The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice.
OBJECTIVE
Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that acts through unknown pathways to induce intestinal growth. We investigated the role of the insulin-like growth factors (IGF-1 and IGF-2) as mediators of GLP-2-enhanced growth in the murine intestine.


METHODS
IGF-1 expression and secretion were determined in GLP-2-responsive primary intestinal cultures treated with GLP-2. Parameters of intestinal growth were assessed in wild-type (CD1, Igf1(+/+) and Igf2+), heterozygous (Igf1(+/-)), and null (Igf1(-/-) and Igf2(-P)) mice treated chronically with saline, GLP-2, IGF-1, or R-Spondin1.


RESULTS
GLP-2 increased IGF-1 messenger RNA expression and IGF-1 secretion in intestinal cultures and increased expression of IGF-1 messenger RNA in mouse small intestine in vivo. Igf1(+/+) and Igf2+ mice responded to .1 microg/g(-1) per day(-1) GLP-2 with increased intestinal weights, morphometric parameters, and proliferative indices. In contrast, Igf1(-/-) mice were unresponsive to the same dose of GLP-2, failing to demonstrate changes in intestinal weight, morphometry, or proliferation. However, a significant effect of 1 microg/g(-1) per day(-1) GLP-2 was observed in Igf1(-/-) mice, but only in terms of small intestinal weight when normalized for body weight. Furthermore, Igf2(-P) mice demonstrated a partially impaired response in terms of small intestinal growth. Both Igf1(-/-) and Igf2(-P) mice exhibited normal-enhanced intestinal growth in response to IGF-1 and/or R-Spondin1.


CONCLUSIONS
GLP-2 enhances intestinal IGF-1 expression and secretion, and IGF-1 is required for small and large intestinal growth in response to GLP-2. These findings identify IGF-1 as an essential mediator of the intestinotropic actions of GLP-2.
Dubé
Philip E
PE
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Forse
Catherine L
CL
Bahrami
Jasmine
J
Brubaker
Patricia L
PL
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D004763:Glucagon-Like Peptides / Q000494:pharmacology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D004763:Glucagon-Like Peptides; D007334:Insulin-Like Growth Factor I; D052216:Glucagon-Like Peptide 1