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Abstract

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References

Summary

Background

Glucagon-like peptide 2 (GLP-2) is an important peptide growth factor secreted from the human intestine. The trophic properties of GLP-2 are very specific to the gut where it is pivotal in the regulation of mucosal morphology, function and integrity.

Aims

This review details the current understanding of the molecular biology of GLP-2, its mechanisms of action and physiological properties. A major focus is the discussion of recent clinical data evaluating the use of GLP-2 as a therapeutic agent.

Methods

Relevant articles were identified using Medline searches and from the reference lists of key papers.

Results and Conclusions

In the treatment of short bowel syndrome, GLP-2 has been shown to be highly effective in improving fluid absorption. In Crohn's disease, GLP-2 is superior to placebo in the induction of remission. Early data also suggest that the effects of GLP-2 on bone metabolism can provide a new treatment approach for patients with osteoporosis. In the future, the positive effects of GLP-2 on intestinal barrier function, splanchnic perfusion and mucosal healing could be utilized to expand its therapeutic application to other causes of intestinal injury. However, important safety aspects need to be considered when using this potent growth-promoting agent for a long term.


Understanding GLP-2 At Molecular level

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References

Glucagon-like peptide 2 (GLP-2) was first recognized as a growth factor in the intestine in 1996.1 It is a 33-amino-acid peptide, formed from the cleavage of proglucagon, a large prohormone that is mainly expressed in pancreas, intestine and brain. Alternative splicing of proglucagon through prohormone convertases leads to the tissue-specific release of GLP-2 and other peptides with diverse biological properties (Figure 1; Table 1).

image

Figure 1.  Main products of proglucagon processing (partial processing is indicated by dashed arrows).

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Table 1.   Function of proglucagon-derived peptides
Proglucagon-derived peptidesBiological effect
GlucagonRegulation of glucose homeostasis
Glucagon-like peptide 1Stimulation of glucose-dependent insulin synthesis and secretion
Inhibition of glucagon secretion
Inhibition of gastric emptying
Control of satiety and food intake
Glucagon-like peptide 2Stimulation of intestinal mucosal growth
Upregulation of nutrient absorption
Inhibition of gastric emptying and acid secretion
Reduction of intestinal permeability
Stimulation of intestinal blood flow
Reduction of nutrient-dependent bone resorption
GlicentinUnclear (possible effect on insulin secretion, gastric acid secretion, intestinal motility and growth)
OxyntomodulinControl of satiety
Inhibition of food intake
Possible effect on gastric acid secretion and intestinal motility
Major proglucagon fragmentUnclear (? by-product)

Intestinal GLP-2 is produced in L cells, a subset of enteroendocrine cells that are abundant in the distal jejunum, ileum and colon. Secretion is subject to complex mechanisms that are not yet fully understood. Some regulatory pathways must be hypothesized from studies of GLP-1, which is cosecreted alongside GLP-2. Nutrient challenges produce a biphasic rise of GLP-2.2 A rapid postprandial increase of GLP-2 is thought to be caused by early indirect L-cell stimulation through neurohumoural signalling, which is followed by a later second rise, triggered by direct L-cell stimulation through nutrients reaching the distal intestine. Postprandial GLP-2 secretion depends on nutrient composition and calorie content. Luminal carbohydrates and lipids have been established as potent GLP-2 secretagogues in humans.2–4 A number of studies have demonstrated a positive effect of short-chain fatty acids (SCFAs) on proglucagon mRNA abundance and GLP-2 secretion.5,6 Although reports of the GLP response following protein ingestion vary,2,7 results from cell line studies have indicated a strong stimulatory effect of glutamine on GLP secretion.8 There is evidence that bile acids play a role in GLP release, possibly mediated through a novel bile acid receptor TGR5.9

Glucagon-like peptide 2 is degraded through cleavage of N-terminal histidine and alanine (Figure 2) by the ubiquitously expressed proteolytic enzyme dipeptidyl peptidase IV (DPPIV). The half-life of intravenous GLP-2 is 7 min in healthy humans.10 Blocking of DPPIV degradation, either through Gly2 substitution (Figure 2) as in teduglutide (NPS Pharmaceuticals, Persipanny, NJ, USA) or through adjuvant use of DPPIV inhibitors, extends the half-life of GLP-2,11,12 and confers greater biological potency.13 The kidneys play a key role in GLP-2 clearance. Increased levels have been demonstrated in humans with chronic renal failure.14

image

Figure 2.  Amino acid sequence of biologically active human GLP-2 (1–33), its main degradation product GLP-2 (3–33) and the long-acting GLP-2 analogue Gly2-GLP-2 (derived through substitution of alanine for glycine at position 2).

