title: Metformin effects on dipeptidylpeptidase IV degradation of glucagon-like peptide-1.
abstract: There is current interest in the use of inhibitors of dipeptidyl peptidase IV (DP IV) as therapeutic agents to normalize glycemic excursions in type 2 diabetic patients. Data indicating that metformin increases the circulating amount of active glucagon-like peptide-1 (GLP-1) in obese nondiabetic subjects have recently been presented, and it was proposed that metformin might act as a DP IV inhibitor. This possibility has been investigated directly using a number of in vitro methods. Studies were performed on DP IV enzyme from three sources: 20% human serum, purified porcine kidney DP IV, and recombinant human DP IV. Inhibition of DP IV hydrolysis of the substrate Gly-Pro-pNA by metformin was examined spectrophotometrically. Effects of metformin on GLP-1([7-36NH2]) degradation were assessed by mass spectrometry. In addition, surface plasmon resonance was used to establish whether or not metformin had any effect on GLP-1([7-36NH2]) or GLP-1([9-36NH2]) interaction with immobilized porcine or human DP IV. Metformin failed to alter the kinetics of Gly-Pro-pNA hydrolysis or GLP-1 degradation tested according to established methods. Surface plasmon resonance recordings indicated that both GLP-1([7-36NH2]) and GLP-1([9-36NH2]) show micromolar affinity (K(D)) for DP IV, but neither interaction was influenced by metformin. The results conclusively indicate that metformin does not act directly on DP IV, therefore alternative explanations for the purported effect of metformin on circulating active GLP-1 concentrations must be considered.
authors.affiliation: Probiodrug Research, Biocenter, Weinbergweg 22, D-06120 Halle (Saale), Germany.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hinke
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kühn-Wache
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Pederson
authors.forename: Christopher H S
authors.initials: CH
authors.lastname: McIntosh
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D006801:Humans; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007700:Kinetics; D008687:Metformin / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013379:Substrate Specificity; D013552:Swine
chemical_list: D004151:Dipeptides; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D011498:Protein Precursors; D011994:Recombinant Proteins; C039234:glycyl-proline-1-naphthylamide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008687:Metformin; D018819:Dipeptidyl Peptidase 4