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Title: Chronic parenteral nutrition induces hepatic inflammation, steatosis and insulin resistance in neonatal pigs

item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item HORST, DAVID - Baylor College Of Medicine
item CUI, LIWEI - Children'S Nutrition Research Center (CNRC)
item CHANG, XIAOYAN - Children'S Nutrition Research Center (CNRC)
item ELLIS, KENNETH - Children'S Nutrition Research Center (CNRC)
item HADSELL, DARRYL - Children'S Nutrition Research Center (CNRC)
item SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC)
item KURUNDKAR, ASHISH - University Of Alabama
item MAHESHWARI, AKHIL - University Of Alabama
item DAVIS, TERESA - Children'S Nutrition Research Center (CNRC)
item Burrin, Douglas - Doug

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/16/2010
Publication Date: 10/27/2010
Citation: Stoll, B., Horst, D.A., Cui, L., Chang, X., Ellis, K.J., Hadsell, D.L., Suryawan, A., Kurundkar, A., Maheshwari, A., Davis, T.A., Burrin, D.G. 2010. Chronic parenteral nutrition induces hepatic inflammation, steatosis and insulin resistance in neonatal pigs. Journal of Nutrition. 140(12):2193-2200.

Interpretive Summary: More than fifty-thousand premature infants born in the United States every year are unable to handle normal oral or enteral feeding, and instead receive total parenteral or intravenous nutrition (TPN). In piglets as well as in people, the amount of glucose in the blood is controlled by insulin, a hormone produced by beta cells in the pancreas. Throughout the body, insulin triggers cells to take up glucose from the blood and use it for energy. Increased blood glucose can occur as a result of a condition known as insulin resistance, or insulin insensitivity and this is commonly found in adolescents who have type 2 diabetes. Earlier clinical studies have suggested an association between premature birth and the occurrence of insulin resistance later on in early adulthood. The aim of this study was to test whether TPN compared to oral feeding leads to increased insulin resistance using neonatal piglets as an animal model. Piglets were chosen for the investigation because their body size, digestive system, and glucose metabolism are similar to that of premature infants. We studied 15 newborn piglets in each treatment feeding group and found that those given continuous TPN for their first two weeks of life, were less able to control their blood glucose levels than those fed a milk-based formula orally four times a day. The TPN piglets’ insulin sensitivity was forty percent lower than that of the orally fed piglets. We also found that the number of new beta cells was reduced by thirty percent in TPN-fed piglets compared to the orally-fed animals. Our results suggest that TPN leads to poor glucose tolerance and insulin action in neonatal piglets. The results suggest that TPN may have long term consequences on the risk for diabetes.

Technical Abstract: Prematurity and overfeeding in infants are associated with insulin resistance in childhood and may increase the risk of adult disease. Total parenteral nutrition (TPN) is a major source of infant nutrition support and may influence neonatal metabolic function. Our aim was to test the hypothesis that TPN induces increased adiposity and insulin resistance compared to enteral nutrition (EN) in neonatal pigs. Neonatal pigs were either fed enteral formula orally or administered a TPN mixture intravenously for 17 d; macronutrient intake was similar in both groups. During the 17 d period, we measured body composition by dual-enter X-ray absorptiometry scanning; fasting intravenous glucose tolerance tests (IVGTT) and hyperinsulinemic-euglycemic clamps were performed to quantify insulin resistance. On d 17, tissue was collected after 1-h low-dose hyperinsulinemic-euglycemic clamp for tissue insulin signaling assays. TPN pigs gained less lean and more body fat and developed hepatic steatosis compared to assays. TPN pigs gained less lean and more body fat and developed hepatic steatosis compared to EN pigs. After 7 and 13 d, IVGTT showed evidence of insulin resistance in the TPN vs. EN group. Fasting plasma glucose and insulin also were higher in TPN pigs. Hyperinsulinemic-euglycemic clamps showed that insulin sensitivity was markedly lower in TPN vs. EN pigs. TPN also reduced the abundance of the insulin receptor, insulin receptor substrate 1 and phosphatidylinositol 3 kinase in skeletal muscle and liver, and proliferation of total pancreatic cell and beta-cells. Hepatic proinflammatory genes as well as c-Jun-N-terminal kinase 1 phosphorylation, plasma interleukin 6, and tumor necrosis factor-alpha were all increased in TPN vs. EN pigs. The results demonstrate that chronic TPN induces a hepatic inflammatory response that is associated with significant insulin resistance, hepatic steatosis, and fat deposition compared to EN in neonatal pigs. Further studies are warranted to establish the mechanism of TPN-induced insulin resistance and hepatic metabolic dysfunction and whether there are persistent metabolic consequences of this life-saving form of infant nutritional support.