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PubMed2002

An absolute requirement of fructose 1,6-bisphosphate for the Lactobacillus casei L-lactate dehydrogenase activity induced by a single amino acid substitution.

Lactobacillus casei allosteric L-lactate dehydrogenase (L-LDH) absolutely requires fructose 1,6-bisphosphate [Fru(1,6)P2] for its catalytic activity under neutral conditions, but exhibits marked catalytic activity in the absence of Fru(1,6)P(2) under acidic conditions through the homotropic activation effect of substrate pyruvate. In this enzyme, a single amino acid replacement, i.e. that of His205 conserved in the Fru(1,6)P(2)-binding site of certain allosteric L-LDHs of lactic acid bacteria with Thr, did not induce a marked loss of the activation effect of Fru(1,6)P(2) or divalent metal ions, which are potent activators that improve the activation function of Fru(1,6)P(2) under neutral conditions. However, this replacement induced a great loss of the Fru(1,6)P(2)-independent activation effect of pyruvate or pyruvate analogs under acidic conditions, consequently indicating an absolute Fru(1,6)P(2) requirement for the enzyme activity. The replacement also induced a significant reduction in the pH-dependent sensitivity of the enzyme to Fru(1,6)P(2), through a slight decrease and increase of the Fru(1,6)P(2) sensitivity under acidic and neutral conditions, respectively, indicating that His205 is also largely involved in the pH-dependent sensitivity of L.casei L-LDH to Fru(1,6)P(2). The role of His205 in the allosteric regulation of the enzyme is discussed on the basis of the known crystal structures of L-LDHs.

Allosteric Regulation↗
PubMed1992

Studies on chimeric fusion proteins of human aldolase isozymes A and B.

Several kinds of fusion proteins between human aldolases A and B were prepared by recombinant DNA technology and their enzymic properties were examined. AB chimeras, which have aldolase A at the N-terminal region and aldolase B at the C-terminal region, were scarcely obtained, while BA chimeras were abundant (Kitajima et al., (1990), J. Biol. Chem., 265, 17493-17498). All the BAB chimeras, aldolase A fragments inserted in aldolase B, showed activity assignable to aldolase B type, which imply an essential role of Tyr residue at the C-terminus of aldolase A in the binding of fructose-1,6-bisphosphate (Fru-1,6-P2). BAB chimeras also showed reactivity to effectors such as fructose-2,6-bisphosphate (Fru-2,6-P2) and pyridoxal 5-phosphate (PLP), in a similar manner to aldolase B. BAB108 has a similarity to the BA108 chimera, but acts differently from other BAB chimeras, suggesting that its structure around active site looks like that of aldolase A.

Escherichia coli↗
PubMed1996

A lysine to arginine substitution at position 146 of rabbit aldolase A changes the rate-determining step to Schiff base formation.

Lys146 of rabbit aldolase A [D-fructose-1,6-bis(phosphate): D-glyceraldehyde-3-phosphate lyase, EC 4.1.2.13] was changed to arginine by site-directed mutagenesis. The kcat of the resulting mutant protein, K146R, was 500 times slower than wild-type in steady-state kinetic assays for both cleavage and condensation of fructose-1,6-bis(phosphate), while the K(m) for this substrate was unchanged. Analysis of the rate of formation of catalytic intermediates showed K146R was significantly different from the wild-type enzyme and other enzymes mutated at this site. Single-turnover experiments using acid precipitation to trap the Schiff base intermediate on the wild-type enzyme failed to show a build-up of this intermediate on K146R. However, K146R retained the ability to form the Schiff base intermediate as shown by the significant amounts of Schiff base intermediate trapped with NaBH4. In the single-turnover experiments it appeared that the Schiff base intermediate was converted to products more rapidly than it was produced. This suggested a maximal rate of Schiff base formation of 0.022 s-1, which was close to the value of kcat for this enzyme. This observation is strikingly different from the wild-type enzyme in which Schiff base formation is > 100 times faster than kcat. For K146R it appears that steps up to and including Schiff base formation are rate limiting for the catalytic reaction. The carbanion intermediate derived from either substrate or product, and the equilibrium concentrations of covalent enzyme-substrate intermediates, were much lower on K146R than on the wild-type enzyme. The greater bulk of the guanidino moiety may destabilize the covalent enzyme-substrate intermediates, thereby slowing the rate of Schiff base formation such that it becomes rate limiting. The K146R mutant enzyme is significantly more active than other enzymes mutated at this site, perhaps because it maintains a positively charged group at an essential position in the active site or perhaps the Arg functionally substitutes as a general acid/base catalyst in both Schiff base formation and in subsequent abstraction of the C4-hydroxyl proton.

