GLP‐2 Administration Results in Increased Proliferation but Paradoxically an Adverse Outcome in a Juvenile Piglet Model of Short Bowel Syndrome

Pereira‐Fantini, Prue M.; Nagy, Éva; Thomas, Sarah; Taylor, Russell G.; Sourial, Magdy; Paris, M.C.J.; Holst, Jens J.; Fuller, Peter J.; Bines, Julie E

doi:10.1097/01.mpg.0000304449.46434.06

Cited by 40 publications

(59 citation statements)

References 45 publications

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“…Exogenous GLP-2 administration inhibits gastric acid secretion and gastric emptying [Wojdemann et al 1998[Wojdemann et al , 1999, stimulates intestinal blood flow [Guan et al 2006;Bremholm et al 2009Bremholm et al , 2011, increases intestinal barrier function [Benjamin et al 2000;Cani et al 2009] and enhances nutrient and fluid absorption in both preclinical and clinical models [Brubaker et al 1997;Jeppesen et al 2001Jeppesen et al , 2009. However, a paradoxical resistance to exogenous GLP-2-induced adaptation was reported in piglets [Pereira-Fantini et al 2008]. GLP-2 has also been suggested to have anti-inflammatory effects [Ivory et al 2008;Sigalet et al 2007].…”

Section: Glucagon-like Peptide 2 and Teduglutidementioning

confidence: 99%

Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome

Jeppesen

2012

Therap Adv Gastroenterol

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Short bowel syndrome results from surgical resection, congenital defect or diseaseassociated loss of absorption. Parenteral support (PS) is lifesaving in patients with short bowel syndrome and intestinal failure who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Together, the symptoms of short bowel syndrome and the inconvenience and complications in relation to PS (e.g. catheter-related blood steam infections, central thrombosis and intestinal failure associated liver disease) may impair the quality of life of patients. The aim of treatment is to maximize intestinal absorption, minimize the inconvenience of diarrhea, and avoid, reduce or eliminate the need for PS to achieve the best possible quality of life for the patient. Conventional treatments include dietary manipulations, oral rehydration solutions, and antidiarrheal and antisecretory treatments. However, the evidence base for these interventions is limited and treatments that improve the structural and functional integrity of the remaining intestine are needed. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth and possibly by restoring gastric emptying and secretion, thereby reducing intestinal losses and promoting intestinal absorption. In a 3-week, phase II balance study, teduglutide reduced diarrhea by around 700 g/day and fecal energy losses by around 0.8 MJ/day. In two randomized, placebo-controlled, 24-week, phase III studies, similar findings were obtained when evaluating the fluid composite effect, which is the sum of the beneficial effects of teduglutide -reduction in the need for PS, increase in urine production and reduction in oral fluid intake. The fluid composite effect reflects the increase in intestinal fluid absorption (and the concomitant reduction in diarrhea) and may be used in studies in which metabolic balance assessments are not performed. In studies of up to 24 weeks' duration, teduglutide appears to be safe and well tolerated. Treatment with teduglutide was associated with enhancement or restoration of the structural and functional integrity of the remaining intestine with significant intestinotrophic and proabsorptive effects, facilitating a reduction in diarrhea and an equivalent reduction in the need for PS in patients with short bowel syndrome and intestinal failure.

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Section: Glucagon-like Peptide 2 and Teduglutidementioning

confidence: 99%

Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome

Jeppesen

2012

Therap Adv Gastroenterol

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“…In another study, newborn total parenteral nutrition-fed pigs were subjected to daily single administration of teduglutide for 7 days; as a result, small bowel growth was increased and minimal effect was elicited on digestive enzyme expression or nutrient absorption (Thymann et al, 2014a). However, GLP-2 treatment resulted in adverse outcomes, including decreased tissue maltase and sucrose in both sham and small bowel resection piglets (Pereira-Fantini et al, 2008). These different effects of GLP-2 on small intestinal brush border function may be dependent on gestational age at birth (Petersen et al, 2002), units of enzyme activities or GLP-2 analogues (Thymann et al, 2014b).…”

Section: Digestive Functionmentioning

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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“…In some cases, the pigs were younger than 7 days [21,29,34,37], but in most cases they were between 3 and 8 weeks [13,16,18,20,24,26,27,28,32,33]. In rare cases, older pigs (3-7 months) were chosen [5,7].…”

Section: Resultsmentioning

confidence: 99%

“…As anesthesia was not the focus of the analyzed models, it was often not described extensively and many authors did not explain how they performed anesthesia at all [20,23,26,32,33,36,38,39,40]. If mentioned, most often anesthesia with halothane and oxygen [17,18,21,24,27] or isoflurane [19,37] was performed, sometimes in combination with ketamine and azaperone [7].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Models of Short Bowel Syndrome in Pigs: A Technical Review

Weih

Nickkholgh²,

Keßler³

et al. 2013

Eur Surg Res

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Background: Short bowel syndrome (SBS) is still a life-threatening disease in both children and adults. Although the therapeutic options are improving, challenges still remain, and to overcome these challenges is a major focus of SBS research today. In order to simulate anatomical and physiological conditions similar to those in humans for research, porcine models of SBS are often used. Various approaches for generating SBS models have been described in the literature. Methods/Results: In this work, we present a review of different types of porcine models of SBS and outline the differences between those models regarding types of animals, surgical procedures, monitoring, and methods of assessment. Conclusion: The aim of this study was to select the most suitable SBS model regarding the purpose of the research.

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GLP‐2 Administration Results in Increased Proliferation but Paradoxically an Adverse Outcome in a Juvenile Piglet Model of Short Bowel Syndrome

Cited by 40 publications

References 45 publications

Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome

Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome

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

Models of Short Bowel Syndrome in Pigs: A Technical Review

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