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Glucagon-like peptide 2 acts through a specific G-protein-coupled receptor (GLP-2R), which is predominantly located in the proximal small intestine.15,16 It has also been demonstrated in brain and lung tissue, albeit in much smaller quantities.16 There has been a recent report of GLP-2 receptor presence in osteoclasts.17 The precise cellular location of the GLP-2R within the gastrointestinal tract has not yet been conclusively established and may differ between species. In humans, receptors have been demonstrated in enteroendocrine cells,16,18 enteric neurons18 and also subepithelial myofibroblasts.19

Physiological role, pharmacological effects and mechanisms of action

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References

Glucagon-like peptide 2 is associated with intestinal growth and adaptation in a variety of pathological conditions, including post-resection intestinal adaptation,20,21 coeliac disease,22 parental nutrition-induced intestinal atrophy23 and inflammatory bowel disease (IBD).24 Studies of GLP-2 deficiency models add strong evidence that GLP-2 is an important factor in the physiological regulation of intestinal growth.25,26

Glucagon-like peptide 2 treatment induces mucosal growth in small and, to a lesser degree, large bowel.1,27–29 Intestinotrophic effects of GLP-2 are mediated through an increase of intestinal crypt cell proliferation and a reduction of villous cell apoptosis resulting in expansion of villous height and, less consistently, crypt depth (Figure 3). Epithelial cells undergo morphological changes, become narrower and longer with elongated microvilli. The trophic effects are more pronounced in the proximal small intestine. After treatment cessation, all changes of intestinal morphology rapidly reverse. There is no effect on intestinal muscle. The GLP-2-related increase of intestinal mass is accompanied by enhanced intestinal digestive and absorptive functional capacity as indicated by enhanced expression and activity of brush border enzymes and absorption of nutrients.30–32

image

Figure 3.  Effect of GLP-2 on murine small intestine. (a) Normal murine small intestine, (b) after 10 days of GLP-2 administration. (Reproduced with permission from Drucker et al.1, © copyright 1996 National Academy of Sciences, USA).

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Glucagon-like peptide 2 infusion in healthy humans reduces stimulated gastric acid secretion but has no effect on basal acid or volume secretion.33 Although GLP-2 inhibits gastrointestinal motility in animal models,34 results from human studies are conflicting.33,35,36 GLP-2 has beneficial effects on intestinal barrier function in rodent models of necrotising pancreatitis,37 food allergy,38 psychological stress39 and thermal injury.40

Glucagon-like peptide 2 causes a rapid upregulation of intestinal blood flow,18,41 probably at least in part through the mediation of nitric oxide.18,42 The GLP-2R has also been colocalized with vasoactive intestinal peptide in enteric neurons and with 5-hydroxytryptamine (serotonin) in enteroendocrine cells.18 As both substances are known to have a potent vasoactive effect on mesenteric blood flow, they too could represent relevant downstream mediators.

Glucagon-like peptide 2 forms part of a larger group of humoural factors, known to affect intestinal growth (Table 2). Although the individual growth-promoting properties of these factors have been well documented, less is known about how they interact. Several factors, including epidermal growth factor, appear to act synergistically with GLP-2.29,43 Nutritional factors like glutamine and SCFAs might exert their growth-enhancing properties by facilitating GLP-2 production and release,6,8 whereas growth factors like keratinocyte growth factor and insulin-like growth factor 1 may act as downstream mediators.19,44

Table 2.   Intestinotrophic growth factors
Growth hormone (GH)
Glucagon-like peptide 2 (GLP-2)
Insulin-like growth factor 1 (IGF-1)
Epidermal growth factor (EGF)
Hepatocyte growth factor (HGF)
Transforming growth factor α (TGF-α)
Keratinocyte growth factor (KGF)
Neurotensin
Leptin
R-Spondin
Glutamine
SCFAs

For more in-depth information about the molecular biology and physiology of proglucagon-derived peptides and their receptors, readers are encouraged to refer to the reviews by Shin et al.45 and Sinclair and Drucker,46 and to the comprehensive web resource provided by Dr Daniel J. Drucker.47

GLP-2 As Therapy: present and future

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References

In short bowel syndrome (SBS), the remnant bowel undergoes a period of morphological and functional adaptation, which is more effective when the residual intestine is ileum rather than jejunum. Those with end jejunostomy and no colon, who have the poorest intestinal adaptation, have a markedly impaired postprandial GLP-2 response, presumably caused by a lack of functioning L-cell mass.48 In contrast, short bowel patients with a preserved colon exhibit increased fasting GLP-2 levels with a postprandial profile comparable to that of healthy controls.21 These findings, combined with strong evidence of a correlation between GLP-2 and intestinal adaptation in animal models, have raised hopes that GLP-2 therapy might be able to produce clinically meaningful enhancement of intestinal mass and function in patients with a short bowel.

