title: The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes.
abstract: Metformin is the most frequently used drug for the treatment of type 2 diabetes in humans. However, only little is known about effects of metformin on brain metabolism. To investigate potential metabolic consequences of an exposure of brain cells to metformin, we incubated rat astrocyte-rich primary cultures with this compound. Metformin in concentrations of up to 30 mM did not acutely compromise the viability of astrocytes, but caused a time- and concentration-dependent increase in cellular glucose consumption and lactate production. For acute incubations in the hour range, the presence of 10 mM metformin doubled the glycolytic flux, while already 1 mM metformin doubled glycolytic flux during incubation for 24 h. In addition to metformin, also other guanidino compounds increased astrocytic lactate production. After 4 h of incubation, half-maximal stimulation of glycolysis was observed for metformin, guanidine and phenformin at concentrations of around 3 mM, 3 mM and 30 µM, respectively. The acute stimulation of glycolytic lactate production by metformin was persistent after removal of extracellular metformin and was also observed, if glucose was absent from the incubation medium or replaced by other hexoses. The metformin-induced stimulation of glycolytic flux was not prevented by compound C, an inhibitor of AMP-dependent protein kinase, nor was it additive to the stimulation of glycolytic flux caused by respiratory chain inhibitors. These data demonstrate that the antidiabetic drug metformin has the potential to strongly activate glycolytic lactate production in brain astrocytes.
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, PO. Box 330440, 28334, Bremen, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Westhaus
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, PO. Box 330440, 28334, Bremen, Germany.|Centre for Environmental Research and Sustainable Technology, Leobener Strasse, 28359, Bremen, Germany.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Blumrich
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, PO. Box 330440, 28334, Bremen, Germany. ralf.dringen@uni-bremen.de.|Centre for Environmental Research and Sustainable Technology, Leobener Strasse, 28359, Bremen, Germany. ralf.dringen@uni-bremen.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dringen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D019344:Lactic Acid / Q000096:biosynthesis*; D008687:Metformin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin; D005947:Glucose
keywords: Astrocytes; Diabetes; Glucose; Glycolysis; Lactate