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)

In humans, endurance training markedly reduces the rate of hepatic glucose production during exercise. To determine whether this is due to a reduction in glycogenolysis, in gluconeogenesis, or in both processes, six men were studied at rest and during 2 h of cycle ergometer exercise at 60% pretraining peak O2 consumption (VO2peak), both before and after completion of a strenuous endurance training program (cycling at 75-100% VO2peak for 45-90 min/day, 6 days/wk for 12 wk). The overall rate of glucose appearance (Ra) was determined using a primed continuous infusion of [6,6-2H]glucose, whereas the rate of gluconeogenesis (Rgng) was estimated from the incorporation of 13C into glucose (via pyruvate carboxylase) from simultaneously infused [13C]bicarbonate. Training did not affect glucose kinetics at rest but reduced the average Ra during exercise by 42% [from 36.8 +/- 3.8 to 21.5 +/- 3.6 (SE) mumol.min-1.kg-1; P < 0.001]. This decrease appeared to be mostly due to a reduction in hepatic glycogenolysis. However, the estimated Rgng during exercise also decreased significantly (P < 0.001) with training, falling from 7.5 +/- 1.6 mumol.min-1.kg-1 (23 +/- 3% of total Ra) before training to 3.1 +/- 0.6 mumol.min-1.kg-1 (14 +/- 3% of total Ra) after training. These training-induced adaptations in hepatic glucose metabolism were associated with an attenuated hormonal response to exercise (i.e., higher insulin and lower glucagon, norepinephrine, and epinephrine concentrations) as well as a reduced availability of gluconeogenic precursors (i.e., lower lactate and glycerol concentrations). We conclude that endurance training reduces both hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men.
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PMID:Effect of endurance training on hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men. 790 Jul 83

Hepatocyte monolayers from neonatal calves were used to determine the effects of glucagon and insulin on incorporation of carbon from [2-14C]propionate, [1-14C]lactate, [U-14C]lactate, and [1,3-14C]glycerol into glucose and glycogen. Glucagon increased gluconeogenesis (nmol substrate incorporated into glucose or glycogen.micrograms DNA-1.h-1) from propionate and lactate but not from glycerol. Insulin decreased gluconeogenesis from [2-14C]propionate but was without effect on gluconeogenesis from [U-14C]lactate or [1,3-14C]glycerol. Net de novo glycogenesis (nmol substrate retained in cell glycogen.micrograms DNA-1.h-1) from propionate, lactate, and glycerol was decreased by glucagon and increased by insulin. Glucagon effects on gluconeogenesis, but not glycogenesis, were mimicked by dibutyryl adenosine 3',5'-cyclic monophosphate. Lactate flux through pyruvate carboxylase accounts for > or = 91% of lactate carbon flux to glucose, and this proportion was unchanged by glucagon or insulin. Gluconeogenesis from propionate and lactate is regulated by substrate concentration and glucagon in bovine hepatocyte monolayers. The data indicate that, in neonatal bovine liver, glucagon acts on a process common to lactate and propionate to increase gluconeogenesis, and insulin opposes these effects on gluconeogenesis from propionate but not lactate.
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PMID:Regulation of gluconeogenesis by insulin and glucagon in the neonatal bovine. 818 66

(1) Liver cells from starved rats were incubated with 10 mM L-lactate, 1 mM pyruvate and 0.3 microM glucagon in the presence and absence of the mild respiratory inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) at 0.5 mM. (2) The whole cell concentrations of phosphoenolpyruvate, 2-phosphoglycerate and 3-phosphoglycerate increased about 2-fold, whilst the triose and hexose phosphate concentrations all decreased significantly. Similar results were obtained with 0.15 microM oligomycin and 10 microM atractyloside. (3) These data can be explained by a substantial decrease in the cytosolic free concentration ratio of ATP/ADP acting on the equilibrium of glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase. (4) The increase in cytosolic phosphoenolpyruvate concentration can account for the observed increase in pyruvate kinase flux that occurs under these conditions (Pryor et al. (1987) Biochem. J. 247, 449-457). (5) An inhibition of pyruvate carboxylase was also implied by a decrease in calculated tissue oxaloacetate concentrations, confirming a role for both enzymes in the inhibition of gluconeogenesis. (6) Whole cell concentrations of effectors of pyruvate carboxylase activity were measured; only the ATP/ADP ratio decreased significantly. (7) Subcellular fractionation studies showed a good correlation between the measured mitochondrial ATP/ADP ratio and rates of gluconeogenesis both in the presence and absence of oleate. (8) A similar correlation could be observed between rates of pyruvate carboxylation and the measured matrix ATP/ADP ratio in isolated liver mitochondria from starved rats. (9) Data are also presented suggesting an additional effect of DCMU on the rate pyruvate carboxylation in situ under some circumstances, mediated by decreases in mitochondrial acetyl-CoA and cytosolic pyruvate concentrations. (10) It is noted that the effects of phenylethylbiguanide (phenformin) on the rate of gluconeogenesis and metabolite profiles in the perfused liver (Cooke et al. (1973) J. Biol. Chem. 248, 5272-5277) are similar to those caused by DCMU, supporting a mitochondrial locus of action for this hypoglycaemic agent.
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PMID:The mechanisms by which mild respiratory chain inhibitors inhibit hepatic gluconeogenesis. 845 80

Previous studies in rat islets have suggested that anaplerosis plays an important role in the regulation of pancreatic beta cell function and growth. However, the relative contribution of islet beta cells versus non-beta cells to glucose-regulated anaplerosis is not known. Furthermore, the fate of glucose carbon entering the Krebs cycle of islet cells remains to be determined. The present study has examined the anaplerosis of glucose carbon in purified rat beta cells using specific 14C-labeled glucose tracers. Between 5 and 20 mM glucose, the oxidative production of CO2 from [3,4-14C]glucose represented close to 100% of the total glucose utilization by the cells. Anaplerosis, quantified as the difference between 14CO2 production from [3,4-14C]glucose and [6-14C]glucose, was strongly influenced by glucose, particularly between 5 and 10 mM. The dose dependence of glucose-induced insulin secretion correlated with the accumulation of citrate and malate in beta(INS-1) cells. All glucose carbon that was not oxidized to CO2 was recovered from the cells after extraction in trichloroacetic acid. This indirectly indicates that lactate output is minimal in beta cells. From the effect of cycloheximide upon the incorporation of 14C-glucose into the acid-precipitable fraction, it could be calculated that 25% of glucose carbon entering the Krebs cycle via anaplerosis is channeled into protein synthesis. In contrast, non-beta cells (approximately 80% glucagon-producing alpha cells) exhibited rates of glucose oxidation that were (1)/(3) to (1)/(6) those of the total glucose utilization and no detectable anaplerosis from glucose carbon. This difference between the two cell types was associated with a 7-fold higher expression of the anaplerotic enzyme pyruvate carboxylase in beta cells, as well as a 4-fold lower ratio of lactate dehydrogenase to FAD-linked glycerol phosphate dehydrogenase in beta cells versus alpha cells. Finally, glucose caused a dose-dependent suppression of the activity of the pentose phosphate pathway in beta cells. In conclusion, rat beta cells metabolize glucose essentially via aerobic glycolysis, whereas glycolysis in alpha cells is largely anaerobic. The results support the view that anaplerosis is an essential pathway implicated in beta cell activation by glucose.
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PMID:Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. 922 23

Pyruvate carboxylase (PC; EC 6.4.1.1), a member of the biotin-dependent enzyme family, catalyses the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC has been found in a wide variety of prokaryotes and eukaryotes. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitter substances, and in glucose-induced insulin secretion by pancreatic islets. The reaction catalysed by PC and the physical properties of the enzyme have been studied extensively. Although no high-resolution three-dimensional structure has yet been determined by X-ray crystallography, structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains three functional domains: the biotin carboxylation domain, the transcarboxylation domain and the biotin carboxyl carrier domain. Different physiological conditions, including diabetes, hyperthyroidism, genetic obesity and postnatal development, increase the level of PC expression through transcriptional and translational mechanisms, whereas insulin inhibits PC expression. Glucocorticoids, glucagon and catecholamines cause an increase in PC activity or in the rate of pyruvate carboxylation in the short term. Molecular defects of PC in humans have recently been associated with four point mutations within the structural region of the PC gene, namely Val145-->Ala, Arg451-->Cys, Ala610-->Thr and Met743-->Thr.
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PMID:Structure, function and regulation of pyruvate carboxylase. 1022 53

The effects of glucagon infusions on expression of mRNA for enzymes that regulate gluconeogenesis were studied in lactating cows. Normal cows and cows with fatty liver that were susceptible to ketosis were assigned to either glucagon-treated or control groups. Glucagon at 0 or 10 mg/d was infused for 14 d beginning at d 21 postpartum. In normal cows, glucagon infusions increased concentrations of both plasma glucagon and glucose, which caused plasma insulin to increase. Consequently, hepatic phosphoenolpyruvate carboxykinase mRNA decreased during wk 1 of glucagon infusions. Glucagon infusions into cows with fatty liver also increased plasma glucagon and glucose, but concentrations of plasma insulin and hepatic phosphoenolpyruvate carboxykinase mRNA did not change. More phosphoenolpyruvate carboxykinase mRNA was present in the livers of cows with fatty liver than in livers of normal cows. In a follow-up experiment with midlactation cows, 3.5-h infusions of glucagon at 14 mg/d increased plasma glucose and insulin and decreased plasma nonesterified fatty acids and hepatic glycogen. Hepatic phosphoenolpyruvate carboxykinase mRNA was decreased 41%, pyruvate carboxylase mRNA was increased 50%, but fructose-1,6-bisphosphatase mRNA did not change. We conclude that the expression of the hepatic phosphoenolpyruvate carboxykinase gene in normal cows is inhibited by insulin to balance elevated carbohydrate status during glucagon infusions; however, inhibited expression of hepatic phosphoenolpyruvate carboxykinase mRNA probably is not involved in the pathogenesis of lactation ketosis.
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PMID:Regulation of messenger ribonucleic acid expression for gluconeogenic enzymes during glucagon infusions into lactating cows. 1038 1

The gluconeogenic response in the liver from rats with chronic arthritis to various substrates and the effects of glucagon were investigated. The experimental technique used was the isolated liver perfusion. Hepatic gluconeogenesis in arthritic rats was generally lower than in normal rats. The difference between normal and arthritic rats depended on the gluconeogenic substrate. In the absence of glucagon the following sequence of decreasing differences was found: alanine (-71.8 per cent) reverse similarglutamine (-71.7 per cent)>pyruvate (-60 per cent)>lactate+pyruvate (-44.9 per cent)>xylitol (n.s.=non-significant) reverse similarglycerol (n.s.). For most substrates glucagon increased hepatic gluconeogenesis in both normal and arthritic rats. The difference between normal and arthritic rats, however, tended to diminish, as revealed by the data of the following sequence: alanine (-48.9 per cent) reverse similarpyruvate (-47.6 per cent)>glutamine (-33.8 per cent)>glycerol (n.s.) reverse similarlactate+pyruvate (n.s.) reverse similarxylitol (n.s.). The causes for the reduced hepatic gluconeogenesis in arthritic rats are probably related to: (a) lower activities of key enzymes catalyzing most probably steps preceding phosphoenolpyruvate (e.g. phosphoenolpyruvate carboxykinase, pyruvate carboxylase, etc. ); (b) a reduced availability of reducing equivalents in the cytosol; (c) specific differences in the situations induced by hormones or by the individual substrates. Since glycaemia is almost normal in chronically arthritic rats, it seems that lower gluconeogenesis is actually adapted to the specific needs of these animals.
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PMID:Gluconeogenesis in the liver of arthritic rats. 1058 14

