The glucagon like peptide-2 'axis': Capacity for production and response following intestinal resection or repair of gastroschisis in infants.

PURPOSE: This study investigates the relationship between the enteric hormone glucagon-like peptide 2 (GLP-2) production, sensitivity, and intestinal adaptation in infants following resection or repair of gastroschisis. METHODS: With IRB approval (UCalgary #10656), consent was obtained from families of infants undergoing surgery for prospective monitoring of nutritional status, GLP-2 levels, and where possible, tissue sampling. RESULTS: Infants who adapted and weaned from parenteral nutrition (PN) had increased GLP-2 (86±32) n=24 vs. controls: 45±20 n=10 and vs. patients on prolonged PN: 42±6 pM, n=10). This was maintained to one year: weaned patients: 72±49 vs. non-weaned: 35±15 pM (p<0.05). Infants with gastroschisis (n=33) had decreased GLP-2 levels until enteral function was achieved and then became elevated: (21±15 with first feeding vs. 102±60 at full feeds and 60±19 pM at one year). There were no changes in the density or distribution of GLP-2 producing L-cells related to gestational age, nor in the expression of the GLP-2 receptor. CONCLUSION: GLP-2 levels correlate with intestinal adaptation in infants, and with recovery of intestinal function in gastroschisis. GLP-2 productive capacity (L-cell expression) and GLP-2 receptor expression do not vary with maturity. The findings support a role for GLP-2 in regulating intestinal function. Further study is suggested.

A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure.

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. METHODS: With parental consent (Health Canada Protocol:150,979), parenteral nutrition (PN)-dependent infants were treated with 5-20-µg/kg/day GLP-2 for 3days (phase 1), and if tolerated continued for 42days (phase 2). Nutritional therapy was by primary caregivers, and follow-up was to one year. RESULTS: Six patients were enrolled, age 5.4±3.2months, bowel length: 27±12% of predicted, PN dependent (67±18% of calories). GLP-2 did not affect vital signs, nor were there significant adverse events during the trial. Dosing 5µg/kg/day gave GLP-2 levels of 52-57pmol/L, with no change in half-life or endogenous GLP-2 levels. Enteral feeds, weight, Z scores, stooling frequency, and citrulline levels improved numerically. The trial was discontinued early because of a drop in potency. CONCLUSIONS: GLP-2 was well tolerated in infants, and pK was similar to children with no changes in endogenous GLP-2 release. The findings suggest that GLP-2 ligands may be safely used in infants and may have beneficial effects on nutritional status. Further study is required. LEVEL OF EVIDENCE: 2b Prospective Interventional Study.

Safety and Dosing Study of Glucagon-Like Peptide 2 in Children With Intestinal Failure.

BACKGROUND AND AIMS: A glucagon-like peptide 2 (GLP-2) analogue is approved for adults with intestinal failure, but no studies of GLP-2 have included children. This study examined the pharmacokinetics, safety, and nutritional effects of GLP-2 in children with intestinal failure. METHODS: Native human GLP-2(1-33) was synthesized following good manufacturing practices. In an open-label trial, with parental consent, 7 parenteral nutrition-dependent pediatric patients were treated with subcutaneous GLP-2 (20 µg/kg/d) for 3 days (phase 1) and, if tolerated, continued for 42 days (phase 2). Nutritional treatment was directed by the primary caregivers. Patients were followed to 1 year. RESULTS: Seven patients were enrolled (age: 4.0 ± 0.8 years; bowel length, mean ± SEM: 24% ± 4% of predicted). All were parenteral nutrition dependent since birth, receiving 44% ± 5% of calories by parenteral nutrition. GLP-2 treatment had no effect on vital signs (blood pressure, heart rate, and temperature) and caused no significant adverse events. Peak GLP-2 levels were 380 pM (day 3) and 295 pM (day 42), with no change in half-life or endogenous GLP-2 levels. Nutritional indices showed a numeric improvement in z scores and citrulline levels; the z score was maintained while citrulline levels returned to baseline once GLP-2 was discontinued. CONCLUSIONS: GLP-2 was well tolerated in children, with a pharmacokinetic profile similar to that of adults. There were no changes in endogenous GLP-2 release or metabolism. These results suggest that GLP-2 ligands may be safely used in pediatric patients; larger trials are suggested to investigate nutritional effects.

