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)

Short-term effects of human proinsulin on metabolic rates and its long-term action on enzyme induction were studied in primary cultures of rat hepatocytes and in the perfused rat liver, and compared with the effects of bovine insulin. In the perfused rat liver, proinsulin decreased the glucagon-dependent increase of glycogenolysis. The action of 0.5 nM glucagon was almost completely suppressed by 100 nM proinsulin. Proinsulin and insulin showed similar potency. In cultured rat hepatocytes, proinsulin stimulated glycolysis up to fivefold with a half-maximal effective dose of 30 nM. Proinsulin induced the key glycolytic enzymes glucokinase and pyruvate kinase by twofold and antagonized the glucagon-dependent induction of phosphoenolpyruvate carboxykinase with a half-maximal effective dose at 3 nM. For the effects in cultured hepatocytes, about 100-fold higher concentrations of proinsulin than of insulin were required.
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PMID:Insulin-like action of proinsulin on rat liver carbohydrate metabolism in vitro. 388 57

We have characterized the sequential changes in plasma glucose, insulin and glucagon concentrations, and hepatic glycogen and phosphoenolpyruvate carboxykinase (PEPCK) during the first 240 min of life in rat pups growth retarded [small for gestational age (SGA)] due to bilateral maternal uterine artery ligation. Pups of sham and nonoperated (normal) mothers served as controls. SGA pups were smaller, had reduced liver mass, and demonstrated a pattern of hypoglycemia. They had significantly reduced plasma glucose concentrations at birth, 20, and 240 min but had normal values at 60 and 120 min. SGA pups had significantly reduced hepatic glycogen stores at birth. Plasma glucagon concentrations in SGA pups increased significantly at 20 and 60 min while insulin concentrations decreased equally in all groups. Hepatic PEPCK activity increased greatly in the sham and normal pups. SGA pups did not induce PEPCK during the first 240 min of life; however, pharmacologic doses of glucagon at birth accelerated PEPCK induction in SGA pups and prevented hypoglycemia. These data indicate that newborn SGA pups develop hypoglycemia because of limited hepatic glycogen stores and retarded gluconeogenesis. The delay in PEPCK induction in SGA pups may result from an inadequate although increased glucagon release at birth or diminished sensitivity to available glucagon.
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PMID:Hypoglycemia in the newborn growth-retarded rat: delayed phosphoenolpyruvate carboxykinase induction despite increased glucagon availability. 388 14

To evaluate the effects of gestational hyperglycemia on glucose metabolism and its regulation in the fasted rat during the early postnatal period, unrestrained rats were continuously infused with glucose during the last week of pregnancy. Control rats were infused with distilled water. Newborns were studied during the first six postnatal hours. At birth, newborns from glucose-infused rats, compared with controls, showed higher plasma glucose levels, increased plasma insulin, and lower plasma glucagon and catecholamine concentrations. Between birth and 2 h postpartum, newborn rats from both groups exhibited a marked hypoglycemia, which was, however, more severe in newborns from glucose-infused rats (15 mg/dl) than in controls (26 mg/dl). During the first four postnatal hours, plasma insulin concentration remained higher, while plasma glucagon and catecholamine concentrations remained lower in newborns from hyperglycemic rats. At 6 h, the glycemia reached normal values and the concentrations of the different hormones were similar in controls and newborns from glucose-infused mothers. Concurrently, in the newborns from glucose-infused rats, hepatic glucose production was altered, as they were unable to mobilize liver glycogen stores during the six postnatal hours. Despite slightly delayed phosphoenolpyruvate carboxykinase induction, the rate of gluconeogenesis from 10 mmol/L lactate estimated on isolated hepatocytes was higher in newborns from hyperglycemic mothers than in controls. These results show that gestational hyperglycemia compromises the metabolic and hormonal adaptation of the newborn rat to early extrauterine life; the striking feature of these neonates is the absence of mobilization of liver glycogen stores, which can probably be explained by fetal and neonatal hyperinsulinism associated with the defect of counterregulatory hormones.
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PMID:Effects of gestational hyperglycemia on glucose metabolism and its hormonal control in the fasted, newborn rat during the early postnatal period. 389 10

