Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats.

Objective: To determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats.

Background: GLP-2 is a gut hormone known to be trophic for small bowel mucosa, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear.

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).

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.

Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs.

Background: The enteroendocrine hormone glucagon like peptide-2 (GLP-2) and its ligands are under development as therapeutic agents for a variety of intestinal pathologies. A number of these conditions occur in neonates and infants, and thus a detailed understanding of the effects of GLP-2 during the phase of rapid growth during infancy is required to guide the development of therapeutic applications. We studied the effects of GLP-2 in the neonatal pig to determine the potential effects of exogenous administration.

Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling.

Glucagon-like peptide 2 (GLP-2) is an enteroendocrine hormone trophic for intestinal mucosa; it has been shown to increase enteric neuronal expression of vasoactive intestinal polypeptide (VIP) in vivo. We hypothesized that GLP-2 would regulate VIP expression in enteric neurons via a phosphatidylinositol-3 kinase-γ (PI3Kγ) pathway. The mechanism of action of GLP-2 was investigated using primary cultures derived from the submucosal plexus (SMP) of the rat and mouse colon.

The influence of nutrients, biliary-pancreatic secretions, and systemic trophic hormones on intestinal adaptation in a Roux-en-Y bypass model.

Purpose: The signals that govern the upregulation of nutrient absorption (adaptation) after intestinal resection are not well understood. A Gastric Roux-en-Y bypass (GRYB) model was used to isolate the relative contributions of direct mucosal stimulation by nutrients, biliary-pancreatic secretions, and systemic enteric hormones on intestinal adaptation in short bowel syndrome.

Methods: Male rats (350-400 g; n = 8/group) underwent sham or GRYB with pair feeding and were observed for 14 days.

Aftiphilin is a component of the clathrin machinery in neurons.

Aftiphilin was identified through a database search for proteins containing binding motifs for the gamma-ear domain of clathrin adaptor protein 1 (AP-1). Here, we demonstrate that aftiphilin is expressed predominantly in brain where it is enriched on clathrin-coated vesicles. In addition to eight gamma-ear-binding motifs, aftiphilin contains two WXXF-acidic motifs that mediate binding to the alpha-ear of clathrin adaptor protein 2 (AP-2) and three FXXFXXF/L motifs that mediate binding to the alpha- and beta2-ear.

Characterization of a gamma-adaptin ear-binding motif in enthoprotin.

Enthoprotin, a newly identified component of clathrin-coated vesicles, interacts with the trans-Golgi network (TGN) clathrin adapters AP-1 and GGA2. Here we perform a multi-faceted analysis of the site in enthoprotin that is responsible for the binding to the gamma-adaptin ear (gamma-ear) domain of AP-1. Alanine scan mutagenesis and nuclear magnetic resonance (NMR) studies reveal the full extent of the site as well as critical residues for this interaction.

Enthoprotin: a novel clathrin-associated protein identified through subcellular proteomics.

Despite numerous advances in the identification of the molecular machinery for clathrin-mediated budding at the plasma membrane, the mechanistic details of this process remain incomplete. Moreover, relatively little is known regarding the regulation of clathrin-mediated budding at other membrane systems. To address these issues, we have utilized the powerful new approach of subcellular proteomics to identify novel proteins present on highly enriched clathrin-coated vesicles (CCVs).