Glucagon-like peptide-2 (GLP-2) is a potent, intestinal-specific trophic hormone. However, the relationship between the dose and timing of GLP-2 administration and these trophic effects is not clear. We investigated the effects of variations in the dose and timing of GLP-2 administration on its intestinal trophic activity. A rodent model of total parenteral nutrition (TPN) mucosal atrophy was used, examining intestinal morphology in the adult male rat after 5 days. Groups were: controls, maintained with TPN alone and GLP-2 treated groups (high dose; 240 microg/kg/day, low dose; 24 microg/kg/day) given by continuous or intermittent (over 1 h, twice daily) intravenous infusion. Body weight and total small bowel length were significantly increased in the high dose, continuous infusion group. Both high dose infusion methods increased total small bowel weight, villus height, crypt depth, and total mucosal surface area. Both high dose infusion and low dose intermittent infusion routes increased crypt cell proliferation (P<0.05 for all comparisons). Both high dose routes gave nearly equivalent exposures; low dose continuous infusion gave higher exposure but intermittent low dose infusion resulted in an increase in crypt proliferation; neither low dose method resulted in morphologic changes. There were no differences in transporter protein expression or apoptosis rates. High dose continuous infusion appears to maximally induce intestinal growth, and also increases weight gain, while high dose GLP-2 intermittent infusion results in similar morphologic effects. A threshold level for the induction of proliferative and morphologic effects was seen in the low dose groups. These observations may be relevant for planning therapeutic trials.