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Metformin Attenuates a Complex I Mediated Increase in Mitochondrial Oxidant Emitting Potential in Skeletal Muscle of Obese Zucker Rats
Author(s) -
Kane Daniel A.,
Anderson Ethan J.,
Woodlief Tracey L.,
Price Jesse W.,
Bickman Benjamin T.,
Cortright Ronald N.,
Neufer P. Darrell
Publication year - 2008
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.22.1_supplement.958.7
Subject(s) - metformin , endocrinology , medicine , skeletal muscle , chemistry , mitochondrial ros , mitochondrion , insulin , biochemistry , oxidative stress
Metformin (MET) is currently the most popular antidiabetic drug, although its insulin sensitizing mechanism of action is unknown. To test the effects of metformin (MET) on skeletal muscle mitochondrial function, we measured both mitochondrial respiration and H 2 O 2 emission in saponin‐permeabilized red gastrocnemius muscle fiber bundles from lean and obese Zucker (fa/fa) rats that had been treated with MET for 4 wks. MET treatment significantly ( p =.03) improved insulin sensitivity (HOMA) in obese, but not lean rats. In permeabilized fibers, ADP‐stimulated state 3, but not basal state 4, respiration rates were greater in obese vs. lean rats. However, MET treatment did not significantly affect permeabilized fibers respiring on palmitoyl‐carnitine (PC), complex I‐ or complex II‐linked substrates. Surprisingly, H 2 O 2 emission induced by reverse electron flow (titration of complex II substrate succinate) was more than 2‐fold higher in obese vs lean rats. MET treatment significantly ( p <.05) attenuated succinate‐ and PC‐induced H 2 O 2 emission in both lean and obese rats. These results suggest that 1) obesity is associated with a marked increase in mitochondrial ROS emitting potential in skeletal muscle, and 2) metformin may exert its antidiabetic effects by inhibiting complex I mediated ROS production, thereby decreasing the susceptibility to conditions favoring ROS emission. Support: NIH DK061314 and DK073488