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)

After the infusion of fructose, 0.25 g/kg body weight, blood uric acid levels were significantly increased above the mean basal value in five patients with glycogen storage disease (GSD), type I (P less than 0.02-P less than 0.05). The mean fasting blood inorganic phosphate (Pi) level in the patients was 3.9 +/- 0.3 mg/100 ml and was significantly lower than the mean Pi value of 4.8 +/- 0.3 mg/100 ml of the control subjects (P less than 0.05). Blood Pi levels were significantly lower in the patients than in the control subjects at varying times after the administration of fructose (P less than 0.005-P less than 0.05). Uric acid excretion did not increase significantly in the patients after fructose was given. In contrast to normal children, the mean peak blood uric level in the patients increased significantly after the administration of glucagon (P less than 0.001). In both patients (P less than 0.005) and control subjects (P less than 0.05), mean blood Pi concentrations decreased significantly after the administration of glucagon; however, the blood Pi concentrations in the patients were significantly lower than in the control subjects. Uric acid excretion increased after glucagon administration in both patients and control subjects, but the differences in uric acid excretion between the two groups were not significant. The data in our patients after fructose and glucagon administration suggest that hyperuricemia in GSD results from enhanced nucleotide catabolism. The concentrations of hepatic Pi and ATP may be low in patients with GSD; hepatic Pi and ATP content would therefore be further diminished by the administration of fructose and glucagon. By a mechanism similar to that of fructose-induced hyperuricemia, diminished hepatic Pi and ATP content might increase the breakdown of adenine nucleotides with resultant hyperuricemia.
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PMID:The pathogenesis of hyperuricemia in glycogen storage disease, type I. 26 62

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

Inhibitory effects on glycogenolysis have been reported for glibenclamide in the presence of insulin after stimulation of glycogenolysis by glucagon. Inhibition of oxidative phosphorylation, which has been equally reported for this drug, however, should stimulate glycogenolysis. The present work aimed to find an answer to the question of how glibenclamide affects glycogen catabolism in the liver of fed rats undergoing substrate- and hormone-free perfusion. The experimental system was the isolated perfused liver of ad libitum fed rats. Metabolites in the outflowing perfusate were assayed enzymatically. Oxygen uptake was measured polarographically. Glibenclamide (25-500 microM) stimulated glucose production and lactate release, with a clear correlation between concentrations and effects. Maximal stimulations were 132 and 127% for lactate production and glucose release, respectively. At low glibenclamide concentrations (up to 100 microM) both oxygen uptake and pyruvate production were stimulated, but at higher concentrations inhibition took place. Uric acid production was stimulated by glibenclamide. All effects of glibenclamide are probably due to decreases in oxidative phosphorylation. Stimulation of glucose release is the opposite of what should be expected for a hypoglycemic drug and it also contrasts with some reports of diminishing effects in the presence of glucagon plus insulin. This means that the stimulatory action on glycogenolysis that was seen as a net effect under the specific conditions of the present work could be counterbalancing inhibitory effects in vivo. This combination of events could eventually diminish the effectiveness of the drug as a hypoglycemic agent in the fed state.
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PMID:The action of glibenclamide on glycogen catabolism and related parameters in the isolated perfused rat liver. 1797 1

Plasma levels of uric acid, the final product of purine degradation in humans, are elevated in metabolic syndrome and are strongly associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD). Hepatic and blood levels of purine metabolites (inosine, hypoxanthine, and xanthine) are also altered in pathophysiological states. We optimized a rat hepatocyte model to test the hypothesis that the production of uric acid by hepatocytes is a potential marker of compromised homeostasis of hepatocellular inorganic phosphate (Pi) and/or ATP. The basal rate of uric acid production from endogenous substrates in rat hepatocytes was comparable to that in human liver and was <10% of the maximum rate with saturating concentrations of purine substrates. It was marginally (~20%) decreased by insulin and increased by glucagon but was stimulated more than twofold by substrates (fructose and glycerol) that lower both cell ATP and Pi, and by inhibitors of mitochondrial respiration (complexes I, III, and V) that lower ATP but raise cell Pi. Clearance of inosine and its degradation to uric acid were also inhibited by cell Pi depletion. Analysis of gene expression in NAFLD biopsies showed an association between mRNA expression of GCKR, the glucokinase regulatory protein that is functionally linked to uric acid production, and mRNA expression of the phosphate transporters encoded by SLC17A1/3. Uric acid production by hepatocytes is a very sensitive index of ATP depletion irrespective of whether cell Pi is lowered or raised. This suggests that raised plasma uric acid may be a marker of compromised hepatic ATP homeostasis.
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PMID:The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. 2404 66

This study investigates the metabolic effects of maize- or wheat-based diets with normal (NP) and lowered (LP) dietary crude protein level [the latter supplemented with limiting amino acids and sodium (n-)butyrate at 1.5 g/kg diet] at different phases of broiler fattening. Blood samples of Ross 308 broilers were tested at the age of 1, 3 and 6 weeks. Total protein (TP) concentration increased in wheat-based and decreased in LP groups in week 3, while butyrate reduced albumin/TP ratio in week 1. Uric acid level was elevated by wheat-based diet in week 1 and by wheat-based diet and butyrate in week 3, but decreased in LP groups in weeks 3 and 6. Aspartate aminotransferase activity was increased by wheat-based diet in week 3, and creatine kinase activity was intensified by LP in weeks 3 and 6. Blood glucose level decreased in wheat-based groups in week 3; however, triglyceride concentration was augmented in the same groups in week 3. No change of glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide and insulin concentration was observed. In conclusion, an age-dependent responsiveness of broilers to dietary factors was found, dietary cereal type was a potent modulator of metabolism, and a low crude protein diet supplemented with limiting amino acids might have a beneficial impact on the growth of chickens.
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PMID:Effect of dietary cereal type, crude protein and butyrate supplementation on metabolic parameters of broilers. 3026 22