Hepatocytes were isolated from the livers of fed rats and incubated, in the presence and absence of 100 nM-glucagon, with a substrate mixture containing glucose (10 mM), fructose (4 mM), alanine (3.5 mM), acetate (1.25 mM), and ribose (1 mM). In any given incubation one substrate was labelled with 14C. Incorporation of 14C into glucose, glycogen, CO2, lactate, alanine, glutamate, lipid glycerol and fatty acids was measured after 20 and 40 min of incubation under quasi-steady-state conditions [Borowitz, Stein & Blum (1977) J. Biol. Chem. 252, 1589-1605]. These data and the measured O2 consumption were analysed with the aid of a structural metabolic model incorporating all reactions of the glycolytic, gluconeogenic, and pentose phosphate pathways, and associated mitochondrial and cytosolic reactions. A considerable excess of experimental measurements over independent flux parameters and a number of independent measurements of changes in metabolite concentrations allowed for a stringent test of the model. A satisfactory fit to the data was obtained for each condition. Significant findings included: control cells were glycogenic and glucagon-treated cells glycogenolytic during the second interval; an ordered (last in, first out) model of glycogen degradation [Devos & Hers (1979) Eur. J. Biochem. 99, 161-167] was required in order to fit the experimental data; the pentose shunt contributed approx. 15% of the carbon for gluconeogenesis in both control and glucagon-treated cells; net flux through the lower Embden-Meyerhof pathway was in the glycolytic direction except during the 20-40 min interval in glucagon-treated cells; the increased gluconeogenesis in response to glucagon was correlated with a decreased pyruvate kinase flux and lactate output; fluxes through pyruvate kinase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase were not coordinately controlled; Krebs cycle activity did not change with glucagon treatment; flux through the malic enzyme was towards pyruvate formation except for control cells during interval II; and 'futile' cycling at each of the five substrate cycles examined (including a previously undescribed cycle at acetate/acetyl-CoA) consumed about 26% of cellular ATP production in control hepatocytes and 21% in glucagon-treated cells.
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PMID:Quantitative analysis of intermediary metabolism in hepatocytes incubated in the presence and absence of glucagon with a substrate mixture containing glucose, ribose, fructose, alanine and acetate. 391 12

The regulation of flux through pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) by fatty acids and glucagon was studied in situ, in intact hepatocyte suspensions. The rate of pyruvate metabolized by carboxylation plus decarboxylation was determined from the incorporation of [1-14C]pyruvate into 14CO2 plus [14C]glucose. The flux through PDH was determined from the rate of formation of 14CO2 from [1-14C]pyruvate corrected for other decarboxylation reactions (citrate cycle, phosphoenolpyruvate carboxykinase and malic enzyme), and the flux through PC was determined by subtracting the flux through PDH from the total pyruvate metabolized. With 0.5 mM pyruvate as substrate the ratio of flux through PDH/PC was 1.9 in hepatocytes from fed rats and 1.4 in hepatocytes from 24 h-starved rats. In hepatocytes from fed rats, octanoate (0.8 mM) and palmitate (0.5 mM) increased the flux through PDH (59-76%) and PC (80-83%) without altering the PDH/PC flux ratios. Glucagon did not affect the flux through PDH but it increased the flux through PC twofold, thereby decreasing the PDH/PC flux ratio to the value of hepatocytes from starved rats. In hepatocytes from starved rats, fatty acids had similar effects on pyruvate metabolism as in hepatocytes from fed rats, however glucagon did not increase the flux through PC. 2[5(4-Chlorophenyl)pentyl]oxirane-2-carboxylate (100 microM) an inhibitor of carnitine palmitoyl transferase I, reversed the palmitate-stimulated but not the octanoate-stimulated flux through PDH, in cells from fed rats, indicating that the effects of fatty acids on PDH are secondary to the beta-oxidation of fatty acids. This inhibitor also reversed the stimulatory effect of palmitate on PC and partially inhibited the flux through PC in the presence of octanoate suggesting an effect of POCA independent of fatty acid oxidation. It is concluded that the effects of fatty acids on pyruvate metabolism are probably secondary to increased pyruvate uptake by mitochondria in exchange for acetoacetate. Glucagon favours the partitioning of pyruvate towards carboxylation, by increasing the flux through pyruvate carboxylase, without directly inhibiting the flux through PDH.
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PMID:Regulation of flux through pyruvate dehydrogenase and pyruvate carboxylase in rat hepatocytes. Effects of fatty acids and glucagon. 393 72

