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Title: Studies into the intestinal growth factor glucagon-like peptide-2
Author: Wallis, Katharina
ISNI:       0000 0004 2682 3590
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Glucagon-like peptide-2 (GLP-2) is a peptide hormone, secreted postprandially from enteroendocrine L-cells. GLP-2 has emerged as a central physiological mediator of intestinal growth and integrity and has recently shown promise as a therapeutic agent in patients with short bowel syndrome and inflammatory bowel disease. Reliable methods for GLP-2 measurement are not widely available. In this work a radioimmunoassay (RIA), using the GLP-2 antiserum (FT-17) has been optimised and validated. Cross-reactivity with GLP-2 precursors and degradation products was investigated using column chromatography. It is shown that accurate estimations of active GLP-2 secretion in response to a physiological stimulus can be made using this RIA. Plasma concentration of GLP-2 and other hormones, secreted from L-cells, were investigated in patients with short bowel syndrome (SBS), morbid obesity and in those following Roux-en-Y gastric bypass (RYGB) surgery. It is shown that, contrary to current thinking, SBS patients with a retained colon can be GLP-2 deficient despite increased L-cell activity as indicated by raised levels of PYY. Differential regulation of peptide generation in L-cells, depending on the residual intestinal anatomy, is a possible explanation. Secretion of PYY and glucagon-like peptides may also differ in obesity. Despite a previously documented attenuated postprandial PYY response in obese compared with normal weight subjects, no difference in glucagon-like peptide secretion was found in a series of test meals. In obese patients undergoing RYGB, an exaggerated postprandial GLP-2 response was noted as early as 2 days following the procedure and persisted for at least 2 years. In diabetic patients this adaptive response was delayed. Enhancing endogenous GLP-2 secretion might serve as a therapeutic strategy for patients in whom intestinal mucosal regeneration is impaired. It is shown that bile acids and glutamine act as effective GLP-2 secretagogues in model L-cells and that diversion of bilio-pancreatic secretions to the distal ileum leads to increased plasma concentration of GLP-2 in rats.
Supervisor: Walters, Julian ; Forbes, Alastair Sponsor: CORE (UK) ; St. Mark's Hospital Research Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral