Short bowel syndrome often requires permanent total parenteral nutrition. Current treatment is inadequate because TPN induces serious complications and is expensive. A greater understanding of the mechanisms underlying intestinal adaptation to resection is needed to develop improved treatments. The focus of this research is to characterize the local and humoral signals that mediate intestinal adaptation to resection during TPN. The long term goal is to understand the mechanisms by which parenteral nutrients and growth factors, such as insulin-like growth factor I (IGF-I) and glucagon-like peptide-2 (GLP-2), regulate intestinal adaptation to design TPN protocols that will optimize intestinal function and permit transition to enteral feeding. There are three specific aims.
Specific aim 1 determines if the stimulation of mucosal hyperplasia induced by IGF-I is modulated by expression of IGF binding protein-5 (IGFBP-5) by conducting TPN studies in IGFBP-5 transgenic knock-out mice treated with rhIGF-I.
Specific aim 2 determines how resection and administration of rhIGF-I and rhGLP-2 mediate adaptation of the jejunum and colon in a resection model which mimics human short bowel syndrome as adaptation does not occur and TPN is required. TPN rats will be subjected to intestinal resection (60 percent jejuno-ileal resection plus cecectomy), treated with growth factors, and weaned to enteral feeding. Adaptation will be assessed by changes in intestinal structure (morphology, composition, proliferation, migration and apoptosis) and function (ion transport using Ussing flux chambers, enzymes and ability to transition to enteral feeding).
Specific aim 3 will determine how the physiological significance of endogenous GLP-2 in resection induced mucosal growth in rats given 70 percent jejuno-ileal resection and maintained with TPN. When there is residual ileum present, plasma bioactive GLP-2 is increased and dramatic resection-induced jejunal hyperplasia occurs with TPN. The hypothesis is that resection and parenteral lipids stimulate GLP-2 secretion, which partially mediates intestinal growth by interaction with GLP-2 receptors. The PI proposes to determine if parenteral lipid and pancreaticobiliary secretions increase ileal proglucagon mRNA and plasma GLP-2 and if the mucosal hyperplasia induced by resection is associated with an increase in jejunal GLP-2 receptor number or affinity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042835-11
Application #
6380657
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
1990-08-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
11
Fiscal Year
2001
Total Cost
$211,600
Indirect Cost
Name
University of Wisconsin Madison
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Sangild, Per T; Ney, Denise M; Sigalet, David L et al. (2014) Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges. Am J Physiol Gastrointest Liver Physiol 307:G1147-68
Murali, Sangita G; Brinkman, Adam S; Solverson, Patrick et al. (2012) Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice. Am J Physiol Gastrointest Liver Physiol 302:G794-804
Brinkman, Adam S; Murali, Sangita G; Hitt, Stacy et al. (2012) Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure. Am J Physiol Gastrointest Liver Physiol 303:G610-22
Baumler, Megan D; Koopmann, Matthew C; Thomas, Diana D H et al. (2010) Intravenous or luminal amino acids are insufficient to maintain pancreatic growth and digestive enzyme expression in the absence of intact dietary protein. Am J Physiol Gastrointest Liver Physiol 299:G338-47
Koopmann, Matthew C; Chen, Xueyan; Holst, Jens J et al. (2010) Sustained glucagon-like peptide-2 infusion is required for intestinal adaptation, and cessation reverses increased cellularity in rats with intestinal failure. Am J Physiol Gastrointest Liver Physiol 299:G1222-30
Koopmann, Matthew C; Baumler, Megan D; Boehler, Christopher J et al. (2010) Total parenteral nutrition attenuates cerulein-induced pancreatitis in rats. Pancreas 39:377-84
Liu, Xiaowen; Murali, Sangita G; Holst, Jens J et al. (2009) Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats. Am J Physiol Regul Integr Comp Physiol 297:R1554-62
Koopmann, Matthew C; Liu, Xiaowen; Boehler, Christopher J et al. (2009) Colonic GLP-2 is not sufficient to promote jejunal adaptation in a PN-dependent rat model of human short bowel syndrome. JPEN J Parenter Enteral Nutr 33:629-38; discussion 638-9
Koopmann, Matthew C; Nelson, David W; Murali, Sangita G et al. (2008) Exogenous glucagon-like peptide-2 (GLP-2) augments GLP-2 receptor mRNA and maintains proglucagon mRNA levels in resected rats. JPEN J Parenter Enteral Nutr 32:254-65
Liu, Xiaowen; Murali, Sangita G; Holst, Jens J et al. (2008) Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats. Am J Physiol Regul Integr Comp Physiol 295:R1794-802

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