Hypoglycaemic action of DIISOpropylammonium salts in experimental diabetes

Lorini, M.; Ciman, M.

doi:10.1016/0006-2952(62)90177-6

Cited by 49 publications

(13 citation statements)

References 3 publications

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“…PDH, a key enzyme in this complex, is inactivated when phosphorylated by a specific PDH kinase and reactivated by dephosphorylation. Diisopropylammonium dichloroacetate was found to lower glucose levels in diabetic animals (20), and dichloroacetate was found to be the active moiety (21). Subsequently, dichloroacetate administration to perfused rat hearts was found to stimulate myocardial PDH activity by inhibiting its phosphorylation by PDH kinase (22,23).…”

Section: Discussionmentioning

confidence: 99%

Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo

Itoh

Esaki

Shimoji

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

265

248

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Neuronal cultures in vitro readily oxidized both D-[ 14 C]glucose and L-[14C]lactate to 14 CO2, whereas astroglial cultures oxidized both substrates sparingly and metabolized glucose predominantly to lactate and released it into the medium. [ 14 C]Glucose oxidation to 14 CO2 varied inversely with unlabeled lactate concentration in the medium, particularly in neurons, and increased progressively with decreasing lactate concentration. Adding unlabeled glucose to the medium inhibited [ 14 C]lactate oxidation to 14 CO2 only in astroglia but not in neurons, indicating a kinetic preference in neurons for oxidation of extracellular lactate over intracellular pyruvate͞ lactate produced by glycolysis. Protein kinase-catalyzed phosphorylation inactivates pyruvate dehydrogenase (PDH), which regulates pyruvate entry into the tricarboxylic acid cycle. Dichloroacetate inhibits this kinase, thus enhancing PDH activity. In vitro dichloroacetate stimulated glucose and lactate oxidation to CO2 and reduced lactate release mainly in astroglia, indicating that limitations in glucose and lactate oxidation by astroglia may be due to a greater balance of PDH toward the inactive form. To assess the significance of astroglial export of lactate to neurons in vivo, we attempted to diminish this traffic in rats by administering dichloroacetate (50 mg͞kg) intravenously to stimulate astroglial lactate oxidation and then examined the effects on baseline and functionally activated local cerebral glucose utilization (lCMRglc). Dichloroacetate raised baseline lCMRglc throughout the brain and decreased the percent increases in lCMRglc evoked by functional activation. These studies provide evidence in support of the compartmentalization of glucose metabolism between astroglia and neurons but indicate that the compartmentalization may be neither complete nor entirely obligatory.G lucose is an essential and normally almost exclusive substrate for cerebral energy metabolism (1). As in other tissues, it is metabolized in brain in two sequential pathways, first to pyruvate͞lactate by glycolysis in cytosol, followed by oxidation in mitochondria to CO 2 and H 2 O. It was recently proposed that the glycolytic and oxidative components of glucose and glycogen metabolism are compartmentalized not only between cytosol and mitochondria but also between astroglia and neurons, i.e., glucose and glycogen metabolism in astroglia to lactate, which is then exported to neurons where it is oxidized to provide the ATP needed for neuronal function (2, 3). Arguments in support of this hypothesis are: (i) capillaries in brain are largely enveloped by astroglial processes that present a barrier to the transport of glucose from blood to neurons; (ii) glycogen in brain is confined almost entirely to astrocytes; (iii) astrocytes in culture readily metabolize glucose to lactate and release it into the medium (4, 5); and (iv) glutamate, the most prevalent excitatory neurotransmitter in brain, stimulates aerobic glycolysis in cultured astrocytes (6, 7). Much of the evidence suppo...

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Section: Discussionmentioning

confidence: 99%

Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo

Itoh

Esaki

Shimoji

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

265

248

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“…From the 1950s-1960s, diisopropylammonium dichloroacetate (DIPA) and other salts or ionic complexes of DCA were investigated experimentally and clinically for diverse indications, with little insight into how or where they acted (Stacpoole, 1969). Among the more intriguing properties of DIPA was its ability to lower blood glucose levels in rats with chemically-induced diabetes, but not in non-diabetic animals (Lorini & Ciman, 1962), a property subsequently found to be due solely to the DCA anion (Stacpoole & Felts, 1970). During the 1970s-1980s, the metabolic effects of DCA as the sodium salt were studied extensively and its primary sites and mechanisms of action were established (Stacpoole, 1989).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

106

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Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.

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“…Evidence is given that dichloroacetate may facilitate the conversion of pyruvate dehydrogenase from an inactive (phosphorylated) form into an active (dephosphorylated) form. Lorini & Ciman (1962) showed that injection of diisopropylammonium dichloroacetate may increase the respiratory quotient in alloxan-diabetic rats, thus suggesting that this compound may stimulate glucose oxidation and inhibit fatty acid oxidation. Experiments with rat diaphragm and rat heart in vitro showed that sodium dichloroacetate stimulates glucose oxidation when this has been inhibited by acetate or 3-hydroxybutyrate or palmitate or by induction of alloxan-diabetes (Stacpoole & Felts, 1970McAllister & Randle, 1970;McAllister et al, 1973).…”

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confidence: 99%

Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate (Short Communication)

Whitehouse

Randle

1973

Biochemical Journal

174

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The activity of pyruvate dehydrogenase was assayed in extracts of rat hearts perfused in vitro with media containing glucose and insulin±acetate±dichloroacetate. Dichloroacetate (100μm, 1mm or 10mm) increased the activity of pyruvate dehydrogenase in perfusions with glucose or glucose+acetate. Evidence is given that dichloroacetate may facilitate the conversion of pyruvate dehydrogenase from an inactive (phosphorylated) form into an active (dephosphorylated) form.

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Hypoglycaemic action of DIISOpropylammonium salts in experimental diabetes

Cited by 49 publications

References 3 publications

Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo

Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate (Short Communication)

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