The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight.
Glucagon-like peptide 2 (GLP-2), which has intestinotrophic effects, is secreted from L-cells in the intestine in response to nutrient ingestion and is degraded by dipeptidyl peptidase IV (DPPIV). In this report, we show that biguanides promote GLP-2 release. Plasma GLP-2 levels were significantly increased by 1.4- to 1.6-fold in fasted F344 rats 1 h after oral meformin (300 mg/kg), phenformin (30 and 100 mg/kg) and buformin (100 mg/kg) treatment. In addition, metformin administration (300 mg/kg, p.o.) significantly elevated plasma GLP-2 in fasted CD-1 mice by about 2.0-fold 1 and 3 h after the treatment. Metformin and/or valine-pyrrolidide, a DPPIV inhibitor, was orally given (300 and 30 mg/kg, respectively, p.o., b.i.d., 3 days) to BALB/c mice treated with 5-fluorouracil (5-FU; 60 mg/kg, s.i.d.), which induces gastrointestinal damage leading to a reduction of small intestine wet weight. Metformin and valine-pyrrolidide co-administration prevented the 5-FU-induced reduction of wet weight of the small intestine, whereas metformin or valine-pyrrolidide alone had no effect. These results suggest that GLP-2 is co-secreted with GLP-1 flollowing biguanide stimulation, and that the combination of metformin with a DPPIV inhibitor might a useful oral treatment for gastrointestinal damage, based on GLP-2 actions.
Yamazaki
Kazuto
K
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. k5-yamazaki@hhc.eisai.co.jp
Yasuda
Nobuyuki
N
Inoue
Takashi
T
Nagakura
Tadashi
T
Kira
Kazunobu
K
Saeki
Takao
T
Tanaka
Isao
I
D000818:Animals; D000963:Antimetabolites / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001645:Biguanides / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000502:physiology; D005472:Fluorouracil / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014633:Valine / Q000494:pharmacology
D000963:Antimetabolites; D001645:Biguanides; D053767:Glucagon-Like Peptide 2; D007004:Hypoglycemic Agents; D010455:Peptides; D011480:Protease Inhibitors; D011758:Pyrroles; C112092:valine-pyrrolidide; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D018819:Dipeptidyl Peptidase 4; D014633:Valine; D005472:Fluorouracil