Safety and Dosing Study of Glucagon‐Like Peptide 2 in Children With Intestinal Failure

Sigalet, David L.; Brindle, Mary; Boctor, Dana; Casey, Linda; Dicken, Bryan; Butterworth, Sonia A.; Lam, Viona; Karnik, Vikram; Heuvel, Elaine de; Hartmann, Bolette; Holst, Jens J.

doi:10.1177/0148607115609566

Cited by 27 publications

(28 citation statements)

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“…Thus, for patients dependent on TPN, a promising strategy to improve intestinal growth and maintain epithelial barrier function has been with the use of exogenous growth factors 56 . GLP-2 and GLP-2 analogues have been used successfully in TPN patients to promote intestinal adaptation, improve small intestinal surface area and absorptive function, and can facilitate withdrawal from parenteral nutrition 5, 6, 57. Similarly, EGF has been shown to have considerable benefit for pediatric patients with SBS and necrotizing enterocolitis 58, 59.…”

Section: Discussionmentioning

confidence: 99%

“…A more detailed understanding of the signaling pathways responsible for TPN-related intestinal complications therefore is needed to improve therapeutic options and clinical outcomes for patients dependent on TPN. Teduglutide, a stable analog of glucagon-like peptide 2 (GLP-2), is one new therapeutic approach that is undergoing extensive clinical trials for the treatment of patients with intestinal failure 5, 6. A recent report showed long-term teduglutide treatment was effective in reducing parenteral support in patients with short-bowel syndrome (SBS), 6 however, the mechanisms underlying the beneficial actions of GLP-2 and its analogs in the gut are complex and still poorly defined.…”

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confidence: 99%

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Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Yang

Demehri

Xiao

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsTotal parenteral nutrition (TPN), a crucial treatment for patients who cannot receive enteral nutrition, is associated with mucosal atrophy, barrier dysfunction, and infectious complications. Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) improve intestinal epithelial cell (IEC) responses and attenuate mucosal atrophy in several TPN models. However, it remains unclear whether these 2 factors use distinct or overlapping signaling pathways to improve IEC responses. We investigated the interaction of GLP-2 and EGF signaling in a mouse TPN model and in patients deprived of enteral nutrition.MethodsAdult C57BL/6J, IEC-Egfrknock out (KO) and IEC-pik3r1KO mice receiving TPN or enteral nutrition were treated with EGF or GLP-2 alone or in combination with reciprocal receptor inhibitors, GLP-2(3-33) or gefitinib. Jejunum was collected and mucosal atrophy and IEC responses were assessed by histologic, gene, and protein expression analyses. In patients undergoing planned looped ileostomies, fed and unfed ileum was analyzed.ResultsEnteral nutrient deprivation reduced endogenous EGF and GLP-2 signaling in mice and human beings. In the mouse TPN model, exogenous EGF or GLP-2 attenuated mucosal atrophy and restored IEC proliferation. The beneficial effects of EGF and GLP-2 were decreased upon Gefitinib treatment and in TPN-treated IEC-EgfrKO mice, showing epidermal growth factor–receptor dependency for these IEC responses. By contrast, in TPN-treated IEC-pi3kr1KO mice, the beneficial actions of EGF were lost, although GLP-2 still attenuated mucosal atrophy.ConclusionsUpon enteral nutrient deprivation, exogenous GLP-2 and EGF show strong interdependency for improving IEC responses. Understanding the differential requirements for phosphatidylinositol 3-kinase/phosphoAKT (Ser473) signaling may help improve future therapies to prevent mucosal atrophy.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Yang

Demehri

Xiao

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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“…Multiple growth factors have been identified that enhance adaptation in animal models, such as growth hormone, insulin-like growth factor-1, epidermal growth factor, glucagon-like peptide 2, and steroids 10 . Of these, growth hormone and glucagon-like peptide 2 have shown promising results in improving nutrient absorption and weight gain in human patients with SBS 11, 12, 13. In our study, RNA sequencing analysis did not show any significant difference in levels of mRNA for growth hormone receptor, epidermal growth factor, insulin-like growth factor-1, epidermal growth factor receptor, or glucagon-like peptide 2 receptor.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche

Wieck

Schlieve

Thornton

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsFor patients with short-bowel syndrome, intestinal adaptation is required to achieve enteral independence. Although adaptation has been studied extensively in animal models, little is known about this process in human intestine. We hypothesized that analysis of matched specimens with and without luminal flow could identify new potential therapeutic pathways.MethodsFifteen paired human ileum samples were collected from children aged 2–20 months during ileostomy-reversal surgery after short-segment intestinal resection and diversion. The segment exposed to enteral feeding was denoted as fed, and the diverted segment was labeled as unfed. Morphometrics and cell differentiation were compared histologically. RNA Sequencing and Gene Ontology Enrichment Analysis identified over-represented and under-represented pathways. Immunofluorescence staining and Western blot evaluated proteins of interest. Paired data were compared with 1-tailed Wilcoxon rank-sum tests with a P value less than .05 considered significant.ResultsUnfed ileum contained shorter villi, shallower crypts, and fewer Paneth cells. Genes up-regulated by the absence of mechanoluminal stimulation were involved in digestion, metabolism, and transport. Messenger RNA expression of LGR5 was significantly higher in unfed intestine, accompanied by increased levels of phosphorylated signal transducer and activator of transcription 3 protein, and CCND1 and C-MYC messenger RNA. However, decreased proliferation and fewer LGR5+, OLFM4+, and SOX9+ intestinal stem cells (ISCs) were observed in unfed ileum.ConclusionsEven with sufficient systemic caloric intake, human ileum responds to the chronic absence of mechanoluminal stimulation by up-regulating brush-border enzymes, transporters, structural genes, and ISC genes LGR5 and ASCL2. These data suggest that unfed intestine is primed to replenish the ISC population upon re-introduction of enteral feeding. Therefore, the elucidation of pathways involved in these processes may provide therapeutic targets for patients with intestinal failure. RNA sequencing data are available at Gene Expression Omnibus series GSE82147.

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“…In PN-dependent neonates with IF, Sigalet and colleagues reported positive correlation between serum GLP-2 levels and tolerance of enteral feeds [12]. In adult studies and preliminary data on children, GLP-2 and its long-acting synthetic analog, teduglutide, have been shown to improve nutrient and fluid absorption, weight gain, and to reduce PN requirements [8,13,14]. In this study, serum GLP-1 levels were decreased during PN, while serum GLP-2 levels were increased irrespective of whether or not patients were currently receiving PN.…”

Section: Discussionmentioning

confidence: 99%

“…In patients with IF, lack of feed-stimulated GLP-2 response may lead to poor intestinal adaptation [4,5,12]. Discovery of enterotrophic effects of GLP-2 has led to novel emerging treatment options in patients with IF [13,14]. A GLP-2 analog teduglutide has been shown to improve nutrient and fluid absorption, endorse mucosal hyperplasia, and decrease PN requirement in IF patients [13,15,16].…”

Section: Introductionmentioning

confidence: 99%

Serum fasting GLP-1 and GLP-2 associate with intestinal adaptation in pediatric onset intestinal failure

Mutanen

Pakarinen

2017

Clinical Nutrition

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Safety and Dosing Study of Glucagon‐Like Peptide 2 in Children With Intestinal Failure

Cited by 27 publications

References 23 publications

Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche

Serum fasting GLP-1 and GLP-2 associate with intestinal adaptation in pediatric onset intestinal failure

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