Diisopropylammonium dichloroacetate: Regulation of metabolic intermediates in muscle of alloxan diabetic rats

Abstract

Diisopropylammonium dichloroacetate (DIPA) is known to produce a significant and prolonged hypoglycemic effect in alloxan-diabetic but not in normal rats. The active component of this compound is its acid moiety, dichloroacetate (DCA). Both DIPA and DCA stimulate glucose oxidation in diabetic muscle in vitro. DCA inhibits fatty acid oxidation in isolated diaphragms from diabetic rats. The present study shows that tissue concentrations of citrate are increased eight-fold in hearts and 4.6-fold in diaphragms of alloxan-diabetic rats. Alpha glycerol phosphate (α-GP) concentrations are reduced in hearts from diabetic rats. DIPA administered intraperitoneally markedly reduces tissue concentrations of citrate in hearts and diaphragms of alloxan-diabetic rats but has no effect on citrate in hearts and diaphragms of normal rats. The reduction of citrate in hearts of diabetic rats is accompanied by an increase in the intracellular concentration of α-GP. In hearts from diabetic animals treated with DIPA, both citrate and α-GP levels are similar to those found in hearts from untreated normal rats. DIPA administration has little effect on the concentrations of pyruvate or lactate in diabetic muscle. In diabetes excess fatty acid oxidation raises intracellular concentrations of citrate, a known inhibitor of phosphofructokinase (PFK). The results of the present investigation are consistent with the hypothesis that the selective hypoglycemic effect of DIPA is due, at least in part, to a suppression of fatty acid oxidation in diabetic muscle that results in a lowering of muscle citrate. The reduction in citrate levels reactivates PFK and promotes accelerated utilization of glucose.