|Burrin, Douglas - Doug|
Submitted to: Gastroenterology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/1/2003
Publication Date: 7/1/2003
Citation: GUAN, X., STOLL, B., LU, X., TAPPENDEN, K., HOLST, J.J., HARTMANN, B., BURRIN, D.G. 2003. GLP-2-MEDIATED UP-REGULATION OF INTESTINAL BLOOD FLOW AND GLUCOSE UPTAKE IS NITRIC OXIDE-DEPENDENT IN TPN-FED PIGLETS. GASTROENTEROLOGY. 125:136-147. Interpretive Summary: This is a important study that could eventually affect the way doctors treat premature babies, who often can't tolerate and digest their food normally. These tiny babies have to be fed not through their mouths, but through tubes implanted in their blood vessels by a method called total parenteral nutrition (TPN). These tiny infants may receive TPN for a week to several weeks or even more, depending on the infant's response. Being on TPN is not good for the baby because its gut (intestine) isn't being used, so it stops growing and starts to wither. This issue has become a significant problem, since modern technology is allowing so many more extremely premature, very low-birth-weight babies to be born these days. In our past study, we gave a small, naturally-occuring hormone called GLP-2 (glucagon-like peptide 2) to prematurely born pigs fed by TPN, which serve as models for premature babies. We found that GLP-2 prevented the gut from withering or losing mass. We wanted to find out the exact mechanism of action of this hormone drug. We wanted to know how the hormone prevented the gut from withering during TPN - what mechanism caused this. We wanted to find whether it affected blood flow to the gut, or changed the use of substrates and nutrients, or whether this action occurred rapidly. We found that it does indeed very rapidly upregulate blood flow and nutrient use in the gut. That rapid action is an important early mechanism that puts the gut in a more anabolic state. We also identified an important secondary signal emanating from the peptide's interaction with its receptor. Based on what we found, we think that signal is nitric oxide, and we will test our theory in our next study.
Technical Abstract: BACKGROUND & AIMS: Our aim was to determine whether the intestinotrophic effects of GLP-2 are mediated by acute up-regulation of intestinal substrate utilization in TPN-fed piglets. METHODS: Twenty-four 12-day-old pigs, fitted with a portal flow probe and carotid, jugular and portal catheters, were fed by TPN for 7 days. On day 8, a group of pigs (n = 8) was infused intravenously with saline (control) for 4 hours and then with GLP-2 (500 pmol x kg(-1) x hour(-1), GLP-2) for 4 hours. (2)H-glucose and (13)C-phenylalanine were infused to estimate their kinetics and protein turnover. Another group (n = 8) received consecutive intravenous infusions of saline, GLP-2, and GLP-2 plus N(G)-Nitro-L-arginine methyl ester (L-NAME, 50 micromol x kg(-1) x hour(-1)) for 4 hours each. RESULTS: GLP-2 acutely increased portal-drained visceral (PDV) blood flow rate (+25%) and intestinal blood volume (+51%) in TPN-fed piglets. GLP-2 also increased intestinal constitutive nitric oxide synthase (NOS) activity and endothelial NOS protein abundance. GLP-2 acutely increased PDV glucose uptake (+90%) and net lactate production (+79%). Co-infusion of GLP-2 plus L-NAME did not increase either PDV blood flow rate or glucose uptake. GLP-2 increased PDV indispensable amino acid uptake by 220% and protein synthesis by 125%, but did not decrease protein breakdown or phenylalanine oxidation. CONCLUSIONS: We conclude that in TPN-fed neonatal pigs, GLP-2 acutely stimulates intestinal blood flow and glucose utilization, and this response is nitric oxide-dependent. These findings suggest that GLP-2 may play an important physiological role in the regulation of intestinal blood flow and that nitric oxide is involved in GLP-2 receptor function.