Animals↗
PubMed1996

Ligand-induced conformational changes in wild-type and mutant yeast pyruvate kinase.

A mutant form of pyruvate kinase in which serine 384 has been mutated to proline has been engineered in the yeast Saccharomyces cerevisiae. Residue 384 is located in a helix in a subunit interface of the tetrameric enzyme, and the mutation was anticipated to alter the conformation of the helix and hence destabilize the interface. Previous results indicate that the mutant favours the T quaternary conformation over the R conformation, and this is confirmed by the results presented here. Addition of phosphoenol-pyruvate (PEP), ADP and fructose-1, 6-bisphosphate (Fru-1.6-P2) singly to the wild-type and mutant enzymes results in a significant quenching of tryptophan fluorescence (12-44%), and for Fru-1,6-P2, a red shift of 15 nm in the emission maximum. Fluorescence titration experiments showed that PEP, ADP and Fru-1,6-P2 induce conformations which have similar ligand-binding properties in the wild-type and mutant enzymes. However, the Fru-1,6-P2 induced conformation is demonstrably different from those induced by either ADP or PEP. The enzymes differ in their susceptibility to trypsin digestion and N-ethylmaleimide inhibition. The thermal stability of the enzyme is unaltered by the mutation. Far-UV CD spectra show that both enzymes adopt a similar overall secondary structure in solution. Taken together, the results suggest that the Ser384-Pro mutation causes the enzyme to adopt a different tertiary and/or quaternary structure from the wild-type enzyme and affects the type and extent of the conformational changes induced in the enzyme upon ligand binding. A simplified minimal reaction mechanism is proposed in which the R and T states differ in both affinity and kcat. Thus, in terms of the models of cooperativity and allosteric interaction, pyruvate kinase is both a K and a V system.

Adenosine Diphosphate↗
PubMed2005

A modified consensus approach to mutagenesis inverts the cofactor specificity of Bacillus stearothermophilus lactate dehydrogenase.

Lactate dehydrogenase from Bacillus stearothermophilus is specific for NAD+. There have been several attempts to alter the cofactor specificity of this enzyme, but these have yielded enzymes with relatively low activities that still largely prefer NAD+. A modified consensus approach was used to create a library of phylogenetically preferred amino acids situated near the cofactor binding site, and variants were screened for their ability to utilize NMN+. A triple mutant (Mut31) was discovered that proved to be more catalytically efficient than wild-type. Mut31 was also better at utilizing NAD+ than the wild-type enzyme and was weakly active with NADP+ and NMN+. An analysis of single amino acid substitutions suggested that all three mutations worked in a concerted fashion to yield robust cofactor utilization. When two previously identified amino acid substitutions were introduced into the Mut31 background, the resultant quintuply substituted enzyme not only utilized NADP+ far better than the wild-type enzyme, it actually inverted its preference for NAD+ and NADP+.

Amino Acid Substitution↗
PubMed1984

Metabolism of pachytene primary spermatocytes from rat testes: pyruvate maintenance of adenosine triphosphate level.

Pachytene primary spermatocytes were prepared and examined for energy metabolism. When the cells were incubated with various substrates (glucose, fructose, pyruvate and lactate) to measure their utilization of substrates and the degree of ATP synthesis, spermatocytes were observed to use pyruvate as much as lactate, but in amounts much greater than those of glucose or fructose. Pyruvate and lactate maintained ATP levels in spermatocytes, while only lactate did in round spermatids and residual bodies. Pyruvate (5 mM) did not inhibit ATP synthesis from lactate in spermatocytes, differing from its behavior in spermatids. Pyruvate was oxidized in the Krebs cycle for further oxidative phosphorylation and was not altered by addition of glucose. Pyruvate and lactate were interconverted, but the intracellular level of pyruvate remained unchanged (approx. 0.2 mM) when either pyruvate or lactate was added to the medium. The maximal activity of lactate dehydrogenase (LDH) of spermatocytes occurred at 0.3-0.7 mM pyruvate, and this enzyme promoted the conversion of pyruvate to lactate rather than the reverse reaction. In addition, activity assays of 11 glycolytic enzymes and concentration assays of glycolytic intermediates showed a possible regulatory role for glyceraldehyde-3-phosphate dehydrogenase (GA3PDH) in glycolysis. These observations suggested that spermatocytes differed strikingly from spermatids with respect to energy metabolism, even though glycolysis in the two categories of germinal cells was presumably regulated by GA3PDH.

