Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.9 (glucose-6-phosphatase)
3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Other investigators have shown that fructose infusion in normal man and rats acutely depletes hepatic ATP and P(i) and increases the rate of uric acid formation by the degradation of preformed nucleotides. We postulated that a similar mechanism of ATP depletion might be present in patients with glucose-6-phosphatase deficiency (GSD-I) as a result of ATP consumption during glycogenolysis and resulting excess glycolysis. The postulate was tested by measurement of: (a) hepatic content of ATP, glycogen, phosphorylated sugars, and phosphorylase activities before and after increasing glycolysis by glucagon infusion and (b) plasma urate levels and urate excretion before and after therapy designed to maintain blood glucose levels above 70 mg/dl and thus prevent excess glycogenolysis and glycolysis. Glucagon infusion in seven patients with GSD-I caused a decrease in hepatic ATP from 2.25 +/- 0.09 to 0.73 +/- 0.06 mumol/g liver (P <0.01), within 5 min, persisting in one patient to 20 min (1.3 mumol/g). Three patients with GSD other than GSD-I (controls), and 10 normal rats, showed no change in ATP levels after glucagon infusion. Glucagon caused an increase in hepatic phosphorylase activity from 163 +/- 21 to 311 +/- 17 mumol/min per g protein (P <0.01), and a decrease in glycogen content from 8.96 +/- 0.51 to 6.68 +/- 0.38% weight (P <0.01). Hepatic content of phosphorylated hexoses measured in two patients, showed the following mean increases in response to glucagon; glucose-6-phosphate (from 0.25 to 0.98 mumol/g liver), fructose-6-phosphate (from 0.17 to 0.45 mumol/g liver), and fructose-1,6-diphosphate (from 0.09 to 1.28 mumol/g) within 5 min. These changes, except for glucose-6-phosphate, returned toward preinfusion levels within 20 min. Treatment consisted of continuous intragastric feedings of a high glucose dietary mixture. Such treatment increased blood glucose from a mean level of 62 (range 28-96) to 86 (range 71-143) mg/dl (P <0.02), decreased plasma glucagon from a mean of 190 (range 171-208) to 56 (range 30-70) pg/ml (P <0.01), but caused no significant change in insulin levels. Urate output measured in three patients showed an initial increase, coinciding with a decrease in plasma lactate and triglyceride levels, then decreased to normal within 3 days after treatment. Normalization of urate excretion was associated with normalization of serum uric acid. We suggest that the maintenance of blood glucose levels above 70 mg/dl is effective in reducing serum urate levels and that transient and recurrent depletion of hepatic ATP due to glycogenolysis is contributory in the genesis of hyperuricemia in untreated patients with GSD-I.
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PMID:ATP depletion, a possible role in the pathogenesis of hyperuricemia in glycogen storage disease type I. 27 29

Subcellular fractionation of liver homogenates from treated rats was carried out in order to study the mechanism of action of the gastrointestinal polypeptides on glucoronidation. Rats were treated for 90 min with an intravenous infusion of secretin (0.4 cU/h/100 g body weight), glucagon (100 micrograms/h/100 g body weight) and vasoactive intestinal polypeptide (VIP) (300 ng/h/100 g body weight); controls were sham-treated rats. For comparison, another group of animals was treated with a daily injection of phenobarbitone (10 mg/kg), a well-established enzyme inducer. Treatment with the different polypeptides produced minor changes in the subcellular localization of the enzyme. The bulk of activity was always recovered in the microsomal fraction, as identified by both differential centrifugation and the enrichment in specific activity of glucose-6-phosphatase, esterase and NADPH-cytochrome c reductase. Secretin produced a specific increase of bilirubin glucuronidation, more evident in all nuclear fractions. Glucagon increased both bilirubin and p-nitrophenol glucuronidation in all subcellular fractions. VIP had a selective action on p-nitrophenol conjugation of similar extent in nuclear and microsomal fractions. The type of changes observed is suggestive of physicochemical modifications occurring into the cell, perhaps at the membrane environment of different organelles, able to modify the overall conjugation of different substrates by the cell.
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PMID:Subcellular localization of UDP-glucuronyltransferase by differential centrifugation. Changes produced by pretreatment of rats with secretin, glucagon, vasoactive intestinal polypeptide and phenobarbitone. 249 35

