can be made for iSEMFs mediating the growth-promoting effects of GLP-2. Not only do iSEMFs express GLP-2 receptors, but they produce the growth factors insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) 23, 44, 45, 46. Both IGF-1 and EGF receptors are expressed in intestinal stem cells where they could affect intestinal growth.…”

Section: Paracrine Actions Of Eecsmentioning

confidence: 99%

Neuropods

Liddle

2019

Cellular and Molecular Gastroenterology and Hepatology

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Enteroendocrine cells (EECs) are sensory cells of the gut that communicate by releasing hormones locally through paracrine action or into the blood stream. Recently it has been discovered that EECs possess cytoplasmic processes known as neuropods that extend to distant cells including nerves. Thus, EECs regulate ingestive behavior through local, hormonal and neural signaling. Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Most EECs reside in the mucosal lining of the stomach or intestine and sense food in the gut lumen. Food signals stimulate the release of hormones into the paracellular space where they either act locally or are taken up into the blood and circulate to distant organs. It recently was recognized that many EECs possess basal processes known as neuropods that not only contain hormones but also connect to nerves. This review describes how neuropods contribute to EEC function beyond typical hormonal actions. For example, gastrointestinal hormones not only act on distant organs, but, through neuropods, some act locally to stimulate other mucosal cells such as intestinal stem cells, enterocytes, or other EECs. With the recent discovery that EECs communicate directly with enteric nerves, EECs not only have the ability to sense food and bacteria in the gastrointestinal tract, but can communicate these signals directly to the nervous system.

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“…Although multiple IGFBPs are expressed in the intestinal mucosa, IGFBP-3, -4, and -5 transcripts have been found at highest levels (1,17) Interestingly, IGFBP-3 and IGFBP-5 have previously been demonstrated to facilitate the growth effects of circulating IGF-1 on the gut, as the trophic effects of systemically administered IGF-1 were profoundly reduced in IGFBP-3/-5 double KO mice (23). In contrast, although IGFBP-4 has been shown to play an inhibitory role in epithelial growth in colorectal cancer cells (35), its role in regulating IGF-1 activity in the intestine is not well defined.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor-binding protein-4 inhibits epithelial growth and proliferation in the rodent intestine

Austin

Tsang

Chalmers

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Insulin-like growth factor-binding protein-4 (IGFBP-4) is a binding protein that modulates the action of insulin-like growth factor-1 (IGF-1), a growth factor whose presence is required for the intestinotrophic effects of glucagon-like peptide-2 (GLP-2). GLP-2 is a gut hormone that uses both IGF-1 and epidermal growth factor (EGF) as intermediary factors to promote intestinal growth. Therefore, to elucidate the mechanism through which IGFBP-4 regulates IGF-1 activity in the intestine, proliferation assays were conducted using rat intestinal epithelial cells (IEC-6). IGF-1 and EGF synergistically enhanced proliferation, an effect that was dose-dependently decreased by IGFBP-4 ( P < 0.05-0.001) in an IGF-1 receptor (R)- and MEK1/2- but not a phosphatidylinositol 3-kinase-dependent manner ( P > 0.05 for IGFBP-4 effects with IGF-1R and MEK1/2 inhibitors). Intestinal organoids derived from IGFBP-4 knockout mice demonstrated significantly greater Ki-67 expression and an enhanced surface area increase in response to IGF-1 treatment, compared with organoids from control mice ( P < 0.05-0.01). GLP-2 is also known to increase the mucosal expression of IGFBP-4 mRNA. To investigate whether this occurs through the actions of its intermediaries, IGF-1 and EGF, inducible intestinal epithelial-IGF-1R knockout and control mice were treated for 10 days with and without the pan-ErbB inhibitor, CI-1033. However, no differences in mucosal IGFBP-4 mRNA expression were found for any of the treatment groups ( P > 0.05). Consistently, IEC-6 cells treated with IGF-1 and/or EGF displayed no alteration in IGFBP-4 mRNA or in cellular and secreted IGFBP-4 protein ( P > 0.05). Overall, this study establishes that endogenous IGFBP-4 plays an important role in inhibiting IGF-1-induced intestinal epithelial proliferation and that mucosal IGFBP-4 expression is independent of IGF-1 and EGF. NEW & NOTEWORTHY This study demonstrates, for the first time, the inhibitory role of locally expressed insulin-like growth factor-binding protein-4 (IGFBP-4) on the intestinal proliferative actions of IGF-1 and supports the notion of the synergistic roles of IGF-1 and EGF in promoting intestinal epithelial growth. In turn, intestinal IGFBP-4 expression was not found to be regulated by IGF-1 and/or EGF.

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Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice

Cited by 17 publications

References 42 publications

Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

Neuropods

Insulin-like growth factor-binding protein-4 inhibits epithelial growth and proliferation in the rodent intestine

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