Glucagon and Insulin Control of Gluconeogenesis in the Perfused Isolated Rat Liver. Effects on Cellular Metabolite Distribution

Parrilla, Roberto L.; Jiménez, Isabel; Ayuso-Parrilla, Matilde S.

doi:10.1111/j.1432-1033.1975.tb02243.x

Cited by 50 publications

(16 citation statements)

References 41 publications

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“…Glucagon, secreted from pancreatic α-cells, acts as a counter-regulatory hormone of blood glucose alongside insulin, promoting elevation of blood glucose through hepatic glycogenolysis and gluconeogenesis during periods of hypoglycaemia. (43)(44)(45)(46)(47)(48) Besides secretion in response to low plasma glucose levels, plasma concentration of glucagon is modulated directly by insulin through regulation of glucagon gene expression and also at an intra-islet level inhibiting secretion when insulin levels increase, e.g. postprandially in response to a meal.…”

Section: Discussionmentioning

confidence: 99%

The role of glucagon in weight loss‐mediated metabolic improvement: a systematic review and meta‐analysis

et al. 2017

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Aims This meta-analysis aimed to investigate the role of glucagon suppression in regulating glucose homeostasis following diet or bariatric surgery. Methods A comprehensive search of intervention and observational studies was conducted in Medline, Scopus, Web of Science, PubMed and Embase. Random effects model meta-analysis was performed. Primary outcomes were (i) body weight change, (ii) fasting glucagon, (iii) fasting glucose and (iv) fasting insulin concentrations. Results Twenty articles reporting data from 29 interventions were eligible for analysis. Bariatric surgery caused greater weight loss than diet (bariatric -29.7 kg [CI:-36.8, -22.6]; diet -5.8 kg [CI: -8.4, -3.3]; P < 0.00001), an effect that remained significant after adjusting for study duration (P < 0.05). Mean fasting glucagon decreased in parallel with weight loss (-11.8 ng/L [CI: -15.9, -7.8]; P < 0.00001) with no difference between bariatric and diet intervention. Both fasting glucose, and insulin decreased following weight loss (both P < 0.00001; glucose -1.7 mmol/L [CI: -2.0, -1.3]; insulin -50.6 pmol/L [CI: -66.5, -34.7] with greater decrease in fasting insulin between bariatric versus diet (P = 0.01). Conclusions Synergistic suppression of fasting glucagon and insulin resistance may act together to restore normoglycaemia following weight loss. Whether suppression of plasma glucagon may contribute to increased hunger after weight loss and gradual weight regain is not yet known.

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Section: Discussionmentioning

confidence: 99%

The role of glucagon in weight loss‐mediated metabolic improvement: a systematic review and meta‐analysis

et al. 2017

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“…This effect had been attributed to enhanced biosynthetic processes, e.g. stimulation of gluconeogenesis or urea formation by glucagon [2,4]. However, glucagon also stimulates hepatic respiration under conditions unfavourable for gluconeogenesis and urea formation, such as in substrate-free perfused livers from fed rats.…”

Section: Discussionmentioning

confidence: 99%

“…This effect was first attributed to the increased ATP demand of the cell for biosynthetic processes, such as gluconeogenesis and ureagenesis, which are stimulated by glucagon [2,4]. An effect of glucagon or its second messenger on the respiratory chain was proposed by Siess and Wieland [5] and Halestrap [6], which persists after isolation of the organelle.…”

