title: Enhanced secretion of glucagon-like peptide 1 by biguanide compounds.
abstract: Metformin was reported to increase plasma active glucagon-like peptide-1 (GLP-1) in humans. There are two possible mechanisms for this effect: (1) metformin inhibits dipeptidyl peptidase IV (DPPIV), an enzyme degrading GLP-1, and (2) metformin enhances GLP-1 secretion. To elucidate the mechanism(s), we examined (1) IC(50) of metformin for DPPIV inhibition, (2) plasma active GLP-1 changes after oral biguanide (metformin, phenformin, and buformin) treatment in fasting DPPIV-deficient F344/DuCrj rats, and (3) plasma intact GLP-1 excursions after oral administration of metformin and/or valine-pyrrolidide, a DPPIV inhibitor, in fasting DPPIV-positive F344/Jcl rats. Our in vitro assay showed that metformin at up to 30mM has no inhibitory activity towards porcine or rat DPPIV. Metformin treatment (30, 100, and 300mg/kg) increased plasma active GLP-1 levels dose-dependently in DPPIV-deficient F344/DuCrj rats (approximately 1.6-fold at 3 and 5h after administration of 300mg/kg). This treatment had no effect on blood glucose levels. Similarly, phenformin and buformin (30 and 100mg/kg) elevated plasma intact GLP-1 levels in F344/DuCrj rats. In DPPIV-positive F344/Jcl rats, coadministration of metformin (300mg/kg) and valine-pyrrolidide (30mg/kg) resulted in elevation of plasma active GLP-1, but neither metformin nor valine-pyrrolidide treatment alone had any effect. These findings suggest that metformin has no direct inhibitory effect on DPPIV activity and that metformin and the other biguanides enhance GLP-1 secretion, without altering glucose metabolism. Combination therapy with metformin and a DPPIV inhibitor should be useful for the treatment of diabetes.
authors.affiliation: Tsukuba Research Laboratories, Eisai Company Limited, 5-1-3, Tokodai, Tsukuba, Ibaraki, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yasuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagakura
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kira
authors.forename: Takao
authors.initials: T
authors.lastname: Saeki
authors.forename: Isao
authors.initials: I
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001645:Biguanides / Q000494:pharmacology*; D002026:Buformin / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008687:Metformin / Q000494:pharmacology; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*; D010629:Phenformin / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014633:Valine / Q000494:pharmacology
chemical_list: D001645:Biguanides; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011498:Protein Precursors; D011758:Pyrroles; C112092:valine-pyrrolidide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008687:Metformin; D010629:Phenformin; D018819:Dipeptidyl Peptidase 4; D014633:Valine; D005947:Glucose; D002026:Buformin