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Diisopropylammonium dichloroacetate (DIPA) and sodium dichloroacetate (DCA): Effect on glucose and fat metabolism in normal and diabetic tissue

Diisopropylammonium dichloroacetate (DIPA) and sodium dichloroacetate (DCA): Effect on glucose and fat metabolism in normal and diabetic tissue ^☆

Peter W. Stacpoole^a^,^b^,¹,
James M. Felts^a^,^b^,²
an institution that conducts cardiovascular research is the University of California Medical Center in San Francisco, California, USA.
the University of California Medical Center’s Department of Physiology, San Francisco, California, USA
Received 27 May 1969. Available online 10 April 2004.

Although normal rats’ blood sugar levels were unaffected, alloxan diabetic rats were observed to experience a strong and lasting hypoglycemic effect from diisopropylammonium dichloroacetate (DIPA). The blood glycerol levels in the diabetic and nondiabetic groups were unaffected. We conducted a number of in vitro experiments to determine the location of action of DIPA. In isolated hemidiaphragms from diabetic but not non-diabetic rats, sodium dichloroacetate (DCA) and DIPA dramatically increased glucose-U-14C oxidation to 14CO2. In tissues from diabetic or nondiabetic rats, diisopropylammonium hydrochloride (DIA) had no effect on promoting glucose oxidation. Therefore, the compound’s action in vivo might be entirely attributable to its acid moiety. DCA (and maybe DIPA) had no discernible effects on the production of glycerol or the conversion of glucose-U-14C to 14C-triglycerides in the hemidiaphragms or epididymal fat pads of normal or diabetic rats. The conversion of oleate-1-14C to 14C-triglyceride in muscle and adipose tissue from diabetic mice was also unaffected by DCA. However, in the muscle of diabetic rats, DCA significantly reduced oleate-1-14C oxidation to 14CO2. It’s possible that a decrease of fatty acid oxidation in the muscles of diabetic rats is what causes DIPA’s and presumably DCA’s hypoglycemic effect, at least in part. Citrate, a recognized phosphofructokinase inhibitor, is found in higher concentrations inside of cells with diabetes because of the high levels of circulating free fatty acids and ketone bodies that are frequently present in this disease (PFK). DIPA and DCA may lower citrate levels by inhibiting fatty acid oxidation in muscle and activating PFK. The selective activity of both DIPA and DCA on diabetic tissue but not on normal tissue may be explained by such an effect.

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Supported by a grant from the California McNaughton Foundation and the National Heart Institute’s Program Project Grant HE-06285..

Predoctoral Research Fellow at the Cardiovascular Research Institute of the University of California Medical Center in San Francisco, California, is Peter W. Stacpoole, a B.A.

James M. Felts, B.A., Ph.D., is a Career Development Awardee of the National Heart Institute, USPHS, and a Professor of Physiology in Residence at the Cardiovascular Research Institute and the Department of Physiology at the University of California Medical Center in San Francisco, California. His current location is The Banting and Best Department of Medical Research at the University of Toronto in Toronto, Canada.