Elsevier

Regulatory Peptides

Volume 184, 10 June 2013, Pages 30-39
Regulatory Peptides

Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1 + GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study

https://doi.org/10.1016/j.regpep.2013.03.025Get rights and content

Highlights

  • We tested glucagon-like peptides 1 and 2 in the treatment of short bowel syndrome.

  • Both glucagon-like peptides 1 and 2 reduced diarrhea and fecal excretions.

  • Glucagon-like peptide 2 proved as the more potent treatment of the two.

  • The combination of glucagon-like peptide 1 and 2 showed an additive effect.

Abstract

Background and aims

The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of glucagon-like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients.

Methods

SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1 + 2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast.

Results

Nine SBS patients (5 women/4 men, aged 52 ± 11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1 + 2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1 + 2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2.

Conclusion

GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1 + 2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the glucagon-like peptides or analogs, alone or in combination, in the treatment of SBS patients.

Introduction

In adults, short bowel syndrome (SBS) is most frequently seen in patients with extensive small bowel resection due to Crohn's disease, ischemic bowel, radiation enteritis, trauma or in relation to complications to surgery. In recent years, it has been hypothesized that, in SBS patients with distal bowel resections, the concurrent malabsorption is not only caused by a diminished absorptive area, but also by the disruption of the ileocolonic brake mechanism mediated by hormones such as glucagon-like peptide (GLP) 1 and 2 and peptide YY [1]. The lack of this meal-stimulated hormonal feedback leads to gastric hypersecretion, rapid gastric and intestinal transit and poor intestinal adaptation [2], [3]. This raises the possibility that SBS patients, conventionally treated with anti-diarrheal and anti-secretory medications, could be supplemented with one or more of these feedback hormones to ameliorate the pathophysiological consequences of the SBS [4].

In this respect, GLP-2 has received a special attention. GLP-2 induces crypt cell proliferation and prevents enterocyte apoptosis [5]. Furthermore, GLP-2 inhibits gastric acid secretion and gastric emptying [6], [7], stimulates intestinal blood flow [8], increases intestinal barrier function [9], and enhances nutrient and fluid absorption in both preclinical and clinical SBS models [10]. Teduglutide, a dipeptidyl-peptidase degradation resistant GLP-2 analog, has also been demonstrated to enhance structural and functional integrity of the remaining intestine in SBS patients [11], [12]. By increasing intestinal absorption, a reduced need for parenteral support in SBS patients with intestinal failure has been documented [13]. GLP-1 has mainly received attention due to the beneficial effects on glucose homeostasis in the treatment of patients with diabetes [14]. However, GLP-1 also reduces gastric secretion and motility, and preliminary data has suggested a role of GLP-1 in the treatment of SBS too [15]. Whereas the hormonal effects of GLP-1 and GLP-2 on the proximal bowel secretion and motility seem to occur immediately after hormone administration, the induction of mucosal hypertrophy in humans by GLP-2 may take days to weeks to occur. In this study, we examined the acute effects of GLP-1 and GLP-2, alone and in combination, compared to placebo on intestinal absorption evaluated by 72-hour balance studies. Since GLP-2 has been described to cause abdominal discomfort and GLP-1 has been described to reduce appetite, these unfavorable subjective effects were evaluated by using visual analogue scale (VAS) questionnaires.

Section snippets

Patients

SBS patients were recruited from the medical department of gastroenterology at Rigshospitalet, Copenhagen, Denmark based on a malabsorption with fecal excretion of wet weight above 1.0 kg/day and energy above 1.5 MJ/day measured at a previous admission.

Study protocol

In the period from April 3rd 2006 to February 22nd 2007, the patients were admitted four times for four days. Washout periods of minimum 30 days between admissions were required. The study was an open-label, sequential, but placebo-controlled study.

Results

Nine patients were recruited and completed the study (Table 2). Five were females and four males. The age was 52 ± 11 years. Remnant small bowel measured at surgery from the ligament of Treiz was 132 ± 68 cm. Seven SBS patients had end-jejunostomies, whereas two patients had 50% of colon and a preserved rectum in continuity. Eight patients had intestinal failure and received home parenteral support (PS); Seven received parenteral nutrition (3.1 ± 2.8 MJ/day, 1.8 ± 1.3 L/d) and one received parenteral

Discussion

In the modern treatment of SBS patients, the pathophysiological consequences of distal bowel resections are ameliorated by hormonal replacement therapy thereby mimicking the ileal-brake mechanism [1]. This open-label, pilot study evaluated the acute restorative effects of the glucagon-like peptides 1 and 2, alone and in combination, compared to placebo, on intestinal absorption, body composition, glucose homeostasis and subjective VAS scores on appetite, nausea, abdominal pain and general

Acknowledgements

We thank Jette Christiansen, Dorte Christensen and Birgitte Schou for their technical assistance.

References (21)

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