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The antidiabetic metformin is toxic to liver mitochondria of Zucker Diabetic Fatty (ZDF) rats: a cellular metabolomic study with 13C‐lactate and carbon 13 NMR
Author(s) -
Baverel Gabriel,
Pinteur Claudie,
Martin Guy,
Gauthier Catherine
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.665.2
Subject(s) - gluconeogenesis , metformin , chemistry , glycolysis , lactic acid , citric acid cycle , medicine , endocrinology , glycogenesis , tricarboxylic acid , ketogenesis , glucose uptake , lactate dehydrogenase , glycogen , metabolism , biochemistry , insulin , ketone bodies , glycogen synthase , biology , enzyme , bacteria , genetics
Metformin decreases hyperglycemia in diabetic subjects and animals. This effect results in part from the inhibition of hepatic gluconeogenesis. The objective of this study was to investigate in vitro the effect of metformin on hepatic lactate gluconeogenesis by using an innovative approach. Precision‐cut liver slices from adult male ZDF rats were incubated with variously 13 C‐labeled lactates (5 mM) or with 5 mM unlabeled lactate plus 25 mM 13 C‐bicarbonate. Substrate removal and product formation were measured by enzymatic and 13 C‐NMR methods. In slices from fasted lean ZDF rats, metformin dose‐dependently inhibited 13 C‐glucose synthesis from [2‐ 13 C]‐lactate (IC50 2.3 mM). The labeling patterns of the glucoses synthesized indicated that lactate gluconeogenesis involved not only the passage of carbons through pyruvate carboxylase and the reversible equilibration of oxaloacetate with fumarate but also the entire tricarboxylic acid cycle. In slices from fed diabetic ZDF rats, 2 mM metformin inhibited lactate consumption, glucose production, the synthesis of all the 13 C‐labeled glucose carbons, the production of 13 CO 2 and reduced the cellular ATP level. By contrast, metformin dramatically increased lactic acid production and ketogenesis. These results strongly suggest that a compound found to be toxic to liver mitochondria in vitro should not necessarily be withdrawn from drug development.