Studies were performed to determine whether hypoglycemia or the glucagon response to hypoglycemia increases uric acid production in glycogen storage disease type I (glucose-6-phosphatase deficiency). Three adults with this disease had hyperuricemia (serum urate, 11.3-12.4 mg/dl) and reduced renal clearance of urate (renal urate clearance, 1.1-3.1 ml/min). These abnormalities were improved in one patient by intravenous glucose infusion for 1 mo, suggesting a role for hypoglycemia and its attendant effects on urate metabolism and excretion. A pharmacologic dose of glucagon caused a rise in serum urate from 11.4 to 13.0 mg/dl, a ninefold increase in urinary excretion of oxypurines, a 65% increase in urinary radioactivity derived from radioactively labeled adenine nucleotides, and a 90% increase in urinary uric acid excretion. These changes indicate that intravenous glucagon increases ATP breakdown to its degradation products and thereby stimulates uric acid production. To observe whether physiologic changes in serum glucagon modulate ATP degradation, uric acid production was compared during saline and somatostatin infusions. Serum urate, urinary oxypurine, radioactivity, and uric acid excretion increased during saline infusion as patients became hypoglycemic. Infusion of somatostatin suppressed these increases despite hypoglycemia and decreased the elevated plasma glucagon levels from a mean of 81.3 to 52.2 pg/ml. These data suggest that hypoglycemia can stimulate uric acid synthesis in glucose-6-phosphatase deficiency. Glucagon contributes to this response by activating ATP degradation to uric acid.
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PMID:Hyperuricemia in glycogen storage disease type I. Contributions by hypoglycemia and hyperglucagonemia to increased urate production. 285 25

Flux through the glucose/glucose 6-phosphate cycle in cultured hepatocytes was measured with radiochemical techniques. Utilization of [2-3H]glucose was taken as a measure of glucokinase flux. Liberation of [14C]glucose from [U-14C]glycogen and from [U-14C]lactate, as well as the difference between the utilization of [2-3H]glucose and of [U-14C]glucose, were taken as measures of glucose-6-phosphatase flux. At constant 5 mM-glucose and 2 mM-lactate concentrations insulin increased glucokinase flux by 35%; it decreased glucose-6-phosphatase flux from glycogen by 50%, from lactate by 15% and reverse flux from external glucose by 65%, i.e. overall by 40%. Glucagon had essentially no effect on glucokinase flux; it enhanced glucose-6-phosphatase flux from glycogen by 700%, from lactate by 45% and reverse flux from external glucose by 20%, i.e. overall by 110%. At constant glucose concentrations cellular glucose 6-phosphate concentrations were essentially not altered by insulin, but were increased by glucagon by 230%. In conclusion, under basic conditions without added hormones the glucose/glucose 6-phosphate cycle showed only a minor net glucose uptake, of 0.03 mumol/min per g of hepatocytes; this flux was increased by insulin to a net glucose uptake of 0.21 mumol/min per g and reversed by glucagon to a net glucose release of 0.22 mumol/min per g. Since the glucose 6-phosphate concentrations after hormone treatment did not correlate with the glucose-6-phosphatase flux, it is suggested that the hormones influenced the enzyme activity directly.
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PMID:Antagonistic regulation of the glucose/glucose 6-phosphate cycle by insulin and glucagon in cultured hepatocytes. 302 41

