Exogenous GLP - 2 and IGF - I induce a differential intestinal response in IGF binding protein - 3 1 and - 5 double knockout mice

19 Glucagon-like peptide-2 (GLP-2) action is dependent on intestinal expression of insulin-like 20 growth factor-I (IGF-I) and IGF-I action is modulated by IGF binding proteins (IGFBP). Our 21 objective was to evaluate if the intestinal response to GLP-2 or IGF-I is dependent on expression 22 of IGFBP-3 and -5. Male, adult mice in 6 treatment groups, 3 wild type (WT) and 3 double 23 IGFBP-3/-5 knockout (KO), received twice daily intraperitoneal injections of GLP-2 (0.5 μg/g 24 body wt), IGF-I (4 μg/g body wt) or PBS (vehicle) for 7d. 25 IGFBP-3/-5 KO mice showed a phenotype of lower plasma IGF-I concentration, but greater 26 body weight and relative mass of visceral organs, compared with WT mice, p<0.001. WT mice 27 showed jejunal growth with either IGF-I or GLP-2 treatment. In KO mice, IGF-I did not 28 stimulate jejunal growth, crypt mitosis, sucrase activity and IGF-I receptor (IGF-IR) expression 29 suggesting that the intestinotrophic actions of IGF-I are dependent on expression of IGFBP-3 30 and -5. In KO mice, GLP-2 induced significant increases in jejunal mucosal cellularity, crypt 31 mitosis, villus height and crypt depth that was associated with increased expression of the ErbB 32 ligand epiregulin and decreased expression of IGF-I and IGF-IR. This suggests that in KO mice, 33 GLP-2 action in jejunal mucosa is independent of the IGF-I system and linked with ErbB ligands. 34 In summary, the intestinotrophic actions of IGF-I, but not GLP-2, in mucosa are dependent on 35 IGFBP-3 and -5. These findings support the role of multiple downstream mediators for the 36 mucosal growth induced by GLP-2. 37