Genetically obese normotensive rats, LA/N-corpulent (cp), were fed ad libitum diets containing either 54% sucrose or cooked corn starch for 12 weeks. Twenty-four rats were used for the study; half were corpulent (cp/cp) and half were lean (cp/+ or +/+). Fasting levels of plasma insulin, glucose, corticosterone, glucagon and growth hormone, and activities of liver and epididymal fat pad glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), and liver and kidney glucose-6-phosphatase (G6Pase), fructose 1,6-diphosphatase (FDPase), and phosphoenolpyruvate carboxykinase (PEPCK) were measured. A significant phenotype effect was observed in insulin, corticosterone, growth hormone, and liver G6PD, ME, FDPase, and kidney PEPCK, G6Pase, FDPase, and epididymal fat pad G6PD and ME (corpulent greater than lean), and glucagon (lean greater than corpulent). Diet effect (sucrose greater than starch) was significant for plasma glucose, liver ME, and kidney G6Pase. Although not significant at the P less than 0.05 level, insulin, corticosterone, liver G6PD and FDPase and kidney FDPase tended to be higher in sucrose-fed rats. This study suggests that the corpulent rat is more lipogenic and gluconeogenic than the lean, and that the hormones responsible are effective in keeping both the lipogenic and gluconeogenic enzyme activity elevated.
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PMID:Hormonal and lipogenic and gluconeogenic enzymatic responses in LA/N-corpulent rats. 399 2

The continuous infusion of a low dose of glucagon (35 micrograms/kg/d, for 5 d) constitutes, in view of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, a reliable experimental model of hyperglucagonemia. By conjunction of monooxygenase assays and immunoquantitation of specific isozymes of cytochrome P-450, the actual inducing ability of glucagon has been shown and it might explain some of the modifications of the drug metabolizing system in diabetic mice. The isozymic pattern of cytochrome P-450 of liver microsomes from diabetic mice appears very different from that produced by classical inducers.
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PMID:The effect of different hyperglucagonemic states on monooxygenase activities and isozymic pattern of cytochrome P-450 in mouse. 402 53

Primary cultures of adult rat hepatocytes were kept for 46 h with either insulin ('insulin cells') or glucagon ('glucagon cells') as the dominant hormone under different oxygen concentrations with 13% (v/v) O2 mimicking arterial and 4% hepatovenous levels. Thereafter metabolic rates were measured for a 2 h period under the same ('overall long-term O2 effects') or a different ('short-term O2 effects') oxygen concentration. From the differences of the two effects the 'intrinsic long-term O2 effects' were derived. Glycolysis, as measured in 'insulin-cells', was stimulated by low O2 levels. It was about threefold faster in cells cultured and tested under 4% O2 as compared to cells cultured and tested under 13% O2, indicating the overall long-term effect. Glycolysis was about twofold faster in cells cultured and tested under 4% O2 as compared to cells cultured under 4% O2 but tested under 13% O2, demonstrating the short-term effect. Glycolysis was about 1.5-fold faster in cells cultured and tested under 4% O2 as compared to cells cultured under 13% O2 but tested under 4% O2, showing the intrinsic long-term effect. This difference was roughly parallel to the difference in levels of glucokinase and pyruvate kinase. Gluconeogenesis, as measured in 'glucagon cells', was stimulated by high O2 levels. Similar to glycolysis overall long-term, short-term and intrinsic long-term effects could be distinguished. The intrinsic long-term effects determined under 13% O2 corresponded to a 1.5-fold stimulation and paralleled the difference in phosphoenolpyruvate carboxykinase levels. The present results show that physiological oxygen concentrations also modulate hepatic carbohydrate metabolism by long-term effects and that the O2 gradient over the liver parenchyma thus contributes to the metabolic differences between periportal and perivenous hepatocytes in vivo.
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PMID:Long-term effects of physiological oxygen concentrations on glycolysis and gluconeogenesis in hepatocyte cultures. 402 36