Adenosine Triphosphate↗
PubMed1986

Studies of metabolism of round spermatids: glucose as unfavorable substrate.

The exposure of spermatids to glucose in the absence of pyruvate and lactate resulted in an extremely low energy charge. The adenosine 5'-triphosphate (ATP) level rapidly declined and the fructose 1,6-bisphosphate (FBP) and triose levels increased. These changes were prevented by the addition of pyruvate or lactate. The levels of ATP and FBP were inversely correlated. In cells exposed to glucose, FBP did not flow appreciably through the step of glyceraldehyde 3-phosphate dehydrogenase (GA3PDH). The lactate level did not change. However, when pyruvate or lactate was administered to cells exposed to glucose, the FBP level declined rapidly. This drop was accompanied by a commensurate increase in lactate. In these cells, pyruvate transport was suppressed, and the pyruvate taken up by these cells was mostly oxidized in the tricarboxylic acid (TCA) cycle without its being reduced to lactate. In this case, the ATP level increased, but to a level still lower than existed before exposure to glucose. Furthermore, when kinetic studies on the activity of 6-phosphofructokinase (PFK) were carried out, PFK appeared to be fully activated at intracellular levels of fructose 6-phosphate, ATP and adenosine 5'-monophosphate (AMP). These results indicate that the rate of glucose metabolism in glycolysis depends heavily on the energy charge. In cells exposed to glucose, the sugar does not flow appreciably through the glycolytic pathway due to inhibition of GA3PDH. Moreover, the ATP level cannot be recovered fully from the lowest level by the addition of pyruvate or lactate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1985

Stimulating effect of fructose 1-6 diphosphate on the phagocytic function of rat RES and on human leukocyte carbohydrate metabolism.

The phagocytic behavior of the reticuloendothelial system in the rat was assessed by a quantitative technique following fructose-1,6-diphosphate (FDP) administration. In addition, the effect of FDP on the carbohydrate metabolism of human leukocytes was investigated. The rate of colloidal carbon clearance from the blood was increased significantly in the FDP-treated rats as compared to dextrose and saline controls (p less than 0.001). FDP also attenuated the hepatic decrease of ATP (p less than 0.005) and creatine phosphate (p less than 0.005) that has been observed after intravenous administration of colloidal carbon. Carbohydrate metabolism in human leukocytes was enhanced by FDP, with a concomitant increase in ATP content (p less than 0.001). Experimental evidence suggests that FDP intervenes in the Embden-Meyerhof pathway both as a metabolic regulator and as a high energy substrate. These properties of FDP in stimulating the carbohydrate metabolism have recently been described in man.

Adenosine Triphosphate↗
PubMed1989

Improved brain metabolism with fructose 1-6 diphosphate during insulin-induced hypoglycemic coma.

The effect of fructose 1-6 diphosphate (FDP) on brain metabolism and brain function was investigated in hypoglycemic rabbits. The electroencephalogram and differences in oxygen content of arterial and cerebral venous blood were used as indicators for brain metabolic activity. Hypoglycemic coma was induced and maintained for 1 hour by insulin administration. At the onset of isoelectric EEG, six rabbits were treated with FDP and five rabbits received 0.9% saline. The animals were killed by an overdose of barbiturate 60 minutes after hypoglycemic recovery with glucose. FDP-treated rabbits had lower arterial glucose concentration after 40 minutes of treatment (p less than .05) and a significantly greater difference between the oxygen content of arterial and venous blood after 40 minutes (p less than .01), and after 60 minutes (p less than .025) of FDP infusion than saline-treated rabbits. FDP-treated rabbits also had a lower cerebral glucose-oxygen index than did saline-treated rabbits (p less than .005, after 20 and 40 minutes of FDP infusion). FDP administration was followed by a return of EEG activity during hypoglycemia, whereas saline produced no such effect. After glucose infusion, EEG activity was improved in FDP-treated rabbits; in saline-treated rabbits, minimal or no EEG activity was observed. The data suggest the possibility that, at the doses given in this study, FDP is taken up and used as a metabolic substrate by the brain.

