GLP-2 (human)

GLP-2(1-33) (human) is an enteroendocrine hormone which can bind to the GLP-2 receptor and stimulate the growth of intestinal epithelium. Sequence: His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp.

In Vitro:GLP-2-treated group demonstrates a 518±22% increase (P<0.05) in mucosal IGFBP-4 mRNA levels as compare with vehicle-treated controls. Because the mucosal expression of IGFBP-4 transcripts is found to be very low relative to that of the whole intestine, FRIC cultures are used as an in vitro model of the entire intestine. FRIC cultures have previously been established to express a functional GLP-2 receptor (GLP-2R) that displays a cAMP response, as well as enhances IGF-1 mRNA expression and IGF-1 secretion in response to GLP-2 treatment. When incubates with GLP-2 (10−8 M) for 2 hours, IGFBP-4 mRNA expression in the FRIC cultures is also found to be increased, by 40.8±15.2% (P<0.05), compare with vehicle-treated cells[1].

In Vivo:GLP-2 quickly increases apoB48 mass in the TRL fraction of plasma, which is indicative of chylomicron number, and this is blocked by L-NAME. GLP-2 treatment alone increases postprandial TRL-lipids (slope 3.65±0.73×10−3 g/L/min vs 1.63±0.28×10−3 g/L/min, GLP-2 vs control), and this effect is completely mitigated by L-NAME pretreatment (slope 3.67±0.15×10−4 g/L/min). The GLP-2-induced rise in TRL-apoB48 occurres within 30 minutes and precedes the rise in TRL-TG. GLP-2 acutely increases plasma tritium levels (slope, 1.66±0.25×102 dpm/mL/min vs 1.11±0.17×102 dpm/mL/min, GLP-2 vs control)[2].

References:
[1]. Kaori Austin, et al. IGF Binding Protein-4 is Required for the Growth Effects of Glucagon-Like Peptide-2 in Murine Intestine. Endocrinology. 2015 Feb; 156(2): 429-436. [2]. Hsieh J, et al. Glucagon-Like Peptide 2 (GLP-2) Stimulates Postprandial Chylomicron Production and Postabsorptive Release of Intestinal Triglyceride Storage Pools via Induction of Nitric Oxide Signaling in Male Hamsters and Mice. Endocrinology. 2015 Oct;156(10):3538-47.

Colonic GLP-2 is not sufficient to promote jejunal adaptation in a PN-dependent rat model of human short bowel syndrome.[Pubmed:19644131]

JPEN J Parenter Enteral Nutr. 2009 Nov-Dec;33(6):629-38; discussion 638-9.

BACKGROUND: Bowel resection may lead to short bowel syndrome (SBS), which often requires parenteral nutrition (PN) due to inadequate intestinal adaptation. The objective of this study was to determine the time course of adaptation and proglucagon system responses after bowel resection in a PN-dependent rat model of SBS. METHODS: Rats underwent jugular catheter placement and a 60% jejunoileal resection + cecectomy with jejunoileal anastomosis or transection control surgery. Rats were maintained exclusively with PN and killed at 4 hours to 12 days. A nonsurgical group served as baseline. Bowel growth and digestive capacity were assessed by mucosal mass, protein, DNA, histology, and sucrase activity. Plasma insulin-like growth factor I (IGF-I) and bioactive glucagon-like peptide 2 (GLP-2) were measured by radioimmunoassay. RESULTS: Jejunum cellularity changed significantly over time with resection but not transection, peaking at days 3-4 and declining by day 12. Jejunum sucrase-specific activity decreased significantly with time after resection and transection. Colon crypt depth increased over time with resection but not transection, peaking at days 7-12. Plasma bioactive GLP-2 and colon proglucagon levels peaked from days 4-7 after resection and then approached baseline. Plasma IGF-I increased with resection through day 12. Jejunum and colon GLP-2 receptor RNAs peaked by day 1 and then declined below baseline. CONCLUSIONS: After bowel resection resulting in SBS in the rat, peak proglucagon, plasma GLP-2, and GLP-2 receptor levels are insufficient to promote jejunal adaptation. The colon adapts with resection, expresses proglucagon, and should be preserved when possible in massive intestinal resection.

Naturally occurring glucagon-like peptide-2 (GLP-2) receptors in human intestinal cell lines.[Pubmed:16448646]

Eur J Pharmacol. 2006 Feb 17;532(1-2):18-23.

