Insulin sensitizers regulate pyruvate oxidation through a mitochondrial target (mTOT) (ADA 2012) - May 25, 2012 - Publication-only abstracts; MSDC-0160 at 10μM reduces uncoupler-stimulated respiration rates by roughly 50% in cells oxidizing pyruvate, but has no effect on the rate of oxidation of glutamate, succinate, or palmitoyl carnitine
Review • Diabetes
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American Diabetes Association - 72nd Scientific Sessions June 8 - 12, 2012, Philadelphia, PA
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Abstract # 2484-PO
Thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, promote insulin sensitization in human skeletal muscle and increase its capacity to oxidize fatty acids. As PPAR-γ agonists, however, these TZDs cause marked side effects that can be clinically prohibitive (including plasma volume expansion, increased adiposity, congestive heart failure, and cardiovascular risk). A target of insulin sensitizers located in the mitochondrial inner membrane, mTOT was recently identified by photoaffinity crosslinking and proteomics. It was suggested that the insulin-sensitizing pharmacology of TZDs involves this target, perhaps through regulation of a mitochondrial signal. We find MSDC-0160, a prototype compound with higher affinity binding to mitochondria versus PPARγ, acutely and selectively inhibits pyruvate oxidation at clinically relevant concentrations in permeabilized human and rodent myocytes. MSDC-0160 at 10μM reduces uncoupler-stimulated respiration rates by roughly 50% in cells oxidizing pyruvate, but has no effect on the rate of oxidation of glutamate, succinate, or palmitoyl carnitine. In contrast, MSDC-1473, a close analog that is not insulin sensitizing and does not bind to mTOT, has no effect on pyruvate-driven respiration. Virally mediated overexpression of mTOT necessitates an increased concentration of MSDC-0160 in order to achieve inhibition of pyruvate oxidation. Prolonged treatment with active compound stimulates a marked increase in the expression of ETF dehydrogenase of β-oxidation. This increase is entirely absent upon mTOT knockdown. Our data indicate mTOT is a previously uncharacterized component of the regulation of mammalian pyruvate oxidation. Moreover, we suggest that insulin sensitizing agents act acutely via mTOT, regulating the utilization of pyruvate and thereby promoting a beneficial shift towards fatty acid oxidation in skeletal muscle myocytes.
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