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

Addition of glucose to cultured chick embryo hepatocytes caused a concentration-dependent impairment of phenobarbital-mediated induction of delta-aminolevulinate (ALA) synthase resembling the "glucose effect" observed in rodents in vivo. This glucose effect occurred in the complete absence of extrahepatic factors such as serum and hormones. Fructose, glycerol, and lactate mimicked the inhibitory glucose effect on ALA synthase induction, whereas 2-deoxyglucose and 3-O-methylglucose augmented the induction evoked by phenobarbital. 2-Deoxyglucose reversed the effect of glucose, glycerol, and lactate on ALA synthase induction suggesting that the glucose effect is mediated by free glucose or glucose 6-phosphate or a nonglycolytic metabolite of glucose 6-phosphate. The phenobarbital-mediated induction of cytochrome P-450 hemoprotein(s) and its monooxygenase function were concomitantly diminished by glucose. However, this inhibitory effect or glucose was reversible by the addition of exogenous heme or ALA suggesting that the primary target of the glucose effect is ALA synthase induction and not synthesis of apocytochrome P-450. Glucagon and dibutyryl cAMP enhanced the induction of ALA synthase and cytochrome P-450 by phenobarbital and partially counteracted the glucose effect on both enzymes suggesting that the glucose effect may be mediated by changes in cAMP levels. Although insulin did not alter induction of ALA synthase, it impaired induction of cytochrome P-450 even in the presence of glucagon and cAMP. These data may be relevant for the treatment with glucose and heme of patients with "inducible" hepatic porphyria.
 ...
PMID:Induction of delta-aminolevulinate synthase and cytochrome P-450 hemoproteins in hepatocyte culture. Effect of glucose and hormones. 627 Jan 45

A new technique was developed for the isolation of chicken liver parenchymal cells. Glucose produced from 10 mM lactate was proportional to the amount of cells present. In the time-course study, gluconeogenesis from lactate and fructose was linear up to 60 min. Fructose proved to be the best substrate. Fructose was converted to glucose at the highest rate; this was followed by lactate, pyruvate, and xylitol. Alanine, glycerol, propionate, alpha-ketoglutarate, and succinate proved to be poor substrates. There was no statistical difference between the results obtained with hepatocytes obtained from fed or fasted chickens. The isolated hepatocytes responded to glucagon, dibutyryl-cAMP, and epinephrine. The dose-response for glucagon was a sigmoid-curve and the half-maximum stimulation was given by approximately 1 x 10(-2) micrometers hormone. The same type of curve was obtained with dibutyryl-cAMP, but the half-maximum stimulation was achieved at around 1.0 micrometer. The response to epinephrine was marginal. In the time-course experiment, prior to glucagon stimulation, glucose accumulated at a linear rate (slope = .2484). After the addition of the hormone, the level of cAMP increased by about 30% in the first minute and reached a peak (100%) in about 2 min; thereafter, it decreased to the level prior to the stimulation by the hormone. Two minutes after the addition of glucagon there was a significant increase in the rate of gluconeogenesis; this continued for another 3 min and then at a slower pace (slope = .2566).
 ...
PMID:A technique for the isolation of chicken hepatocytes and their use in a study of gluconeogenesis. 627 59

An enzyme activity that catalyzes the hydrolysis of phosphate from the C-2 position of fructose 2,6-bisphosphate has been detected in rat liver cytoplasm. The S0.5 for fructose 2,6-bisphosphate was about 15 microM and the enzyme was inhibited by fructose 6-phosphate (Ki 40 microM) and activated by Pi (KA 1 mM). Fructose 2,6-bisphosphatase activity was purified to homogeneity by specific elution from phosphocellulose with fructose by specific elution from phosphocellulose with fructose 6-phosphate and had an apparent molecular weight of about 100,000, 6-phosphofructo 2-kinase activity copurified with fructose 2,6-bisphosphatase activity at each step of the purification scheme. Incubation of the purified protein with [gamma-32P]ATP and the catalytic subunit of the cAMP-dependent protein kinase resulted in the incorporation of 1 mol of 32P/mol of enzyme subunit (Mr = 50,000). Concomitant with this phosphorylation was an activation of the fructose 2,6-bisphosphatase and an inhibition of the 6-phosphofructo 2-kinase activity. Glucagon addition to isolated hepatocytes also resulted in an inhibition of 6-phosphofructo 2-kinase and activation of fructose 2,6-bisphosphatase measured in cell extracts, suggesting that the hormone regulates the level of fructose 2,6-bisphosphate by affecting both synthesis and degradation of the compound. These findings suggest that this enzyme has both phosphohydrolase and phosphotransferase activities i.e. that it is bifunctional, and that both activities can be regulated by cAMP-dependent phosphorylation.
 ...
PMID:Regulation of rat liver fructose 2,6-bisphosphatase. 628 46