Animals↗
PubMed1986

Effects of fructose-1,6-diphosphate, glucose, and saline on cardiac resuscitation.

Severe hypoxemia causes respiratory and cardiac arrest, in part, because severe hypoxemia decreases glycolysis and adenosine triphosphate (ATP) production by a lactic acid-induced decrease in the activity of phosphofructokinase and glyceraldehyde-3-P dehydrogenase. Fructose-1,6-diphosphate (FDP) administration increases the ATP concentration of blood. The authors hypothesized that FDP might increase the number of rabbits that could be resuscitated from hypoxemic cardiac arrest. To test this hypothesis, heart rate, arterial pressure, left ventricular end-diastolic pressure, and blood gases and pH were measured during normoxemia (FIO2 = 0.21) and again during hypoxemia (FIO2 = 0.04) in 28 adult, white, New Zealand rabbits anesthetized with pentobarbital. With the onset of hypoxemia, we gave either 40 mg/kg of 5% FDP (n = 10), 5% glucose (n = 11), or an equal volume (2.5 ml) of normal saline (n = 7) intravenously and began a continuous infusion of 2.0 mg X kg-1 X min-1 of the same sugar or 0.12 ml/min of saline. FDP-treated rabbits breathed for 20.9 +/- 4.9 (mean +/- SEM) min after initiation of hypoxemia; glucose-treated rabbits breathed for 1.4 +/- 0.2 min, and saline-treated rabbits breathed 10.3 +/- 4 min. Cardiac arrest occurred 2.5 +/- 0.5 min after the onset of respiratory arrest in FDP-treated rabbits, 4.1 +/- 0.2 min in glucose-treated rabbits, and 2.9 +/- 0.4 min in saline-treated rabbits. We could resuscitate all ten FDP-treated rabbits; two of 11 glucose-treated (FDP vs. glucose, P less than 0.001); and one of seven saline-treated rabbits (FDP vs. saline, P less than 0.001) from cardiac arrest.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1998

Fructose-1,6-bisphosphate preserves adenosine triphosphate but not intracellular pH during hypoxia in respiring neonatal rat brain slices.

BACKGROUND: Fructose-1,6-bisphosphate (FBP) sometimes provides substantial cerebral protection during hypoxia or ischemia. 31P/1H nuclear magnetic resonance spectroscopy of cerebrocortical slices was used to study the effects of FBP on hypoxia-induced metabolic changes. In addition, 13C-labeled glucose was administered and 13C nuclear magnetic resonance spectroscopy was used to search for FBP-induced modulations in glycolysis and the pentose-phosphate pathway. METHODS: In each experiment, 80 slices (350 microm) obtained from ten 7-day-old Sprague-Dawley rat litter mates were placed together in a 20-mm nuclear magnetic resonance tube, perfused, and subjected to 30 min of hypoxia (PO2 < 3 mmHg). Nine experiments were performed, with n = 3 in each of three groups: (1) no treatment with FBP; (2) 60 min of prehypoxia treatment with FBP (2 mM); and (3) 60 min of posthypoxia treatment with FBP (2 mM). 31P/1H Interleaved nuclear magnetic resonance spectra at 4.7 T provided average adenosine triphosphate, intracellular pH, and lactate. Cresyl violet stains of random slices taken at predetermined time points were studied histologically. Some experiments had [2-13C]glucose in the perfusate. Slices from these studies were frozen for perchloric acid extraction of intracellular metabolites and studied with high-resolution 13C nuclear magnetic resonance spectroscopy at 11.75 T. RESULTS: With no pretreatment with FBP, hypoxia caused an approximately 50% loss of adenosine triphosphate, an approximately 700% increase in lactate, and a decrease in intracellular pH to approximately 6.4. Pretreatment with FBP resulted in no detectable loss of adenosine triphosphate, no increase in lactate, and minimal morphologic changes but did not alter decreases in intracellular pH. 13C Nuclear magnetic resonance spectra of extracted metabolites showed that pretreatment caused accumulation of [1-13C]fructose-6-phosphate, an early pentose-phosphate pathway metabolite. Posthypoxic treatment with FBP had no effects compared with no treatment. CONCLUSIONS: During severe hypoxia, pretreatment with FBP completely preserves adenosine triphosphate and almost completely preserves cell morphology but does not alter hypoxia-induced decreases in intracellular pH. Pretreatment also substantially augments the flux of glucose into the pentose-phosphate pathway.

