Supraphysiological doses of glucagon-like peptide-2 (GLP-2) have been shown to induce intestinal growth by increasing villus height and crypt depth and by decreasing apoptosis, but a physiological effect of GLP-2 has not yet been demonstrated. Earlier, we found elevated levels of endogenous GLP-2 in untreated streptozotocin diabetic rats associated with marked intestinal growth. In the present study, we investigated the role of endogenous GLP-2 for this adaptive response. We included four groups of six rats: (1) diabetic rats treated with saline, (2) diabetic rats treated with non-specific antibodies, (3) diabetic rats treated with polyclonal GLP-2 antibodies and (4) non-diabetic control rats treated with saline. All animals were treated with once daily intraperitoneal injections for 13 days and killed on day 14. Diabetic rats treated with saline or non-specific antibodies had a significantly (P<0.01) increased area of mucosa (13.00+/-0.64 and 13.37+/-0.60 mm(2), respectively) in the proximal part of the small intestine compared with non-diabetic controls (7.97+/-0.70 mm(2)). In contrast, diabetic rats treated with GLP-2 antibodies had a significantly (P<0.01) smaller increase in area of mucosa in the proximal part of the small intestine (10.84+/-0.44 mm(2)). Antibody treatment had no effect on body weight, blood glucose concentrations and food intake. Thus, blocking of endogenous GLP-2 in a model of adaptive intestinal growth reduces the growth response, providing strong evidence for a physiological growth factor function of GLP-2.