We studied the effects of insulin and glucagon on energy and carbohydrate metabolism of rat hepatocytes in primary culture. The aim of this study is to elucidate the mechanism of the synergistic action of insulin and glucagon and to evaluate the combined effects of these hormones on liver injury. Insulin increased the level of adenosine triphosphate in hepatocytes in the presence of glucagon. Insulin increased the activities of glucokinase (EC 2.7.1.1), phosphofructokinase (EC 2.7.1.11), pyruvate kinase (EC 2.7.1.40) type L and glucose 6-phosphate dehydrogenase (EC 1.1.1.49). Glucagon had no antagonistic effect on these increases. Glucagon increased the activity of glucose 6-phosphate (EC 3.1.3.9) (G6Pase) in the presence or absence of insulin, while insulin had no effects on the levels of G6Pase and fructose 1,6-bisphosphatase (EC 3.1.3.11) in the presence or absence of glucagon. Metabolite analysis of cultured hepatocytes indicated that insulin and glucagon have antagonistic effects on the glycolytic activity of hepatocytes. These combined effects of insulin and glucagon may partially explain the preventive effects of these hormones on liver injury.
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PMID:Effects of insulin and glucagon on energy and carbohydrate metabolism of rat hepatocytes in primary culture. 306 23

An 8-month-old female, maintained on breast feeding for 6 months, experienced numerous attacks of hyperventilation when weaned to baby food and was admitted with severe lactic acidosis (20 mM) and hypoglycemia. Physical examination was negative except for hepatomegaly. Fasting (18 hr) after stabilization on a high carbohydrate diet resulted in hypoglycemia (plasma glucose 40 mg/100 ml), lactic acidosis (6-10 mM), and a rise in plasma alanine. Glucagon produced a glycemic response after 6 hr, but not after 18 hr fasting. Intravenous galactose increased plasma glucose (Delta 45 mg/100 ml) but intravenous fructose, glycerol, and alanine caused a 40-50% fall in plasma glucose and a significant rise in lactate (Delta 3-4 mM). Liver biopsy showed fatty infiltration. Liver slices incubated with galactose, lactate, fructose, alanine, or glycerol converted only galactose to glucose. Hepatic glycolytic intermediates were increased below the level of fructose-1,6-diphosphate and decreased above. Hepatic phosphorylase, glucose-6-phosphatase, amylo-1,6-glucosidase, phosphofructokinase, fructose-1-phosphate aldolase, and fructose-1,6-diphosphate aldolase levels were normal, but no fructose-1,6-diphosphatase (FDPase) activity was detected. Further studies on the liver homogenate of this patient revealed the presence of an acid-precipitable activator of FDPase. Normal plasma glucose and lactate levels were maintained on an 800 cal diet of 66% carbohydrate (sucrose and fructose excluded). 5% protein, and 20% fat. When carbohydrate was reduced to 35% and protein or fat increased to 23 and 53% respectively, lactic acidosis and hypoglycemia recurred. These studies show that a deficiency of FDPase produced infantile lactic acidosis and hypoglycemia and can be controlled by an appropriate diet.
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PMID:Hepatic fructose-1,6-diphosphatase deficiency. A cause of lactic acidosis and hypoglycemia in infancy. 434 Oct 15

