Long-term treatment with dipeptidyl-peptidase-IV-inhibitors (DPPIV-I) or glucagon-like peptide-(GLP)-1 analogs may potentially affect intestinal growth by down- or up-regulating the intestinotrophic hormone GLP-2. This study compared the intestinotrophic effects of 12 weeks administration of vehicle, exendin-4 (Ex-4; 5 nmol/kg, bid sc), or DPPIV-I (NN7201, 10 mg/kg, qd orally) in GK-rats. Some animals were observed additionally for 9 weeks after ending treatment. Both treatments lowered HbA1c at week 12 vs control (Ex-4, -0.8%; DPPIV-I, -0.4%). Bodyweight was reduced by Ex-4 compared to control (361±4 vs 399±5 g, p<0.001) due to reduced food intake, whereas neither parameter was affected by DPPIV-I. Linear bone-growth was unaffected by either treatment. After treatment end, food intake in Ex-4 animals increased and by week 21, bodyweight was identical in all groups. The small intestine of Ex-4 treated animals was larger at week 12 compared to control (length, 135.6±1.6 vs 124.5±2.3 cm, p<0.001; absolute weight, 8.4±0.2 vs 6.4±0.4 g, p<0.001), being most pronounced proximally, where the absolute cross-sectional area related to bodyweight increased by 24%, due to increased mucosal thickness. These effects were reversible, and 9 weeks after ending treatment, no differences between Ex-4 and control were apparent. Plasma GLP-2 concentrations were unaltered by either treatment, and Ex-4 had no agonistic or antagonistic effects on the transfected GLP-2 receptor. DPPIV-I had no intestinal effects. In conclusion, the continued presence of Ex-4 is necessary to maintain weight-loss in GK-rats. Effective anti-hyperglycemic treatment with Ex-4 increases intestinal mass reversibly, while DPPIV-I lack intestinal effects.