Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.

Clark, A. Clay; Goodman, M N; Fagan, Julie M.; Goheer, M. Anwar; Curnow, Randall T.

doi:10.1172/jci112851

Cited by 42 publications

(21 citation statements)

References 35 publications

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“…Our data are consistent with those of previous studies in isolated skeletal and cardiac muscles (6,10,11,27). Pearce and Connett (27) showed that 8 mM lactate resulted in profound decreases in insulin-stimulated glucose oxidation and lactate production in isolated soleus muscles.…”

Section: Discussionsupporting

confidence: 94%

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Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

Choi

Kim

Lee

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

122

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tion of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding insulin resistance and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport decreased 25-30% (P Ͻ 0.05) in soleus but not in epitrochlearis muscles of lactate-infused rats. Lactate infusion did not alter insulin's ability to phosphorylate the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1-and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively (P Ͻ 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle. glucose transport; euglycemic clamp; rat GLUT4

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Section: Discussionsupporting

confidence: 94%

“…Lactate was shown to decrease glycolysis, and thus its own production, in isolated rat skeletal muscle (6,27). In humans, lactate infusion inhibited endogenous lactate production (32).…”

mentioning

confidence: 99%

Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

Choi

Kim

Lee

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

122

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“…These findings are consistent with a reduction in fatty acid oxidation, increased glucose oxidation, and decreased lipolysis in DCAtreated animals. Plasma lactate concentrations were also reduced, consistent with an increased level of lactate oxidation and a reduction in skeletal muscle glycolysis 43 after DCA administration. The levels of ␤-hydroxybutyrate, which were elevated in the T3 animals relative to controls, were further increased in the DCA-treated animals.…”

Section: Effects Of Dichloroacetic Acid Treatment On the Hyperthyroidmentioning

confidence: 53%

Role of Pyruvate Dehydrogenase Inhibition in the Development of Hypertrophy in the Hyperthyroid Rat Heart

et al. 2011

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Background-Hyperthyroidism increases heart rate, contractility, cardiac output, and metabolic rate. It is also accompanied by alterations in the regulation of cardiac substrate use. Specifically, hyperthyroidism increases the ex vivo activity of pyruvate dehydrogenase kinase, thereby inhibiting glucose oxidation via pyruvate dehydrogenase. Cardiac hypertrophy is another effect of hyperthyroidism, with an increase in the abundance of mitochondria. Although the hypertrophy is initially beneficial, it can eventually lead to heart failure. The aim of this study was to use hyperpolarized magnetic resonance spectroscopy to investigate the rate and regulation of in vivo pyruvate dehydrogenase flux in the hyperthyroid heart and to establish whether modulation of flux through pyruvate dehydrogenase would alter cardiac hypertrophy. Methods and Results-Hyperthyroidism was induced in 18 male Wistar rats with 7 daily intraperitoneal injections of freshly prepared triiodothyronine (0.2 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ). In vivo pyruvate dehydrogenase flux, assessed with hyperpolarized magnetic resonance spectroscopy, was reduced by 59% in hyperthyroid animals (0.0022Ϯ0.0002 versus 0.0055Ϯ0.0005 second Ϫ1 ; Pϭ0.0003), and this reduction was completely reversed by both short-and long-term delivery of dichloroacetic acid, a pyruvate dehydrogenase kinase inhibitor. Hyperpolarized [2-13 C]pyruvate was also used to evaluate Krebs cycle metabolism and demonstrated a unique marker of anaplerosis, the level of which was significantly increased in the hyperthyroid heart. Cine magnetic resonance imaging showed that long-term dichloroacetic acid treatment significantly reduced the hypertrophy observed in hyperthyroid animals (100Ϯ20 versus 200Ϯ30 mg; Pϭ0.04) despite no change in the increase observed in cardiac output.Conclusions-This work has demonstrated that inhibition of glucose oxidation in the hyperthyroid heart in vivo is mediated by pyruvate dehydrogenase kinase. Relieving this inhibition can increase the metabolic flexibility of the hyperthyroid heart and reduce the level of hypertrophy that develops while maintaining the increased cardiac output required to meet the higher systemic metabolic demand. (Circulation. 2011;123:2552-2561.)Key Words: hyperthyroidism Ⅲ magnetic resonance spectroscopy Ⅲ pyruvate dehydrogenase complex T hyroid hormones regulate many aspects of growth, development, and energy metabolism, and are critical for normal cell function in multiple organs. [1][2][3] The heart is particularly sensitive to the action of thyroid hormones, with thyroid dysfunction having detrimental effects on the cardiovascular system. Minimal alterations in circulating thyroid hormone concentrations significantly alter many cardiac parameters. For instance, an increase in circulating thyroid hormone markedly increases heart rate, contractility, and cardiac output. 4 -7 Furthermore, hyperthyroid patients often develop hypertrophy, tachycardia, palpitations, fatigue, and atrial arrhythmias. 8 Clinical Perspective on p 2561Hyperthyroidism is acc...

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“…Because of its known mechanism of action, high doses of DCA have been used clinically to treat lactic acidosis (36 -38) via lactate suppression, and it is also currently in clinical trials for the treatment of cancer (39 -41). In addition, DCA has been shown to stimulate glycogen synthesis in isolated primary hepatocytes (42) in the liver (43) and muscle (44) after oral administration and reported to stimulate insulin secretion and lower glucose concentration in the periphery after intracerebra ventricular administration (45), which is very similar to that of L-lactate (45). It is important to note that the concentration for DCA is often very high when administered in vivo (100 mg/kg to 1 g/kg) or used in the cell culture (1-10 mM), which suggests that the DCA concentrations might be sufficient to activate GPR81.…”

Section: Discussionmentioning

confidence: 99%

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

Liu

Zhu

et al. 2009

Journal of Biological Chemistry

449

439

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Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1-20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders. GPR81(1) is an orphan G-protein-coupled receptor that is highly homologous to GPR109a and GPR109b. GPR109a and GPR109b were recently identified as receptors for niacin (also known as nicotinic acid) (2, 3) and subsequently characterized as receptors for the endogenous ketone body ␤-hydroxybutyrate (4). Niacin has been used clinically for a half-century as an effective treatment for dyslipidemia (5); however, its utility is somewhat hampered by a target-related effect on dendritic Langerhans cells, which release prostaglandin D2 in response to GPR109a stimulation, resulting in a cutaneous flushing response (6 -8). GPR81 is highly expressed in fat, similar to GPR109a, but is not expressed significantly in spleen; nor is it highly detected in any other tissue, and it has thus been hypothesized to be a potential target for the treatment of dyslipidemia that would be analogous to GPR109a/niacin but without the potential side effects (9).In this report, we demonstrate the initial identification of the ligand activity for GPR81 from the rat tissue extracts, the purification of L-lactate from porcine brain as the source of the ligand activity, and the pharmacological characterization of L-lactate as a ligand for GPR81. In addition, we show that in its physiological concentration range, L-lactate effectively inhibits lipolysis in adipocytes from humans, mice, and rats. Adipocytes from GPR81-deficient mice lack responses to L-lactate, indicating that the antilipolytic effect of L-lactate is mediated by GPR81. Despite a long history of being considered as waste or a by-product of metabolism, L-lactate has maintained some attention as a potential signaling molecule (10). As early as the 1960s, researchers have demonstrated significant effects of lactate on adipocytes (11); however, the mechanism by which this occurs has remained unknown. Our...

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Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.

Cited by 42 publications

References 35 publications

Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

Role of Pyruvate Dehydrogenase Inhibition in the Development of Hypertrophy in the Hyperthyroid Rat Heart

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

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