Nutritional support of infants with intestinal failure: something more than fishy is going on here!

BACKGROUND: This review will highlight recent advances in the care of infants with Intestinal Failure, focusing on the benefits of a multi-disciplinary team and the types of nutrition used. METHODS: Recent best "practices" from the literature are described, including strategies for promoting intestinal adaptation, the use of lipid sparing Parenteral Nutrition (PN) and the effects of the associated high glucose infusion rates. Special emphasis will be placed on lipid minimization and specialized lipid emulsions including fish oil, and blended lipid sources such as SMOF. Enteral nutritional therapy will be reviewed, including the rationale for the use of expressed breast milk or elemental formula in preference to partial milk hydrolysates. The utility and indications for the use of formula additives and the use of nutritional supplements and the timing and rate of advancement of feeds, and the optimal strategy for preserving oral feeding skills will be reviewed. Treatments to optimize intestinal adaptation such as the use of dietary supplements including vegetable oils, fat emulsions and medium-chain triglycerides will be discussed. Feeding strategies will be described. The rationale and effects of using rotating antibiotics to treat small intestinal bacterial overgrowth will be reviewed. RESULTS: The long-term consequences and complications of the different types of nutritional therapy will be examined, with a focus on growth and development. The potential and described effects of established and novel lipid therapies on neurological development will be reviewed in detail. CONCLUSION: Areas of interest for potential future research will be explored for all aspects of nutritional therapy with a discussion of future strategies which may enhance the intestinal adaptive process, and thus aid our goal of making the adaptation process occur more quickly and shortening the time of PN.

Elements of successful intestinal rehabilitation.

PURPOSE: The optimal therapy for intestinal failure (IF) is unknown. The results of a systematic, protocol-driven management strategy by a multidisciplinary team are described. METHODS: Intestinal failure was defined as bowel length of less than 40 cm or parenteral nutrition (PN) for more than 42 days. A multidisciplinary team and protocol to prevent PN-associated liver disease (PNALD) were instituted in 2006. Data were gathered prospectively with consent and ethics board approval. RESULTS: From 1998 to 2006, 33 patients were treated (historical cohort) with an overall survival of 72%. Rotating prophylactic antibiotics for bacterial overgrowth were given to 27% of patients; 6% had lipid-sparing PN, and none received fish oil-based lipids. Median time to intestinal rehabilitation was 7 ± 3.1 months, and 27% of patients who developed PNALD died. From 2006 to 2009, 31 patients were treated. Seventy-seven percent received PAB; 60%, lipid-sparing PN; and 47%, parenteral fish oil emulsion. Eighty-seven percent weaned from PN at 3.9 ± 3.8 months, and no patients developed PNALD with 100% survival. Novel lipid therapies were associated with changes in essential fatty acid profile and one case of clinical essential fatty acid deficiency. CONCLUSION: The institution of a multidisciplinary team and a protocol-driven strategy to prevent PNALD improves survival in IF. Further studies are recommended.

The assessment, and glucagon-like peptide-2 modulation, of intestinal absorption and function.

The treatment of patients with short bowel syndrome is hampered by a lack of treatment and measurement methods. This article reviews our evolving understanding of the role of glucagon-like peptide 2 (GLP-2) in controlling the adaptive process. The ability of the remnant intestine to produce GLP-2 appears to be predictive of the adaptive process; exogenous GLP-2 may be a therapy to augment adaptation. Strategies for monitoring patients, including conventional means, such as anthropomorphic measurements, plasma levels of specific nutrients, and vitamins and radiological contrast studies are reviewed. Investigational methods, such as nutrient balance studies, plasma citrulline levels, and the absorption of inert sugars (3-0 methyl glucose, mannitol, and lactulose) are discussed with the evidence to support their use.