Although clinical trials with GLP-2 receptor agonists are currently ongoing, the mechanisms behind GLP-2-induced intestinal epithelial growth remain to be understood. To approach the GLP-2 mechanism of action this study aimed to identify intestinal cell lines endogenously expressing the GLP-2 receptor. Here we report the first identification of a cell line endogenously expressing functional GLP-2 receptors. The human intestinal epithelial cell line, FHC, expressed GLP-2 receptor encoding mRNA (RT-PCR) and GLP-2 receptor protein (Western blot). In cultured FHC cells, GLP-2 induced concentration dependent cAMP accumulation (pEC(50)=9.7+/-0.04 (mean+/-S.E.M., n=4)). In addition, a naturally occurring human intestinal fibroblast cell line, 18Co, endogenously expressing GLP-2 receptor encoding mRNA (RT-PCR) and protein (Western blot) was identified. No receptor functionality (binding or G-protein signalling) could be demonstrated in 18Co cells. The identified gut-relevant cell lines provide tools for future clarification of the mechanisms underlying GLP-2-induced epithelial growth.

GLP-2 receptors in human disease: high expression in gastrointestinal stromal tumors and Crohn's disease.[Pubmed:22951144]

Mol Cell Endocrinol. 2012 Nov 25;364(1-2):46-53.

Peptide hormones of the glucagon-like peptide (GLP) family play an increasing clinical role, as reported for GLP-1 in diabetes therapy and insulinoma diagnostics. GLP-2, despite its known trophic and anti-inflammatory intestinal actions translated into preliminary clinical studies using the GLP-2 analogue teduglutide for treatment of short bowel syndrome and Crohn's disease, remains poorly characterized in terms of expression of its receptor in tissues of interest. Therefore, the GLP-2 receptor expression was assessed in 237 tumor and 148 non-neoplastic tissue samples with in vitro receptor autoradiography. A GLP-2 receptor expression was present in 68% of gastrointestinal stromal tumors (GIST). Furthermore, GLP-2 receptors were identified in the intestinal myenteric plexus, with significant up-regulation in active Crohn's disease. The GLP-2 receptors in GIST may be used for clinical applications like in vivo targeting with radiolabelled GLP-2 analogues for imaging and therapy. Moreover, the over-expressed GLP-2 receptor in the myenteric plexus may represent the morphological correlate of the clinical target of teduglutide in Crohn's disease.

Human [Gly2]GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis.[Pubmed:9886982]

Am J Physiol. 1999 Jan;276(1):G79-91.

The pathology of Crohn's disease and ulcerative colitis is characterized by chronic inflammation and destruction of the gastrointestinal epithelium. Although suppression of inflammatory mediators remains the principle component of current disease therapeutics, strategies for enhancing repair and regeneration of the compromised intestinal epithelium have not been widely explored. The demonstration that a peptide hormone secreted by the intestinal epithelium, glucagon-like peptide-2 (GLP-2), is a potent endogenous stimulator of intestinal epithelial proliferation in the small bowel prompted studies of the therapeutic efficacy of GLP-2 in CD1 and BALB/c mice with dextran sulfate (DS)-induced colitis. We report here that a human GLP-2 analog (h[Gly2]GLP-2) significantly reverses weight loss, reduces interleukin-1 expression, and increases colon length, crypt depth, and both mucosal area and integrity in the colon of mice with acute DS colitis. The effects of h[Gly2]GLP-2 in the colon are mediated in part via enhanced stimulation of mucosal epithelial cell proliferation. These observations suggest that exploitation of the normal mechanisms used to regulate intestinal proliferation may be a useful adjunct for healing mucosal epithelium in the presence of active intestinal inflammation.

Glucagon-like peptide-2: divergent signaling pathways.[Pubmed:15313368]

J Surg Res. 2004 Sep;121(1):5-12.

BACKGROUND AND AIMS: Glucagon-like peptide 2 (GLP-2) is an endogenous hormone with potent and specific intestinotrophic activity in vivo and in vitro. The aim of this study was to define the initial signal transduction mechanisms mediating the proliferative actions of GLP-2 on intestinal epithelial cells. METHODS: The proliferative actions of GLP-2 on the human Caco-2 cell line were assessed. Specific G-protein inhibitors, pertussis and cholera toxin, were used to characterize the roles of early signal transduction mechanisms in mediating the proliferative actions of GLP-2 in these cells. RESULTS: GLP-2 directly stimulated proliferation in the Caco-2 cells. GLP-2 stimulated proliferation was (1) inhibited in a dose-dependent fashion by both pertussis and cholera toxin and (2) augmented by 2',5'-dideoxyadenosine. Proliferation rates were inversely proportional to changes in intracellular cAMP concentration. CONCLUSIONS: Our findings suggest that a G-protein-linked signaling pathway is involved with GLP-2 bioactivity in the intestinal epithelial cell line Caco-2.

GLP-2(1-33) (human) is an enteroendocrine hormone which can bind to the GLP-2 receptor and stimulate the growth of intestinal epithelium.

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