Comprehensive Physiology Wiley Online Library

Glucagon‐like Peptide‐2 and the Regulation of Intestinal Growth and Function

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ABSTRACT

Glucagon‐like peptide‐2 (GLP‐2) is an intestinally derived hormone that enhances intestinal growth, digestion, absorption, barrier function, and blood flow in healthy animals as well as preventing damage and improving repair in preclinical models of enteritis and colitis and following massive small bowel resection. These beneficial effects of GLP‐2 on the intestinal tract are largely recapitulated in humans with intestinal failure. The high‐specificity of this peptide for the intestinal tract and the development of degradation‐resistant, long‐acting GLP‐2 receptor agonists have rapidly led to clinical implementation of GLP‐2‐based therapy for the treatment of patients with short bowel syndrome, with few reported side effects. This comprehensive review covers the biology of GLP‐2, from the control of proglucagon gene expression and the posttranslational processing of proglucagon to liberate GLP‐2 to the regulation of GLP‐2 secretion from the intestinal L cell, and from the mechanism of action of GLP‐2 through its highly localized receptor to the biological activities of GLP‐2 in the intestine and other restricted locations in the body, under physiological conditions as well as in animal models of intestinal disease and in patients with short bowel syndrome. Collectively, the history of GLP‐2 serves as a remarkable bench‐to‐bedside story of translational medicine. © 2017 American Physiological Society. Compr Physiol 8:1185‐1210, 2018.

Figure 1. Figure 1. Schematics of the proglucagon (Gcg) gene, mammalian mRNA transcript, prohormone, and intestinal proglucagon‐derived peptides (not exactly to scale). The vertical lines in the sequences of proglucagon and some of the proglucagon‐derived peptides represent consensus sites for cleavage by prohormone convertases (PCs). C, carboxyterminus; CPE, carboxypeptidase E; E, exon; GLP, glucagon‐like peptide; GRPP, glicentin‐related pancreatic peptide; I, intron; IP, intervening peptide; N, amino terminus; PAM, peptidyl α‐amidating monooxygenase; Sig, signal peptide/leader sequence; UTR, untranslated region.
Figure 2. Figure 2. Schematic of the intestinal L cell, which resides within the epithelial layer of the intestinal mucosa, and some of its known luminal, endocrine, and neural secretagogues and their signaling pathways. Involvement of the circadian clock genes is indicated by the “sun,” which permits entrainment of the L cell clock by nutrients, and is linked to the expression of Bmal1. The known L cell SNARE proteins include munc18‐1, SNAP25, synaptotagmin 7, syntaxin1a, and VAMP2. AC, adenylyl cyclase; CaSR, calcium‐sensing receptor; FATP4, fatty acid transporter 4; GIP, glucose‐dependent insulinotropic polypeptide; GPR, G‐protein‐coupled receptor; LCFA, long‐chain fatty acids; 2‐MG, 2‐monoglyceride; OEA, oleoylethanolamide; PLC, phospholipase C; PK, protein kinase; SCFA, short‐chain fatty acids; SGLT1, sodium‐glucose cotransporter‐1.
Figure 3. Figure 3. Schematic of the demonstrated indirect mechanisms of action of GLP‐2 to stimulate crypt cell proliferation and enhance intestinal barrier function in the small intestine. The arrow showing an interaction between ErbB and IGF‐1R is postulated based upon in vitro data. BBM, brush border membrane; CBC, crypt base columnar/active stem cell; EGF, epidermal growth factor; ErbB, family of receptors for EGF and related ligands; GLP‐2, glucagon‐like peptide‐2; IGF‐1, insulin‐like growth factor‐1; TJ, tight junction; R, receptor; RSC, reserve stem cell; TA, transit‐amplifying cell; VIP, vasoactive intestinal peptide.
Figure 4. Figure 4. Schematic of the main biological actions of GLP‐2 in the intestinal tract, including increased functional surface area, enhanced capacity for nutrient uptake, and improved barrier function. Of note, as the GLP‐2R is not expressed by the various cells that respond to this hormone, all of these biological activities are thought to be mediated indirectly, through one or more paracrine factors released by other intestinal cells that do express the GLP‐2R. CBC, crypt base columnar/active stem cell; EEC, enteroendocrine cell; RSC, reserve stem cell; TA, transit‐amplifying cell.