Adenosine Triphosphate↗
PubMed1984

Metabolic intervention to affect myocardial recovery following ischemia.

Myocardial recovery during reperfusion following ischemia is critical to patient survival in a broad spectrum of clinical settings. Myocardial functional recovery following ischemia correlates well with recovery of myocardial adenosine triphosphate (ATP). Adenosine triphosphate recovery is uniformly incomplete during reperfusion following moderate ischemic injury and is therefore subject to manipulation by metabolic intervention. By definition ATP recovery is limited either by (1) energy availability and application in the phosphorylation of adenosine monophosphate (AMP) to ATP or (2) availability of AMP for this conversion. Experimental data suggest that substrate energy and the mechanisms required for its application in the creation of high energy phosphate bonds (AMP conversion to ATP) are more than adequate during reperfusion following moderate ischemic injury. Adenosine monophosphate availability, however, is inadequate following ischemia due to loss of diffusable adenine nucleotide purine metabolites. These purine precursors are necessary to fuel adenine nucleotide salvage pathways. Metabolic interventions that enhance AMP recovery rather than those that improve substrate energy availability during reperfusion are therefore recommended. The mechanisms of various metabolic interventions are discussed in this framework along with the rationale for or against their clinical application.

Adenine↗
PubMed1991

Fructose-1,6-bisphosphate, when given immediately before reoxygenation, or before injury, does not ameliorate hypoxic ischemic injury to the central nervous system in the newborn pig.

BACKGROUND AND METHODS: We demonstrated earlier in our laboratories that fructose-1,6-bisphosphate (FDP) would improve the outcome of hypoxic ischemic injury to the brain in the adult rabbit. Since many human newborns suffer hypoxic injury to the brain, with a secondary ischemic component due to hypoxic cardiac failure, we set out to reproduce similar experiments in newborn piglets. Hypoxic ischemic CNS damage was induced by ligating both carotid arteries and reducing BP to 66% of normal for 30 min; in the last 15 min, FIO2 was reduced to 0.6. Twelve piglets were randomized to receive either 175 mg/kg of FDP in the last 5 min before reoxygenation or the equivalent volume of saline. The other 20 piglets received 75 mg/kg of FDP in the 5 min immediately before carotid ligation, followed by 1.8 mg/kg.min continuous infusion for the 30 min of hypoxia and ischemia or an equivalent volume of saline. RESULTS: There were no significant differences in the neurologic exam scores or pathologic exam scores between the FDP and control animals at either dose level. CONCLUSIONS: In this animal model, FDP at the doses given was not effective in ameliorating hypoxic ischemic injury to the CNS.

Animals↗
PubMed1992

Fructose-1,6-bisphosphate does not ameliorate hypoxic ischemic injury to the central nervous system in the newborn pig.

BACKGROUND AND METHODS: Fructose-1,6-bisphosphate has been shown to improve the outcome of hypoxic ischemic brain injury in adult rabbits. We wished to see if these results could be extended to a newborn animal. Twenty-four 0- to 3-day-old piglets were randomized to receive 300 mg/kg of fructose-1,6-bisphosphate 5 mins before injury, followed by a continuous infusion of 15 mg/kg/min of fructose-1,6-bisphosphate for the next 90 mins, or the equivalent volume of normal saline. Hypoxic ischemic central nervous system damage was induced by ligating both carotid arteries and reducing their BP to two thirds of the normal value for 30 mins. In the last 15 mins of this 30 mins, the FIO2 was reduced to 0.6. At 30 mins, the piglets were resuscitated with an FIO2 of 1.0, the carotid ligatures were released, and the removed blood was reinfused. RESULTS: The neurologic examination scores at 1, 2, and 3 days after injury and pathologic examination scores at 3 days after injury were not different in the fructose-1,6-bisphosphate-treated and the control animals. CONCLUSION: Fructose-1,6-bisphosphate does not ameliorate hypoxic ischemic brain injury in the newborn pig.

Animals↗
PubMed2002

Fructose-1,6-diphosphate attenuates acute lung injury induced by ischemia-reperfusion in rats.