Plasma glucose concentrations in neonates are influenced by colostrum feeding and by glucocorticoids. We have tested whether a high-glucocorticoid status after birth, as well as colostrum feeding, influences glucose metabolism in association with changes of hepatic expression and activities of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) and pyruvate carboxylase (PC; EC 6.4.1.1) in neonatal calves. Calves (n = 14 per group) were fed either colostrum or a milk-based formula with nutrient and energy contents similar to colostrum. Half the calves in each feeding group were treated with dexamethasone (DEXA; 30 microg/[kg BW x d]). Pre- and postprandial blood samples were taken on d 1, 2, 4, and 5 and liver samples were collected on d 5 of life. Dexamethasone treatment increased (P < or = 0.05) plasma concentrations of glucose, insulin, and glucagon more in colostrum-fed than in formula-fed calves but increased (P < or = 0.05) urea concentrations and decreased (P < or = 0.05) concentrations of NEFA, ACTH, and cortisol independent of colostrum vs. formula feeding. Colostrum feeding increased (P < 0.05) plasma glucose, but decreased (P < 0.05) plasma urea concentrations. Glucagon-to-insulin ratios in DEXA-treated and colostrum-fed calves were decreased (P < 0.05). Dexamethasone treatment decreased hepatic mRNA levels and activities of PC (P < 0.001 and P < 0.10) and activities of PEPCK (P < 0.001) but increased (P < 0.001) the glycogen content. Colostrum feeding increased (P < 0.05) mitochondrial PEPCK mRNA levels and PEPCK activities in calves not treated with DEXA but decreased (P < 0.1) amounts of PC mRNA. In conclusion, increased plasma glucose concentrations after DEXA treatment were not associated with a stimulation of hepatic gluconeogenic enzyme activities; however, colostrum feeding probably raised plasma glucose concentrations because of increased hepatic gluconeogenic activities.
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PMID:Dexamethasone and colostrum feeding affect hepatic gluconeogenic enzymes differently in neonatal calves. 1467 66

Krebs cycle enzyme activities and levels of five metabolites were determined from livers of old mice (30 months) maintained either on control or on long-term caloric restriction (CR) diets (28 months). In CR mice, the cycle was divided into two major blocks, the first containing citrate synthase, aconitase and NAD-dependent isocitrate dehydrogenase which showed decreased activities, while the second block, containing the remaining enzymes, displayed increased activity (except for fumarase, which was unchanged). CR also resulted in decreased levels of citrate, glutamate and alpha-ketoglutarate, increased levels of malate, and unchanged levels of aspartate. The alpha-ketoglutarate/glutamate and malate/alpha-ketoglutarate ratios were higher in CR, in parallel with previously reported increases with CR in pyruvate carboxylase activity and glucagon levels, respectively. The results indicate that long-term CR induces a differential regulation of Krebs cycle in old mice and this regulation may be the result of changes in gene expression levels, as well as a complex interplay between enzymes, hormones and other effectors. Truncation of Krebs cycle by CR may be an important adaptation to utilize available substrates for the gluconeogenesis necessary to sustain glycolytic tissues, such as brain.
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PMID:Krebs cycle enzymes from livers of old mice are differentially regulated by caloric restriction. 1528 89

Liver X receptors (LXRs) alpha and beta, transcription factors of a nuclear hormone receptor family, are expressed in pancreatic islets as well as glucagon-secreting and insulin-secreting cell lines. Culture of pancreatic islets or insulin-secreting MIN6 cells with a LXR specific agonist T0901317 caused an increase in glucose-dependent insulin secretion and islet insulin content. The stimulatory effect of T0901317 on insulin secretion was observed only after >72 h of islet culture with the compound. In MIN6 cells, T0901317 increased protein expression of lipogenic enzymes, fatty acid synthase, and acetyl-CoA carboxylase. LXR activation also produced an increase in glucokinase protein and pyruvate carboxylase (PC) activity levels. The PC inhibitor phenylacetic acid abolished the increase in insulin secretion in cells treated with T0901317. The results suggest that LXRs can control insulin secretion and biosynthesis via regulation of glucose and lipid metabolism in pancreatic beta-cells.
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PMID:Liver X receptor activation stimulates insulin secretion via modulation of glucose and lipid metabolism in pancreatic beta-cells. 1556 26


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