Figure 1. Schematics of the proglucagon (Gcg) gene, mammalian mRNA transcript, prohormone, and intestinal proglucagon‐derived peptides (not exactly to scale). The vertical lines in the sequences of proglucagon and some of the proglucagon‐derived peptides represent consensus sites for cleavage by prohormone convertases (PCs). C, carboxyterminus; CPE, carboxypeptidase E; E, exon; GLP, glucagon‐like peptide; GRPP, glicentin‐related pancreatic peptide; I, intron; IP, intervening peptide; N, amino terminus; PAM, peptidyl α‐amidating monooxygenase; Sig, signal peptide/leader sequence; UTR, untranslated region.


Figure 2. Schematic of the intestinal L cell, which resides within the epithelial layer of the intestinal mucosa, and some of its known luminal, endocrine, and neural secretagogues and their signaling pathways. Involvement of the circadian clock genes is indicated by the “sun,” which permits entrainment of the L cell clock by nutrients, and is linked to the expression of Bmal1. The known L cell SNARE proteins include munc18‐1, SNAP25, synaptotagmin 7, syntaxin1a, and VAMP2. AC, adenylyl cyclase; CaSR, calcium‐sensing receptor; FATP4, fatty acid transporter 4; GIP, glucose‐dependent insulinotropic polypeptide; GPR, G‐protein‐coupled receptor; LCFA, long‐chain fatty acids; 2‐MG, 2‐monoglyceride; OEA, oleoylethanolamide; PLC, phospholipase C; PK, protein kinase; SCFA, short‐chain fatty acids; SGLT1, sodium‐glucose cotransporter‐1.


Figure 3. Schematic of the demonstrated indirect mechanisms of action of GLP‐2 to stimulate crypt cell proliferation and enhance intestinal barrier function in the small intestine. The arrow showing an interaction between ErbB and IGF‐1R is postulated based upon in vitro data. BBM, brush border membrane; CBC, crypt base columnar/active stem cell; EGF, epidermal growth factor; ErbB, family of receptors for EGF and related ligands; GLP‐2, glucagon‐like peptide‐2; IGF‐1, insulin‐like growth factor‐1; TJ, tight junction; R, receptor; RSC, reserve stem cell; TA, transit‐amplifying cell; VIP, vasoactive intestinal peptide.


Figure 4. Schematic of the main biological actions of GLP‐2 in the intestinal tract, including increased functional surface area, enhanced capacity for nutrient uptake, and improved barrier function. Of note, as the GLP‐2R is not expressed by the various cells that respond to this hormone, all of these biological activities are thought to be mediated indirectly, through one or more paracrine factors released by other intestinal cells that do express the GLP‐2R. CBC, crypt base columnar/active stem cell; EEC, enteroendocrine cell; RSC, reserve stem cell; TA, transit‐amplifying cell.
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Teaching Material

P. L. Brubaker. Glucagon-like Peptide-2 and the Regulation of Intestinal Growth and Function. Compr Physiol 8: 2018, 1185-1210.

Didactic Synopsis

Major Teaching Points:

  • GLP-2 is peptide hormone synthesized by the enteroendocrine L cell.
  • GLP-2 is secreted in response to nutrient ingestion.
  • Intestinal expression of the 7-transmembrane G protein-coupled GLP-2 receptor is restricted to subepithelial myofibroblasts and subsets of enteric neurons and enteroendocrine cells; expression outside of the intestine is extremely limited.
  • GLP-2 enhances intestinal epithelial growth through increased proliferation and decreased apoptosis.
  • GLP-2 improves intestinal function, by increasing nutrient digestion and absorption, transit time, and blood flow as well as by improving barrier function and Paneth-cell mediated immune protection.
  • GLP-2 decreases intestinal damage and inflammation in models of enteritis and colitis.
  • A degradation-resistant, long-acting GLP-2 receptor agonist increases intestinal growth and function in both normal humans and patients with intestinal failure consequent to massive intestinal resection (short bowel syndrome).
  • The relative safety of an FDA-approved GLP-2 receptor agonist is explained, at least in part, by the highly targeted effects on intestinal growth and function.
  • The cellular mechanism of action of GLP-2 remains elusive, but requires the actions of multiple intermediary factors, including insulin-like growth factor-1 and epidermal growth factor.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Biosynthesis of the intestinal hormone, glucagon-like peptide-2 (GLP-2) is a multistep process. Transcription of the proglucagon gene (Gcg) produces the mRNA transcript for proglucagon, which is then translated to the proglucagon protein. Posttranslation processing of proglucagon in the intestinal L cell by prohormone convertase1/3, and removal of residual C–terminal basic residues by carboxypeptidase E, liberates the intestinal proglucagon-derived peptides, including the satiety factor oxyntomodulin, the incretin hormone GLP-1 (which also requires C-terminal amidation by the enzyme PAM) and GLP-2.

Figure 2 Teaching points: The intestinal L cell is localized in the epithelial layer of the distal small and large intestines, with apical microvilli that extend into the lumen and a basolateral membrane that is exposed to the blood as well as the nervous system. Circadian control of nutrient ingestion permits exposure of the L cell to luminal stimuli, including glucose, fatty acid, and amino acids, which increase GLP-2 secretion through a variety of different receptors and intracellular signaling pathways. Circulating hormones, including glucose-dependent insulinotrophic polypeptide (GIP) and insulin, also stimulate GLP-2 secretion, as do neurotransmitters, such as acetylcholine, from the nervous system, all of which also exert their effects through distinct receptors and signaling pathways. Collectively, the input from all of these sources results in controlled release of GLP-2 into the blood stream.

Figure 3 Teaching points: One of the major physiologic actions of GLP-2 is to increase intestinal crypt cell proliferation. Unexpectedly, the GLP-2 receptor (R) is not expressed by the crypt epithelial cells that respond to GLP-2 but, rather, is localized to subepithelial myofibroblast cells and some enteric nervous system (ENS) neurons (as well as rare enteroendocrine cells; not shown). Numerous studies to date have therefore shown that the actions of GLP-2 on the gut require indirect mediators. Hence, the actions of GLP-2 on the subepithelial myofibroblasts increase the production of another growth factor, insulin-like growth factor-1 (IGF-1). IGF-1 then acts on its receptor (IGF-1R) which is expressed on the intestinal stem cells (ISC) as well as on the epithelial cells—the actions of GLP-2 to increase proliferation and improve barrier function (by increasing the tightness of the tight junction (TJ) proteins connecting these cells) have been shown to require this IGF-1 signaling pathway. GLP-2 also increases production of epidermal growth factor (329) which acts on its own family of receptors (ErbB) to increase proliferation. The IGF-1 and ErbB receptors have been shown to work synergistically in some cell types although this remains to be established for the actions of GLP-2. Finally, GLP-2 increases the production of vasoactive intestinal peptide (VIP) from the ENS, which has been suggested to play a role in the actions of GLP-2 to enhance repair and reduce inflammation under conditions of intestinal damage.

Figure 4 Teaching points: The major biological actions of GLP-2 in the intestine include: stimulation of growth, through increased epithelial cell proliferation and survival; increased capacity for uptake of ingested nutrients, as demonstrated by increased digestive enzymes and nutrient transporter activity, increased length of the microvilli, where digestion and absorption occur, increased blood flow to deliver absorbed nutrients to the body, and increased transit time allowing greater exposure of ingested nutrients to the epithelial cells; and improved function as a barrier between toxic agents in the lumen (i.e., bacteria) and the blood supply, through increased expression of the tight junction proteins that couple neighboring cells together, and enhanced activity of the Paneth cells that secrete bactericidal agents.

 


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How to Cite

Patricia L. Brubaker. Glucagon‐like Peptide‐2 and the Regulation of Intestinal Growth and Function. Compr Physiol 2018, 8: 1185-1210. doi: 10.1002/cphy.c170055