Exogenous glucagon-like peptide 2 (GLP-2) mimics the stimulatory effect of enteral nutrition on intestinal mucosal growth in preterm neonatal pigs. Little is known about its effects on small intestinal function. In this study, we investigated whether the trophic actions of GLP-2 and enteral nutrition are paralleled by effects on small intestinal function. Cesarean-delivered piglets (92% of gestation) were given either a parenteral nutrient infusion [total parenteral nutrition (TPN), n ϭ 7], TPN ϩ human GLP-2 (25 nmol/kg/d, n ϭ 8), or enteral nutrition (ENT, n ϭ 6) for 6 d. Gene expression (mRNA) and activities of lactase phlorizin hydrolase (LPH), maltase-glucoamylase (MGA), sucrase-isomaltase (SI), aminopeptidase N (ApN), and A (ApA) and dipeptidyl peptidase IV (DPP IV) were measured. Both GLP-2 and enteral nutrition increased mucosal weight (ϩ30 -40%, p Ͻ 0.05) relative to TPN. GLP-2 stimulated jejunal MGA and SI mRNA abundance and activity levels but did not change LPH in parenterally fed pigs (p Ͻ 0.05). Enteral nutrition decreased jejunal LPH and MGA mRNA abundance and activity and increased ileal ApN, ApA, and DPP IV activities relative to TPN (p Ͻ 0.05). We conclude that GLP-2 and enteral nutrition exert different effects on intestinal enzyme function despite similar effects on intestinal growth. In addition, the effects of GLP-2 on intestinal function in these parenterally fed, premature neonatal pigs differed from those previously reported for similarly fed term neonates. (Pediatr Res 52: 498-503, 2002) Abbreviations ApN, aminopeptidase N ApA, aminopeptidase A AS, antisense BB, brush border DEPC, diethylpyrocarbonate DPP IV, dipeptidyl peptidase IV ENT, enteral nutrition GIT, gastrointestinal tract GLP-2, glucagon-like peptide 2 LPH, lactase-phlorizin hydrolase MGA, maltase-glucoamylase S, sense SI, sucrase-isomaltase TPN, total parenteral nutrition TPN is frequently administered to premature infants unable to tolerate enteral nutrition. TPN provides systemic energy and nutrients but has been associated with intestinal atrophy, abnormal BB hydrolase activities, and reduced circulating GLP-2 concentrations (1-5). GLP-2 is a 33-amino acid peptide released from the specific post-translational cleaving of the proglucagon gene in the enteroendocrine L cells of the small intestine. This gut peptide stimulates significant mucosal proliferation (6), hexose transport (7), and duodenal hydrolase activity (8), seemingly via a specific G-protein-coupled receptor present in the small intestine (9). GLP-2 is released in response to enteral nutrient intake (5, 10) and is thought to mediate the response of the small intestine to enteral nutrients (11). Recently, however, it has been shown that GLP-2 stimulates intestinal growth by inhibiting apoptosis and proteolysis, and enteral nutrition also inhibits apoptosis but furthermore increases protein synthesis and cell proliferation (11). Thus, despite the similarity in the extent of small intestinal mucosal growth induced by GLP-2 and enteral nutrition, the mechanisms inv...