A new activator of phosphofructokinase, which is bound to the enzyme and released during its purification, has been discovered. Its structure has been determined as beta-D Fructose-2,6-P2 by chemical synthesis, analysis of various degradation products and NMR. D-Fructose-2,6-P2 is the most potent activator of phosphofructokinase and relieves inhibition of the enzyme by ATP and citrate. It lowers the Km for fructose-6-P from 6 mM to 0.1 mM. Fructose-6-P,2-kinase catalyzes the synthesis of fructose-2,6-P2 from fructose-6-P and ATP, and the enzyme has been partially purified. The degradation of fructose-2,6-P2 is catalyzed by fructose-2,6-bisphosphatase. Thus a metabolic cycle could occur between fructose-6-P and fructose-2,6-P2, which are catalyzed by these two opposing enzymes. The activities of these enzymes can be controlled by phosphorylation. Fructose-6-P,2-kinase is inactivated by phosphorylation catalyzed by either cAMP dependent protein kinase or phosphorylase kinase. The inactive, phospho-fructose-6,P,2-kinase is activated by dephosphorylation catalyzed by phosphorylase phosphatase. On the other hand, fructose-2,6-bisphosphatase is activated by phosphorylation catalyzed by cAMP dependent protein kinase. Investigation into the hormonal regulation of phosphofructokinase reveals that glucagon stimulates phosphorylation of phosphofructokinase which results in decreased affinity for fructose-2,6-P2 appears to be due to the decreased synthesis by inactivation of fructose-2,6-P2,2-kinase and increased degradation as a result of activation of fructose-2,6-bisphosphatase. Such a reciprocal change in these two enzymes has been demonstrated in the hepatocytes treated by glucagon and epinephrine. The implications of these observations in respect to possible coordinated controls of glycolysis and glycogen metabolism are discussed.
 ...
PMID:Fructose-2,6-P2, chemistry and biological function. 629 99

The inhibition of hepatocyte 6-phosphofructo-1-kinase by glucagon was suppressed by insulin when the enzyme was measured in crude extracts. However, no effect of either hormone was observed after the removal of allosteric effectors from the enzyme, suggesting that the alterations in activity may be due to changes in the level of fructose 2,6-bisphosphate, a potent allosteric activator of the enzyme. Insulin opposed the action of both glucagon and exogenous cyclic AMP to lower fructose 2,6-bisphosphate levels. The concentration of glucagon and of cyclic AMP that gave a half-maximal decrease in fructose 2,6-bisphosphate levels was increased in the presence of 10 nM insulin from 0.03 to 0.09 nM and from 12 to 36 microM, respectively. Insulin also counteracted the effect of maximal concentrations of epinephrine on fructose 2,6-bisphosphate levels. In the presence of 0.02 nM glucagon or 10 microM epinephrine, 10 nM insulin enhanced 6-phosphofructo-2-kinase and decreased fructose 2,6-bisphosphatase activity in (NH4)2SO4-treated hepatocyte extracts. The bifunctional enzyme 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase was shown to be a substrate for the cAMP-dependent protein kinase but not for phosphorylase kinase. It was concluded that insulin opposed the action of glucagon and epinephrine by affecting the phosphorylation state of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase. Fructose 2,6-bisphosphate levels were decreased in liver cells from diabetic rats. Addition of 30 mM glucose elevated fructose 2,6-bisphosphate levels in cells from fed and 24-h-starved rats but not in cells from diabetic rats. This was probably due to decreases in both 6-phosphofructo-2-kinase and glucokinase activity in the diabetic state. These results show that insulin has both short and long term effects on fructose 2,6-bisphosphate metabolism in liver.
 ...
PMID:The action of insulin on hepatic fructose 2,6-bisphosphate metabolism. 629 99

