Diisopropylammonium dichloroacetate (DIPA) and sodium dichloroacetate (DCA): Effect on glucose and fat metabolism in normal and diabetic tissue ☆
- Peter W. Stacpoolea, b, 1,
- James M. Feltsa, b, 2
- a Cardiovascular Research Institute, University of California Medical Center, San Franciso, Calif., USA
- b the Department of Physiology, University of California Medical Center, San Francisco, Calif., USA
- Received 27 May 1969. Available online 10 April 2004.
Diisopropylammonium dichloroacetate (DIPA) was found to exert a significant and prolonged hypoglycemic effect in alloxan diabetic rats, but did not alter blood sugar levels of normal rats. It did not affect blood glycerol levels in either the diabetic or nondiabetic group. In order to establish the site of action of DIPA, we carried out a series of in vitro studies. Both DIPA and sodium dichloroacetate (DCA) significantly stimulated glucose-U-14C oxidation to 14CO2 in isolated hemidiaphragms from diabetic but not from nondiabetic rats. Diisopropylammonium hydrochloride (DIA) was not effective in promoting glucose oxidation in tissues from diabetic or nondiabetic rats. Thus, the effect of the compound in vivo may be due entirely to its acid moiety. DCA (and presumably DIPA) produced no significant changes in glycerol output or on glucose-U-14C conversion to 14C-triglyceride in hemidiaphragms or epididymal fat pads from normal or diabetic rats. In addition, DCA did not alter oleate-1-14C conversion to 14C-triglyceride in muscle or adipose tissue from diabetic animals. However, DCA markedly inhibited oleate-1-14C oxidation to 14CO2 in muscle from diabetic rats. It is possible that the hypoglycemic activity of DIPA, and presumably DCA, may be due, at least partly, to a suppression of fatty acid oxidation in muscles of diabetic rats. The high levels of circulating free fatty acids and ketone bodies which commonly occur in diabetes increase intracellular concentrations of citrate, a known inhibitor of phosphofructokinase (PFK). By suppressing fatty acid oxidation in muscle, DIPA and DCA may thus reduce citrate levels and reactivate PFK. Such an effect may explain the selective action of both DIPA and DCA on diabetic but not on normal tissue.
Supported by a grant from the McNaughton Foundation of California and by NIH Program Project Grant HE-06285 from the National Heart Institute.
Peter W. Stacpoole, B.A.: Predoctoral Research Fellow, Cardiovascular Research Institute, University of California Medical Center, San Francisco, Calif.
James M. Felts, B.A., Ph.D.: Professor of Physiology in Residence, Cardiovascular Research Institute and the Department of Physiology, University of California Medical Center, San Francisco, Calif.: Career Development Awardee of the National Heart Institute, USPHS; present address: The Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada.
Copyright © 1970 Published by Elsevier Inc.