This was confirmed when native GLP-2 was given to eight ileum-resected SBS patients in an open-label study for 35 days (400 μg, twice daily subcutaneous injection).36 Significant improvement of the absolute (420 ± 480 g/day; mean ± s.d.) and relative (10.6% ± 11.6%) wet weight absorptions and small increases in relative energy absorption (3.5% ± 4%) were demonstrated. Small increases in macronutrient and electrolyte absorption were observed, with relative absorption of nitrogen (4.7% ± 5.4%) and potassium (4.85% ± 10.2%) achieving significance. There was an overall increase in mean body weight (1.2 ± 1 kg), lean body mass (2.9 ± 1.9 kg) and a small increase in bone mass (100 g). Gastric emptying time for solids was increased, but there was no difference in overall gastrointestinal transit.

Following on from these encouraging results; the long-acting GLP-2 analogue teduglutide was tested in an uncontrolled open-label trial for 21 days in 16 short bowel patients in whom 6 had a preserved colon (0.03, 0.10 and 0.15 mg/kg/day, once daily subcutaneous injection). A subgroup of five patients was subsequently rechallenged with twice daily dosing.11

Again, the most noteworthy result was the significant increase in absolute (743 ± 477 g/day) and relative (22% ± 16%) wet weight absorptions. The magnitude of this effect was almost doubled when compared with the effect of native GLP-2. There was a decrease of faecal sodium and potassium loss with a significant increase of relative sodium absorption equal to a mean of 38% of intake. Effects on energy and macronutrient absorption were comparatively minor. There was an overall decrease in faecal energy excretion. Effects on absolute and relative energy absorption were shown to be significant in certain subgroups. Small increases in fat, carbohydrate and nitrogen absorption did not reach significance. There was no overall increase in body weight, although a numerical trend was seen.

Both studies reported good drug compliance, tolerance and safety profile. The most common adverse events were oedema of the lower limbs, stomal swelling (which can be interpreted as a positive sign of mucosal hypertrophy), headache and abdominal pain. There were no serious adverse events linked to the study drug.

It appears that GLP-2 is a highly effective agent in improving fluid absorption in steady-state patients considered to have received optimal conventional management. Less anticipated was the observation that similar results were achieved in patients with and without preserved colon, which implies that supraphysiological GLP-2 treatment levels exert additional benefit. It could also be inferred that treatment with GLP-2 might be especially useful for SBS patients who mainly require fluid and/or electrolyte replacement. The clinical benefit may be particularly pronounced in a subgroup of patients whose parenteral requirements are ‘borderline’ and in whom a small volume reduction could mean a discontinuation of parenteral support, thereby avoiding the many complications that this incurs. But even in patients with need for substantial parenteral support, a reduction of infusion volume will grant greater flexibility and personal freedom. For patients with an end jejunostomy, the reduced faecal wet weight can make a significant difference in the consistency and frequency of their stomal output, again with important implications for their quality of life. A beneficial role of GLP-2 could also be envisaged for the treatment of patients who suffer from postsurgical acute or chronic high stomal output without being parental nutrition dependent.

The promising results of these pilot studies have paved the way for a phase 3 multicentre trial that is currently underway to evaluate the efficacy of long-term treatment with teduglutide in patients with stable SBS.49

In rodent models of IBD, local deficiency of GLP-2 in the inflamed mucosa has been demonstrated,24 providing a rationale for trials of therapeutic GLP-2 replacement. In mice with dextran-sulphate-sodium-induced colitis50 and in HLA-B27 transgenic rats with IBD,51,52 GLP-2 treatment reduces mortality, weight loss, diarrhoea, mucosal damage and expression of inflammatory cytokines.

