The “cryptic” mechanism of action of glucagon-like peptide-2

Abstract

Glucagon-like peptide-2 (GLP-2) is a peptide hormone with multiple beneficial effects on the intestine, including expansion of the mucosal surface area through stimulation of crypt cell proliferation, as well as enhancement of nutrient digestion and absorption. Recent advances in clinical trials involving GLP-2 necessitate elucidation of the exact signaling pathways by which GLP-2 acts. In particular, the GLP-2 receptor has been localized to several intestinal cell types that do not include the proliferating crypt cells, and the actions of GLP-2 have thus been linked to a complex network of indirect mediators that induce diverse signaling pathways. The intestinotropic actions of GLP-2 on the colon have been shown to be mediated through the actions of keratinocyte growth factor and insulin-like growth factor (IGF)-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands, as well as the IGF-1 receptor and ErbB. The cellular source of these mediators remains unclear, but it likely includes the intestinal subepithelial myofibroblasts. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal polypeptide released from submucosal enteric neurons and nitric oxide, respectively. Finally, recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross-talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is clearly warranted.

Glucagon-Like Peptide 2 Increases Efficacy of Distraction Enterogenesis

“…Both distraction groups demonstrated a significantly increased rate of EC proliferation compared to the control group (p<0.01). EC proliferation was also significantly increased in the GLP-2 control compared to the Control group (p<0.05); and this was consistent with previously reported literature (15). The GLP-2 stretch group showed significantly greater EC proliferation compared to the PEG stretch group; and the GLP-2 stretch group had the greatest rate of EC proliferation of all groups studied (p<0.05).…”

“…Recent studies describe GLP-2's action to be associated with increased EC proliferation, crypt fission and an increase in villus height (15). Other reports on the administration of exogenous GLP-2 have shown the growth factor to increase wet weights of rodent jejunum and ileum, enhance crypt cell proliferation, reduce enterocyte apoptosis, and increase thickness of the epithelial mucosa (16)(17)(18).…”

Food intake in lean and obese mice after peripheral administration of glucagon-like peptide 2

“…After secretion, GLP2 is degraded by the enzyme dipeptidyl peptidase-IV (DPP-IV), which renders the peptide inactive by N-terminal truncation of the alanine at position 2 . The degradation-resistant analog of GLP2, [Gly 2 ]GLP2 has increased efficacy compared with native GLP2 and is currently in clinical trials as a therapeutic for a variety of intestinal insufficiencies and diseases (Rowland & Brubaker 2011). …”

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

“…GLP-2 has mainly trophic effects on the intestine including enhancement of crypt cell proliferation, inhibition of apoptosis, and stimulation of nutrient digestion and absorption (38). GLP-2 regulates the size and integrity of the gut following insult, as well as in response to disease and altered nutrient status (8,11).…”