Glucagon (0.04-0.09 mg/kg/min) was given intravenously for either 2 or 3 min to eight patients with fasting-induced hypoglycemia. One child had hepatic phosphorylase deficiency, two children had glucose-6-phosphatase deficiency, two children had debrancher enzyme (amylo-1,6-glucosidase) deficiency, and two children and one adult had decreased hepatic fructose-1,6-diphosphatase (FDPase) activity. Liver biopsy specimens were obtained before and immediately after the glucagon infusion. The glucagon caused a significant increase in the activity of FDPase (from 50+/-10.0 to 72+/-11.7 nmol/mg protein/min) and a significant decrease in the activities of phosphofructokinase (PFK) (from 92+/-6.1 to 41+/-8.1 nmol/mg protein/min) and pyruvate kinase (PK) (from 309+/-39.4 to 165+/-23.9 nmol/mg protein/min). The glucagon infusion also caused a significant increase in hepatic cyclic AMP concentrations (from 41+/-2.6 to 233+/-35.6 pmol/mg protein). Two patients with debrancher enzyme deficiency who had biopsy specimens taken 5 min after the glucagon infusion had persistence of enzyme and cyclic AMP changes for at least 5 min. One child with glucose-6-phosphatase deficiency was given intravenous glucose (150 mg/kg/min) for a period of 5 min after the glucagon infusion and biopsy. The plasma insulin concentration increased from 8 to 152 muU/ml and blood glucose increased from 72 to 204 mg/100 ml. A third liver biopsy specimen was obtained immediately after the glucose infusion and showed that the glucagon-induced effects on PFK and FDPase were completely reversed. The glucagon infusion caused an increase in hepatic cyclic AMP concentration from 38 to 431 pmol/mg protein but the glucose infusion caused only a slight decrease in hepatic cyclic AMP concentration (from 431 to 384 pmol/mg protein), which did not appear to be sufficient to account for the changes in enzyme activities. Hepatic glucose-6-phosphatase and fructose-1,6-diphosphate aldolase activities were not altered by either the glucagon or the glucose infusion in any patients. Cyclic AMP (0.05 mmol/kg) was injected into the portal vein of adult rats and caused enzyme changes similar to those seen with glucagon administration in humans. Our findings suggest that rapid changes in the activities of PFK, PK, and FDPase are important in the regulation of hepatic glycolysis and gluconeogenesis, respectively, in humans and that cyclic AMP may mediate the glucagon- but probably not the glucose-insulin-induced changes in enzyme activities.
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PMID:The rapid changes of hepatic glycolytic enzymes and fructose-1,6-diphosphatase activities after intravenous glucagon in humans. 435 16

Adult rat hepatocytes were kept in primary culture for 48 h under different hormonal conditions to induce an enzyme pattern which with respect to carbohydrate metabolism approximated that of periportal and perivenous hepatocytes in vivo. 1. Glucagon-treated cells compared with control cells possessed a lower activity of glucokinase, a 4.5-fold higher activity of phosphoenolpyruvate carboxykinase and unchanged levels of glucose-6-phosphatase, phosphofructokinase, fructose-bisphosphatase and pyruvate kinase; they resembled in a first approximation the periportal cell type and are called for simplicity 'periportal'. Inversely, insulin-treated cells compared with control cells contained a 2.2-fold higher activity of glucokinase, a slightly decreased activity of phosphoenolpyruvate carboxykinase, increased activities of phosphofructokinase and pyruvate kinase and unaltered levels of glucose-6-phosphatase and fructose-bisphosphatase; they resembled perivenous cells and are called simply 'perivenous'. Gluconeogenesis and glycolysis were studied under various substrate and hormone concentrations. 2. Physiological concentrations of glucose (5 mM) and lactate (2 mM) gave about 80% saturation of gluconeogenesis from lactate and less than 15% saturation of glycolysis at a simultaneous 40% inhibition of the glycolytic rate by lactate. 3. Comparison of the two cell types showed that under identical assay conditions (5 mM glucose, 2 mM lactate, 0.5 nM insulin, 0.1 muM dexamethasone) gluconeogenesis was 1.5-fold faster in the 'periportal' cells and glycolysis was 2.4-fold faster in the 'perivenous' cells. 4. Metabolic rates were under short-term hormonal control. Insulin increased glycolysis three fold in both cell types with a half-maximal effect at about 0.4 nM, but did not influence the gluconeogenic rate. Glucagon inhibited glycolysis by 70% with a half-maximal effect at about 0.1 nM. Gluconeogenesis was stimulated by glucagon (half-maximal dose: 0.5 nM) 1.8-fold only in 'periportal' cells containing high phosphoenolpyruvate carboxykinase activity, not in the 'perivenous' cells with a low level of this enzyme. 5. A comparison of the two cell types showed that with maximally stimulating hormone concentrations gluconeogenesis was threefold faster in 'periportal' cells and glycolysis was eightfold faster in 'perivenous' cells. The results support the view that periportal and perivenous hepatocytes in vivo catalyse gluconeogenesis and glycolysis at inverse rates.
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PMID:Induction in primary culture of 'gluconeogenic' and 'glycolytic' hepatocytes resembling periportal and perivenous cells. 675 22

