Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dichloroacetate (DCA) is gaining use as an alternative to bicarbonate therapy in the treatment of lactic acidosis. To determine the mechanism(s) by which DCA lowers blood lactate levels, we studied its effect on the kinetic interrelationships between pyruvate, lactate, alanine, and glucose in the hindlimb of dogs during hormonal stimulation of pyruvate production (Ra) and its conversion to lactate. Three groups of dogs (n = 6) were infused with 1-13C-pyruvate to measure whole body pyruvate Ra, and pyruvate Ra and utilization (Rd) across the hindlimb during either a 4-hr infusion of saline (controls), or somatostatin, glucagon, and epinephrine (SGE), or SGE plus dichloroacetate (SGE + DCA). Pyruvate Ra was used as an index of rate of glycolysis and Rd as an index of pyruvate oxidation. In the controls, all kinetic parameters were constant during the saline infusion. Hindlimb pyruvate Ra and Rd were almost equal, and lactate release negligible. Compared to controls, SGE administration significantly increased (P < 0.05) wholebody pyruvate Ra (48.5 +/- 6.2 vs 33.6 +/- 2.4 mumol/kg/min) and blood lactate levels (P < 0.05). Hindlimb pyruvate Ra increased by approximately 150%, but Rd remained unchanged resulting in marked increases in lactate and alanine effluxes. Adding DCA to the SGE infusion significantly reduced wholebody pyruvate Ra (P < 0.05) and blood lactate levels (P < 0.01). In the hindlimb, however, there was no decrease in lactate output, despite a 91% increase in pyruvate utilization because pyruvate Ra also increased. These results suggest that during stimulation of rate of glycolysis, DCA lowers lactate levels by reducing the overall availability of pyruvate for lactate synthesis. This is accomplished by suppressing the rate of glycolysis in tissues other than skeletal muscle and stimulating pyruvate oxidation.
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PMID:Mechanisms by which dichloroacetate lowers lactic acid levels: the kinetic interrelationships between lactate, pyruvate, alanine, and glucose. 790 82

The purpose of this study was to examine the relationship of peripheral metabolism of glucose, lactate, alanine, and muscle protein catabolism to pyruvate availability during stress. Peripheral catabolic stress was simulated by the infusion of epinephrine, cortisol, and glucagon into the femoral artery of 12 healthy volunteers, 6 of whom received prior treatment with dichloroacetate while 6 served as controls. The catabolic hormone infusion reproduced the peripheral stress response in which glucose consumption increased and the efflux of lactate, alanine, and total amino acid nitrogen (i.e., net muscle protein catabolism) from the leg increased. Dichloroacetate (DCA), which is known to increase pyruvate oxidation, reduced the hormonally stimulated efflux of pyruvate and alanine from the leg and decreased the rate of extremity glucose consumption. DCA had no effect on the rate of lactate efflux and except for alanine had no effect on the stimulated rate of total amino acid nitrogen loss. These results demonstrate the dependence of alanine efflux on pyruvate availability during stress and suggest that the rate of glycolysis within peripheral tissues is a major factor in regulating the quantity of alanine efflux. This study further illustrates that except for alanine, pyruvate kinetics are not salient in the regulation of muscle protein catabolism and elucidates the dichotomy between alanine kinetics and true muscle protein breakdown.
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PMID:Dichloroacetate inhibits peripheral efflux of pyruvate and alanine during hormonally simulated catabolic stress. 841 69

The use of the labeling pattern of hepatic glutamate during infusion of L-[3-13C]- or [3-14C]lactate to calculate rates of citric acid cycle activity and gluconeogenesis has been proposed. We tested the validity of this approach by perfusing isolated rat livers (48 h starved) with pyruvate and lactate (10% enriched with [3-13C]lactate) without (control) or with infusion of glucagon (to inhibit pyruvate kinase), mercaptopicolinate (to inhibit phosphoenolpyruvate carboxykinase), or dichloroacetate (to stimulate pyruvate dehydrogenase). Compared with control experiments, glucagon increased glucose output (P < 0.05) and decreased the calculated flux through pyruvate kinase (P < 0.05). Mercaptopicolinate almost totally suppressed glucose production and dramatically reduced the calculated gluconeogenic rate and flux through phosphoenolpyruvate carboxykinase (P < 0.001). Dichloroacetate moderately increased the calculated flux through pyruvate dehydrogenase (P < 0.05). In experiments with perfused livers from fed rats, the calculated gluconeogenic rate and flux through phosphoenolpyruvate carboxykinase were very low compared with control experiments (P < 0.001), whereas the pyruvate dehydrogenase flux was increased (P < 0.05). Therefore, the expected modifications of the citric acid cycle activity and gluconeogenic rate were clearly detected using the labeling pattern of glutamate to calculate these metabolic rates. Except for the perfusions with mercaptopicolinate, the dilution by isotopic exchange in the oxaloacetate pool calculated from the model agreed with the actual dilution of enrichment between liver pyruvate and phosphoenolpyruvate. The present results support the validity of this approach to trace liver metabolism.
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PMID:Use of labeling pattern of liver glutamate to calculate rates of citric acid cycle and gluconeogenesis. 903 51

Dichloroacetate (DCA), a by-product of water chlorination, causes liver cancer in B6C3F1 mice. A hallmark response observed in mice exposed to carcinogenic doses of DCA is an accumulation of hepatic glycogen content. To distinguish whether the in vivo glycogenic effect of DCA was dependent on insulin and insulin signaling proteins, experiments were conducted in isolated hepatocytes where insulin concentrations could be controlled. In hepatocytes isolated from male B6C3F1 mice, DCA increased glycogen levels in a dose-related manner, independently of insulin. The accumulation of hepatocellular glycogen induced by DCA was not the result of decreased glycogenolysis, since DCA had no effect on the rate of glucagon-stimulated glycogen breakdown. Glycogen accumulation caused by DCA treatment was not hindered by inhibitors of extracellular-regulated protein kinase kinase (Erk1/2 kinase or MEK) or p70 kDa S6 protein kinase (p70(S6K)), but was completely blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin. Similarly, insulin-stimulated glycogen deposition was not influenced by the Erk1/2 kinase inhibitor, PD098509, or the p70(S6K) inhibitor, rapamycin. Unlike DCA-stimulated glycogen deposition, PI3K-inhibition only partially blocked the glycogenic effect of insulin. DCA did not cause phosphorylation of the downstream PI3K target protein, protein kinase B (PKB/Akt). The phosphorylation of PKB/Akt did not correlate to insulin-stimulated glycogenesis either. Similar to insulin, DCA in the medium decreased IR expression in isolated hepatocytes. The results indicate DCA increases hepatocellular glycogen accumulation through a PI3K-dependent mechanism that does not involve PKB/Akt and is, at least in part, different from the classical insulin-stimulated glycogenesis pathway. Somewhat surprisingly, insulin-stimulated glycogenesis also appears not to involve PKB/Akt in isolated murine hepatocytes.
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PMID:Dichloroacetate stimulates glycogen accumulation in primary hepatocytes through an insulin-independent mechanism. 1215 48