By using very low concentrations of cells to minimize alterations in substrate concentrations, we demonstrated that the lactate/pyruvate ratio of the incubation medium, which determines the cytosolic NADH/NAD+ ratio, affects gluconeogenic flux in suspensions of isolated hepatocytes from fasted rats. At a fixed extracellular pyruvate concentration of 1 mM and with the lactate/pyruvate ratio varied from 0.6 to 10 and to 50, glucose production rates increased from 2.5 to 5.5 and then decreased to 1.8 nmol/mg of cell protein/min. This finding paralleled the observation of Sugano et al. (Sugano, T., Shiota, M., Tanaka, T., Miyamae, Y., Shimada, M., and Oshino, N. (1980) J. Biochem. (Tokyo) 87, 153-166) who noted a similar biphasic response in the perfused liver system when lactate was held constant and pyruvate varied. The biphasic relationship can be explained by the influence of the NADH/NAD+ ratio on the near-equilibrium reactions catalyzed by glyceraldehyde-3-phosphate dehydrogenase and malate dehydrogenase in the hepatocyte cytosol. By shifting the equilibrium of the glyceraldehyde-3-phosphate dehydrogenase reaction, a rise in the NADH/NAD+ ratio decreases the concentration of 3-phosphoglycerate which, because of the linkage of 3-phosphoglycerate to phosphoenolpyruvate through two near-equilibrium reactions, reduces the concentration of phosphoenolpyruvate and therefore causes a decline in flux through pyruvate kinase. This decrease in pyruvate kinase flux results in an enhanced gluconeogenic flux. At higher NADH/NAD+ ratios, however, the oxalacetate concentration drops to such an extent that the consequent decreased flux through phosphoenolpyruvate carboxykinase exceeds the decline in flux through pyruvate kinase, producing a decrease in gluconeogenic flux. The lactate/pyruvate ratio was found to influence the actions of three hormones thought to stimulate gluconeogenesis by different mechanisms. Except for an inhibition by glucagon seen at the lowest lactate/pyruvate ratio tested, the stimulations by this hormone were relatively insensitive to lactate/pyruvate ratios, while angiotensin II produced greater stimulations of gluconeogenesis as the lactate/pyruvate ratio was increased. Dexamethasone, added in vitro, stimulated gluconeogenesis significantly only at very low and very high lactate/pyruvate ratios.
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PMID:The interaction between the cytosolic pyridine nucleotide redox potential and gluconeogenesis from lactate/pyruvate in isolated rat hepatocytes. Implications for investigations of hormone action. 404 7

Hepatocytes, isolated from fasted rats, were incubated with graded concentrations of lactate and pyruvate, at a mean constant ratio of 10-13:1, to alter systematically the concentrations of gluconeogenic intermediate metabolites and rates of glucose production. By analyzing glucose production rates as a function of corresponding concentrations of extracellular pyruvate, cytosolic oxalacetate, and cellular 3-phosphoglycerate in the presence and absence of hormones and assuming no primary activation of phosphoenolpyruvate carboxykinase, estimates were made of the relative contributions of stimulation of formation of cytosolic oxalacetate and inhibition of pyruvate kinase to hormonal stimulations of gluconeogenesis. Addition of dexamethasone, glucagon, or angiotensin II did not cause a shift in the relationship between cellular 3-phosphoglycerate concentrations and rates of glucose production, indicating that there was no effect of these agents on the reactions involved in conversion of phosphoenolpyruvate to glucose. All three agents shifted the relationships between rates of glucose production and both cytosolic oxalacetate and extracellular pyruvate. The following conclusions were drawn from computer analyses of these results. At low concentrations of pyruvate, stimulation of oxalacetate production and pyruvate kinase inhibition were approximately equally contributory to the overall stimulations of gluconeogenesis by angiotensin II and dexamethasone. At higher pyruvate concentrations, pyruvate kinase inhibition by angiotensin II played a greater role, accounting for 90% of the overall stimulation. For dexamethasone, as the pyruvate concentration was increased, stimulation of gluconeogenesis resulting from enhanced formation of oxalacetate diminished as did overall stimulation of gluconeogenesis. Glucagon addition resulted in an inhibition of pyruvate kinase flux that accounted for 75% of the hormone's overall effect at low pyruvate concentrations; this increased to 95% at high pyruvate concentrations.
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PMID:Estimation of the relative contributions of enhanced production of oxalacetate and inhibition of pyruvate kinase to acute hormonal stimulation of gluconeogenesis in rat hepatocytes. An analysis of the effects of glucagon, angiotensin II, and dexamethasone on gluconeogenic flux from lactate/pyruvate. 404 8


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