The outcome of the first phase 2 clinical study of teduglutide has recently been presented in abstract form.53 This 8-week trial compared teduglutide (0.05, 0.1 or 0.2 mg/kg/day once daily as a subcutaneous injection) with placebo in 100 patients with moderate-to-severe Crohn's disease [Crohn's disease activity index (CDAI) 220–450]. Although there was a high placebo response, the results suggested a dose-dependent benefit. At week 2, 36.8% of patients receiving the highest dose of teduglutide compared with 16.7% of the placebo group reached clinical remission (CDAI ≤ 150). By week 8, 55.6% of patients in the highest dose group were in remission compared with 33.3% of the placebo group. Further data are needed to determine whether these results mainly relate to symptomatic disease control (e.g. decrease in stool frequency secondary to enhanced fluid absorption) or reflect decreases in inflammatory activity and improved mucosal healing.

A role for GLP-2 as treatment for osteoporosis appears possible as a dose-dependent reduction of bone resorption7,54 and stimulation of bone formation54 has been demonstrated in healthy postmenopausal women. The presence of GLP-2Rs in osteoclasts17 suggests that GLP-2 may form part of an ‘entero-osseous axis’,7 coordinating nutrient-dependent bone turnover.

In a first clinical evaluation of this effect, a significant increase in total bone mass (100 g) and spinal bone mineral density (1.1% ± 0.4%) was demonstrated in ileum-resected SBS patients, after 35 days of treatment with native GLP-2.55 Effects of longer term treatment with teduglutide are currently under investigation.49

The growth-promoting properties of GLP-2 in the setting of parenteral-nutrition-induced mucosal atrophy have been clearly demonstrated in animal models.28,56 In humans, exclusive parenteral nutrition is responsible for less dramatic morphological and functional changes in the intestine, but a potential benefit of GLP-2 treatment (e.g. in a critical care setting) could be postulated and awaits clinical evaluation.

Animal models also indicate beneficial effects of GLP-2 in chemotherapy-induced,57 radiotherapy-induced58 and nonsteroidal-induced59 enteritis. Improved survival, with less weight loss and mucosal damage may reflect reduction in apoptosis as well as enhancement of intestinal barrier function and subsequent reduction in bacterial sepsis. Human studies have to date been limited, given the finding of GLP-2 receptors on cancer cell lines,16,60 and the concern that tumour growth might be stimulated.61

In rodent models of ischaemia–reperfusion injury, GLP-2 treatment improves mucosal mass, morphology, nutrient absorption and reduces bacterial translocation.62 As there are also stimulatory effects on splanchnic perfusion, a role for GLP-2 in augmenting blood flow and minimizing tissue ischaemia could be envisaged in acute mesenteric ischaemia, intestinal transplantation and necrotizing enterocolitis.

Potential dangers

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References

There are legitimate concerns about carcinogenesis linked to long-term use of growth factors. In the case of GLP-2, receptor expression has been demonstrated in human intestinal carcinoid tumours and cervical cancer cell lines. GenBank database search has identified expressed sequence tags, corresponding to the GLP-2R nucleotide sequence, in large cell lung cancer.16,60 GLP-2 also exerts a direct proliferative effect on transformed intestinal cell lines despite the apparent lack of a specific receptor.63In vivo, GLP-2 treatment of tumour-bearing rats and mice showed no effect on tumour growth.64 However, GLP-2 (and especially the long-acting analogue Gly2-GLP-2) promoted the growth of dimethyl-hydrazine-induced colonic neoplasms in mice.61 Although none of the mice developed malignant tumours, it must be assumed that in time, the tubular adenomas observed could undergo malignant transformation. Accordingly, prospective patients must be screened for premalignant lesions (particularly colonic adenomas) prior to treatment with GLP-2.

Conclusions

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References

Glucagon-like peptide 2 is a specific intestinal growth factor that is emerging as a novel treatment modality in a variety of conditions with intestinal injury. Early clinical data give reason for cautious optimism that GLP-2 will be a useful therapeutic adjunct in the treatment of SBS and IBD. More research is needed to determine its optimal indications, timing and dose, and the possible gains from coadministration with other growth factors. Additional applications of GLP-2 may emerge, if promising results from animal models can be replicated in human disease. Although its growth-promoting properties appear to be specific to the intestine, caution is warranted in the use of GLP-2, especially if the colon is present or there is a history of malignant disease.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References

The authors are involved in patient recruitment for an ongoing multinational trial of teduglutide administration in short bowel syndrome. Prof. Forbes previously acted as an advisor to NPS Pharmaceuticals whose portfolio includes teduglutide.

References

  1. Top of page
  2. Abstract
  3. Understanding GLP-2 At Molecular level
  4. Physiological role, pharmacological effects and mechanisms of action
  5. GLP-2 As Therapy: present and future
  6. Potential dangers
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. References
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