Twelve men with abnormally high insulin responses to a sucrose load and 12 normal men were fed diets containing 0, 7.5, or 15% of the calories as fructose for 5 weeks each. The diets contained approximately 43% of the calories as total carbohydrate, 42% as fat and 15% as protein. Mean insulin responses of the hyperinsulinemic men were initially 235% of control responses. Plasma glucose concentrations 1 hour after the sucrose load were significantly higher in hyperinsulinemic men than in controls. There were no initial differences between the two groups in glucagon or gastric inhibitory polypeptide (GIP) responses. Consumption of 7.5 and 15% Fructose diets increased fasting plasma glucose and GIP responses in both groups. Consumption of the 15% fructose diet resulted in significantly higher insulin and glucose responses than consumption of the other two diets. These results indicate that moderate levels of dietary fructose can produce undesirable changes in glucose metabolism of both normal and hyperinsulinemic men.
 ...
PMID:Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men. 635 May 44

Studies were conducted to determine whether the direction of hepatic carbohydrate and lipid metabolism in the rat could be switched simultaneously from a "fasted" to a "fed" profile in vitro. When incubated for 2 h under appropriate conditions hepatocytes from fasted animals could be induced to synthesize glycogen at in vivo rates. There was concomitant marked elevation of the tissue malonyl-coenzyme A level, acceleration of fatty acid synthesis, and suppression of fatty acid oxidation and ketogenesis. In agreement with reports from some laboratories, but contrary to popular belief, glucose was not taken up efficiently by the cells and was thus a poor substrate for eigher glycogen synthesis or lipogenesis. The best precursor for glycogen formation was fructose, whereas lactate (pyruvate) was most efficient in lipogenesis. In both case the addition of glucose to the gluconeogenic substrates was stimulatory, the highest rates being obtained with the further inclusion of glutamine. Insulin was neither necessary for, nor did it stimulate, glycogen deposition or fatty acid synthesis under favorable substrate conditions. Glucagon at physiological concentrations inhibited both glycogen formation and fatty acid synthesis. Insulin readily reversed the effects of glucagon in the submaximal range of its concentration curve. The following conclusions were drawn. First, the fasted-to-fed transition of hepatic carbohydrate and lipid metabolism can be accomplished in vitro over a time frame similar to that operative in vivo. Second, reversal appears to be a substrate-driven phenomenon, in that insulin is not required. Third, unless an unidentified factor (present in protal blood during feeding) facilitates the uptake of glucose by liver it seems unlikely that glucose is the immediate precursor for liver glycogen or fat synthesis in vivo. A likely candidate for the primary substrate in both processes is lactate, which is rapidly formed from glucose by the small intestine and peripheral tissues. Fructose and amino acids may also contribute. Fourth, the requirement for insulin in the reversal of the fasting state of liver metabolism in vivo can best be explained by its ability to offset the catabolic actions of glucagon.
 ...
PMID:In vitro reversal of the fasting state of liver metabolism in the rat. Reevaluation of the roles of insulin and glucose. 701 43

Fructose-2,6-bisphosphate is a potent activator of 6-phosphofructo-1-kinase, a key enzyme in glycolysis. We previously revealed that sulfonylureas stimulate fructose-2,6-bisphosphate production in the rat liver by activating 6-phosphofructo-2-kinase. In the present study, we show that CS-045, a new antidiabetic agent, activated 6-phosphofructo-2-kinase and raised fructose-2,6-bisphosphate levels in dispersed rat hepatocytes. This action was time- and dose-dependent. Ten micromolar CS-045 raised the fructose-2,6-bisphosphate content linearly to the submaximal level in 20 min. Dose dependency was observed in the range of 1-30 microM. Thirty micromolar CS-045 completely reversed the inhibitory effect of 0.1 nM glucagon on fructose-2,6-bisphosphate production. CS-045 activated 6-phosphofructo-2-kinase by decreasing the Km value for the substrate (fructose-6-phosphate) without affecting the Vmax. The combination of suboptimal doses of CS-045 and tolbutamide increased fructose-2,6-bisphosphate content more than that induced by each agent alone. These results indicate that CS-045 may reduce plasma glucose by facilitating glycolysis in the liver.
 ...
PMID:CS-045, a new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes. 801 60