OBJECTIVE: To determine whether fructose-1,6-diphosphate (FDP) pretreatment can attenuate acute lung injury induced by ischemia-reperfusion in our isolated lung model in rats. DESIGN: Randomized, controlled study. SETTING: Animal care facility procedure room. SUBJECTS: Twenty-four adult male Sprague-Dawley rats each weighing 250-350 g. INTERVENTIONS: Typical acute lung injury in rats was induced successfully by 10 mins of hypoxia followed by 75 mins of ischemia and 50 mins of reperfusion. Ischemia-reperfusion significantly increased microvascular permeability as measured by the capillary filtration coefficient, lung weight gain, lung weight to body weight ratio, pulmonary arterial pressure, and protein concentration of bronchoalveolar lav-age fluid. MEASUREMENTS AND MAIN RESULTS: Pretreatment with FDP significantly attenuated the acute lung injury induced by ischemia-reperfusion as shown by a significant decrease in all of the assessed variables (p <.05 p <.001). The protective effect of FDP was nearly undetectable when promazine (an ecto-adenosine 5-triphosphatase inhibitor) was added before FDP pretreatment. CONCLUSIONS: Pretreatment with FDP significantly ameliorates acute lung injury induced by ischemia-reperfusion in rats.

Animals↗
PubMed2002

Physiopathological studies in septic rats and the use of fructose 1,6-bisphosphate as cellular protection.

OBJECTIVE: The aim of this research project was to test the ability of fructose 1,6-bisphosphate (FBP), which has anti-inflammatory effects and maintains cellular energy levels, to inhibit the septic process in an experimental model in rats. DESIGN: Prospective, controlled animal trial. SETTING: Research laboratory. SUBJECTS: Fed male Wistar rats. INTERVENTIONS: Three experimental groups were formed for the test: control group, untreated septic group, and septic group treated with FBP (500 mg/kg). MEASUREMENTS AND MAIN RESULTS: In the control group, there were no deaths; in the untreated septic group, the mortality rate was 100% within 15 hrs; in the septic group treated with FBP, the mortality rate reached 20% within 15 hrs. The blood cell tests revealed that concentrations of hematocrit, leukocytes, monocytes, and immature cells increased significantly in the untreated septic group compared with both the FBP-treated septic group and the control group. The histologic lesions verified in the heart, lungs, liver, and kidneys of septic animals were smaller and even absent in those treated with FBP. CONCLUSION: FBP reduced the mortality rate provoked by experimental sepsis and ameliorated hematologic and histologic alterations.

Animals↗
PubMed1984

Biochemical quantification of crypt hyperplastic villous atrophy by aldolase activity assay.

Aldolase activity with the two substrates fructose-1-phosphate and fructose-1,6-diphosphate was measured in the homogenate of small intestinal biopsy specimens from children with different malabsorptive diseases (celiac disease, cow's milk protein intolerance, infectious diarrhea, giardiasis, and Crohn's disease) and controls. It is demonstrated that the ratio of fructose-1,6-diphosphate/fructose-1-phosphate activity, which reflects the relative amounts of the crypt enzyme aldolase A (EC 4.1.2.13) and the villous enzyme aldolase B (EC 4.1.2.7), correlates very well with both the ratio of crypt to villous height (correlation factor r = 0.92) and the mitotic index (r = 0.80).

Biopsy↗
PubMed1986

Hepatic glycolytic intermediates in fed and fasted rats after severe hemorrhage.

The responses of key liver carbohydrate intermediates to severe hemorrhage were investigated in fed and fasted young adult male rats. Forty per cent of intravascular blood was withdrawn and liver was sampled by freeze-clamp at 0, 0.25, 1.0, 3.0, and 4.0-5.0 hours. Fed rats with abundant glycogen showed a threefold increase in glucose-6-phosphate (G6P) concentration, and fasted rats showed a 75% decline in G6P immediately after hemorrhage. This significant difference in response traces to the fact that G6P is one of the first catabolites in fed liver formed by glycogenolysis but is the last intermediate of the gluconeogenic pathway in fasted animals. Phosphoenolpyruvate (PEP), the high-energy intermediate, was markedly depleted in both fed and fasted rats at zero time. In the fasted animal, however, the PEP was rapidly restored, and by 1.0 hour was threefold above normal. The ability of fasted rats to rapidly synthesize glucose from accumulated lactate is attributed to increased amount of gluconeogenic enzymes induced by fasting. In prolonged shock states, this synthetic capacity plays a protective role. Contrariwise, in brief shock states such as hemorrhage, the immediate availability of glucose from stored glycogen appears to be a more important determinant of survival. In the present experiments, fed rats were more resistant to the hemorrhage protocol.

Animals↗