Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats.
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 upregulating the intestinotrophic hormone GLP-2. This study compared the intestinotrophic effects of 12-wk administration of vehicle, exendin-4 (Ex-4; 5 nmol/kg bid sc), or DPPIV-I (NN-7201, 10 mg/kg qd orally) in GK rats. Some animals were observed additionally for 9 wk after the end of treatment. Both treatments lowered glycated hemoglobin A1c at wk 12 vs. control (Ex-4, -0.8%; DPPIV-I, -0.4%). Body weight was reduced by Ex-4 compared with control (361 +/- 4 vs. 399 +/- 5 g; P < 0.001) because of 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 wk 21, body weight was identical in all groups. The small intestine of Ex-4-treated animals was larger at wk 12 compared with 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 body weight increased by 24% because of increased mucosal thickness. These effects were reversible, and 9 wk after the end of 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 antihyperglycemic treatment with Ex-4 increases intestinal mass reversibly, whereas DPPIV-I lacks intestinal effects.
Simonsen
Lotte
L
Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Pilgaard
Sofie
S
Orskov
Cathrine
C
Rosenkilde
Mette M
MM
Hartmann
Bolette
B
Holst
Jens J
JJ
Deacon
Carolyn F
CF
D000818:Animals; D001835:Body Weight; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004435:Eating; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D000067758:Glucagon-Like Peptide-2 Receptor; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology*; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists* / Q000187:drug effects; D014162:Transfection; D014688:Venoms / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology*
D000242:Cyclic AMP; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D000067758:Glucagon-Like Peptide-2 Receptor; D006442:Glycated Hemoglobin; D010455:Peptides; D011480:Protease Inhibitors; D018027:Receptors, Glucagon; D014688:Venoms; D014970:Xanthines; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; C522532:NN 7201