Glucose can modulate the transcription of many genes, particularly those encoding enzymes of liver metabolism. The transcriptional effect of glucose can be indirect, being mediated in vivo by hormonal variations, especially increase in insulin and decrease in glucagon secretion. Whereas the transcription of the glucokinase gene, for example, is stimulated by insulin without the aid of glucose, the transcriptional activation of most glycolytic and lipogenic genes in hepatocytes requires the presence of both glucose and insulin. The role of insulin in the activation of these genes seems mainly to stimulate glucokinase synthesis, and thus to permit glucose phosphorylation. In some cells in which hexokinase activity is constitutive, the glucose-dependent activation of the same genes does not require insulin and, in addition, can be produced by the nonmetabolisable analog, 2-deoxyglucose. In hepatocytes, the insulin effect on the glucose-dependent activation of the L-pyruvate kinase gene can be reproduced by fructose at low concentrations. Fructose probably acts through the fructose 1-phosphate dependent deinhibition of glucokinase activity. A glucose/carbohydrate element has been identified on the L-type pyruvate kinase and spot 14 gene promoters. It is able to bind, in vitro, transcriptional factors of the MLTF/USF family and could act in cooperation with tissue-specific contiguous elements, such as the HNF4 binding site in the L-type pyruvate kinase gene.
 ...
PMID:Transcriptional control of metabolic regulation genes by carbohydrates. 829 88

Increased endogenous glucose production (EGP) and gluconeogenesis contribute to the pathogenesis of hyperglycaemia in non-insulin-dependent diabetes mellitus (NIDDM). In healthy subjects, however, EGP remains constant during administration of gluconeogenic precursors. This study was performed in order to determine whether administration of fructose increases EGP in obese NIDDM patients and obese non-diabetic subjects. Eight young healthy lean subjects, eight middle-aged obese NIDDM patients and seven middle-aged obese non-diabetic subjects were studied during hourly ingestion of 13C fructose (0.3 g.kg fat free mass-1.h-1) for 3 h. Fructose failed to increase EGP (measured with 6,6 2H glucose) in NIDDM (17.7 +/- 1.9 mumol.kg fat free mass-1.min-1 basal vs 15.9 +/- 0.9 after fructose), in obese non-diabetic subjects (12.1 +/- 0.5 basal vs 13.1 +/- 0.5 after fructose) and in lean healthy subjects (13.3 +/- 0.5 basal vs 13.8 +/- 0.6 after fructose) although 13C glucose synthesis contributed 73.2% of EGP in lean subjects, 62.6% in obese non-diabetic subjects, and 52.8% in obese NIDDM patients. Since glucagon may play an important role in the development of hyperglycaemia in NIDDM, healthy subjects were also studied during 13C fructose ingestion + hyperglucagonaemia (232 +/- 9 ng/l) and during hyperglucagonaemia alone. EGP increased by 19.8% with ingestion of fructose + glucagon (p < 0.05) but remained unchanged during administration of fructose or glucagon alone. The plasma 13C glucose enrichment was identical after fructose ingestion both with and without glucagon, indicating that the contribution of fructose gluconeogenesis to the glucose 6-phosphate pool was identical in these two conditions. We concluded that during fructose administration: 1) gluconeogenesis is increased, but EGP remains constant in NIDDM, obese non-diabetic, and lean individuals; 2) in lean individuals, both an increased glucagonaemia and an enhanced supply of gluconeogenic precursors are required to increase EGP; this increase in EGP occurs without changes in the relative proportion of glucose 6-phosphate production from fructose and from other sources (i.e. glycogenolysis + gluconeogenesis from non-fructose precursors).
 ...
PMID:Effects of ingested fructose and infused glucagon on endogenous glucose production in obese NIDDM patients, obese non-diabetic subjects, and healthy subjects. 873 18


<< Previous 1 2 3 4 Next >>