Cui, Xue-Lin, Anna M. Schlesier, Elda L. Fisher, Carla Cerqueira, and Ronaldo P. Ferraris. Fructose-induced increases in neonatal rat intestinal fructose transport involve the PI3-kinase/Akt signaling pathway. Am J Physiol Gastrointest Liver Physiol 288: G1310 -G1320, 2005. First published February 3, 2005 doi:10.1152/ajpgi.00550.2004.-Expression of rat glucose transporter-5 (GLUT5) is tightly regulated during development. Expression and activity are low throughout the suckling and weaning stages, but perfusion of the small intestinal lumen with fructose solutions during weaning precociously enhances GLUT5 activity and expression. Little is known, however, about the signal transduction pathways involved in the substrate-induced precocious GLUT5 development. We found that wortmannin and LY-294002, inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) specifically inhibited the increase in fructose uptake rate and brushborder GLUT5 protein abundance but not GLUT5 mRNA abundance. Perfusion of EGF, an activator of PI3-kinase, also resulted in a marked wortmannin-inhibitable increase in fructose uptake. Perfusion of fructose for 4 h increased cytosolic immunostaining of phosphatidylinositol-3,4,5-triphosphate (PIP 3), the primary product of PI3-kinase, mainly in the mid-to upper-villus regions in which the brush-border membrane also stained strongly with GLUT5. Perfusion of glucose for 4 h had little effect on fructose or glucose uptake and PIP 3 or GLUT5 staining. SH-5, an Akt inhibitor, prevented the increase in fructose uptake and GLUT5 protein induced by fructose solutions, and had no effect on glucose uptake. The PI3-kinase/Akt signaling pathway may be involved in the synthesis and/or recruitment to the brush border of GLUT5 transporters by luminal fructose in the small intestine of weaning rats. Increases in fructose transport during the critical weaning period when rats are shifting to a new diet may be modulated by several signaling pathways whose cross talk during development still needs to be elucidated. development; glucose; intestine; epidermal growth factor; mucosa BECAUSE OF DRAMATIC INCREASES in consumption of soft drinks and fruit juices, per capita consumption of fructose in the United States has increased by 10 times in 30 yr to almost 60 g fructose per day (4, 39). Paralleling this remarkable increase in fructose consumption is an alarming increase in incidence of obesity and in prevalence of type II diabetes (4,14). What makes this correlation disturbing is that per capita fructose consumption in very young children has increased faster than that of the general population and in the 1980s was already ϳ30 -40 g fructose per day representing 10% of their energy intake (39). The top 10th percentile of subjects in all age groups typically consume approximately two times more fructose, exposing this particular age group (1-6 yr of age) to potential metabolic derangements caused by excessive fructose consumption. There are very few studies on physiological adaptations to excessive fructose consumpti...