Genetically diabetic db/db mice and their normoglycemic littermates (+/+ mice) were studied to determine plasma levels of glucose, glucagon and insulin and hepatic gluconeogenic enzyme activities. Plasma glucose levels did not differ significantly between the 5-week-old db/db and +/+ mice, but increased with age in the former until the animals were 16-week-old. Similar age-associated changes were observed in the activities of the gluconeogenic enzymes, glucose-6-phosphatase (G-6-Pase) and fructose-1,6-diphosphatase (F-1,6-DPase). While the plasma levels of insulin and glucagon that peaked at 7 weeks of age did not parallel the hyperglycemia, the plasma glucagon/insulin (G/I) ratio roughly paralleled the hyperglycemia. Analysis of individual values for the db/db mice revealed statistically significant (P < 0.001) correlations between plasma glucose levels and hepatic G-6-Pase (r = 0.78) or F-1,6-DPase (r = 0.74) activity. There were also significant correlations between the G/I ratio and plasma glucose levels (P < 0.001, r = 0.66), hepatic G-6-Pase (P < 0.01, r = 0.48) or F-1,6-DPase (P < 0.01, r = 0.57) activity. It is thus concluded that the relative predominance of glucagon over insulin action plays an important role in the age-associated development of hyperglycemia in db/db mice. Glucagon presumably activates the hepatic gluconeogenic enzymes to enhance hepatic glucose output.
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PMID:The possible role of age-related increase in the plasma glucagon/insulin ratio in the enhanced hepatic gluconeogenesis and hyperglycemia in genetically diabetic (C57BL/KsJ-db/db) mice. 786 14

An immortalized cell line, called P9, was derived from hepatocytes by transfection with SV40 DNA. These cells expressed enzyme activities characteristic of hepatocytes, namely glucose-6-phosphatase, glycogen phosphorylase, bilirubin glucuronyltransferase and both glucagon- and prostaglandin E1 (PGE1)-stimulated adenylate cyclase activities, albeit at decreased levels compared with native hepatocytes. Levels of the G-protein subunits alpha-Gi-2, alpha-Gi-3, G beta and the 'long' form of alpha-G2 (45 kDa) were approximately 4-fold higher relative to native hepatocytes, whereas those of the 'short' form of alpha-G2 (42 kDa) were lower by approximately 40%. Associated with this were marked alterations in the guanine nucleotide regulation of adenylate cyclase. Receptor-mediated stimulation, achieved by either PGE1 or glucagon, was apparent in P9 cells, although the latter was only evident upon amplification with forskolin. Glucagon-stimulated cyclic AMP accumulation in P9 cells did not exhibit desensitization, as in hepatocytes, nor was the phosphorylation of alpha-Gi-2 evident. Culture of P9 cells with insulin led to a dose-dependent decrease (EC50 0.2 +/- 0.1 nM) in the ability of PGE1 to stimulate adenylate cyclase activity, with the maximum effect attained after approximately 6 h. A comparable attenuation of stimulation was seen for glucagon- and guanine-nucleotide-stimulated adenylate cyclase activities. In cells cultured with insulin, lower levels of GTP were required to stimulate adenylate cyclase, ADP-ribosylation of the 45 kDa form of alpha-Gs with cholera toxin was attenuated, and the expression of both alpha Gi-2 and alpha-Gi-3 was increased. It is suggested that the expression of alpha-Gi-2 and alpha-Gi-3 may be directly regulated by the action of insulin in hepatocytes and P9 cells.
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PMID:Analysis of the adenylate cyclase signalling system, and alterations induced by culture with insulin, in a novel SV40-DNA-immortalized hepatocyte cell line (P9 cells). 801 Sep 67


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