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confidence: 99%

Actions of glucagon on flux rates in perfused rat liver

Mauch

Scholz

1983

European Journal of Biochemistry

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The relationship between inhibition of glycolysis and stimulation of oxygen consumption by glucagon was studied in perfused rat livers. The two effects exhibit similar kinetics and dose-response curves; they are slower and less sensitive to the glucagon concentration than the stimulatory effect on glycogenolysis. A stoichiometry of 1 mol extra oxygen consumed/l.8 mol of diminished lactate plus pyruvate production was found. Under conditions where glucagon did not cause a marked inhibition of glycolysis (i.e. low glycolytic flux rates in the fasted state or in the presence of ethanol), oxygen consumption was also not markedly increased. These findings provide evidence that the major portion of glucagon-induced stimulation of hepatic respiration in the fed state is due to an enhanced demand for mitochondrial oxidative phosphorylation to compensate for the diminished extramitochondrial ATP production following inhibition of glycolysis by glucagon.It is known that glucagon stimulates hepatic respiration [l -31. This effect was first attributed to the increased ATP demand of the cell for biosynthetic processes, such as gluconeogenesis and ureagenesis, which are stimulated by glucagon [2,4]. An effect of glucagon or its second messenger on the respiratory chain was proposed by Siess and Wieland [5] and Halestrap [6], which persists after isolation of the organelle. It is also known that glucagon inactivates glycolytic enzymes [7-111 and diminishes glycolytic flux [12]. A possible explanation for the stimulatory effect of glucagon on hepatic respiration, therefore, could be an interaction between glycolysis and respiratory chain, since mitochondrial oxidative phosphorylation has to compensate for diminished extramitochondrial ATP production. Such a mechanism would be similar to that described for the stimulation of oxygen consumption following ethanol addition [13]. In the present communication we provide evidence that, in fact, the stimulation of respiratory rate correlates well with the inhibition of glycolysis. Thus, a major portion of the glucagon effect on hepatic respiration can be explained simply on the basis of interdependencies in energyyielding metabolism. MATERIALS AND METHODSThe sources of materials employed in these studies and the following procedures were described in the preceding paper [12]: perfusion of isolated livers from fed and 48-h-fasted rats with Krebs-Henseleit bicarbonate buffer [14] in a nonrecirculating system [15] ; experimental protocol of the perfusion experiments; enzymatic analyses of glucose, lactate, pyruvate, 3-hydroxybutyrate, acetoacetate, ammonia and urea [16]; calculation of metabolic rates from the arteriovenous concentration differences and the flow rate of perfusate (4.5 -5.5 ml x min-' x g liver wet weight-'). The oxygen Enzyme. Phosphofructokinase or ATP:D-fructose 6-phosphate 1-phosphotransferase (EC 2.7.1.1 1). concentration in the effluent perfusate was monitored continuously by a teflon-shielded platinum electrode [15]. RESULTS Stimulation of oxygen consumption and inh...

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“…32 In addition, insulin might regulate hepatic acylCoA concentration at the tissue level: the hormone moderately reversed the glucagon-mediated elevation of CoA-activated long-chain fatty acids in the isolated perfused rat liver. 33 In our experiments the decline of the necessary mediator of the insulin effect on intrahepatic lipolysis, cyclic AMP, 34 preceded the decrease of the acyl-CoA level. Thus, the release of fatty acids from endogenous triglycerides may have contributed to the observed rapid fall in the hepatic acyl-CoA level.…”

Section: Kinetics Of the Insulin-induced Changes Greenbaum Etmentioning

confidence: 92%

Rapid Conversion by Insulin of Hepatic Intermediary Metabolism from Glucose Production to Glucose Utilization in the Liver of Alloxan-diabetic Rats

Seitz¹,

Müller²,

Krone³

et al. 1977

Diabetes

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The concentration of free fatty acids in the blood, the tissue concentrations of hepatic cyclic AMP, long-chain acyl-CoA (LCA), adenine nucleotides, inorganic phosphate, the intermediates of the Embden-Meyerhof pathway and the citric acid cycle (including acetyl-CoA and free CoA), and the cytopiasmic and mitochondria! redox couples were determined in alloxan-diabetic rats 15, 30, 60, and 90 minutes after insulin injection. From the measured values, the energy state of the adenine nucleotide system in the liver, the redox state of the NAD system, and the concentrations of malate, oxaloacetate, citrate, and a-ketoglutarate were estimated for the cytopiasmic and mitochondria! compartment by the use of established calculation methods.Insulin injection into alloxan-diabetic rats caused a rapid decline in the concentration of serum free fatty acids and a coordinate decline in hepatic LCA concentration. The latter alteration was accompanied by an increase in the cytopiasmic and a synchronous decrease in the mitochondrial ATP/ADPxP ratio. Simultaneously, the redox state of the cytopiasmic NAD system was shifted towards the oxidized state. When the appropriate data were plotted against each other, a highly significant correlation between the concentration of free fatty acids in the blood and that of LCA in the liver, between the hepatic LCA concentration and the cytopiasmic energy state, and between the cytopiasmic energy state and the cytopiasmic redox state was obtained. These findings are interpreted to support the hypothesis derived from in-vitro experiments that insulin, because of the concentration of hepatic LCA, might affect the translocation of adenine nucleotides between the cytopiasmic and the mitochondrial compartment, thereby regulating the cytopiasmic energy state and, consequently, the redox state of the cytopiasmic NAD system.Insulin injection into alloxan-diabetic rats provoked rapid, coordinate changes in the concentration of the intermediates of both the citric acid cycle and the Embden-Meyerhof chain, indicating the altered substrate flow through these pathways. Those metabolites known to modulate the activity of key regulatory enzymes in vitro were analyzed with respect to their proposed regulatory function. As to the insulin-induced shift from pyruvate carboxylatlon to pyruvate decarboxylatIon, the data reveal that the decrease in pyruvate carboxylase activity can be attributed to the decrease in the intramitochondrial ATP/ADP ratio and the simultaneous fall in acetyl-CoA concentration, while the coordinate increase in pyruvate dehydrogenase activity can be ascribed to the decline in the concentration of LCA and, consequently, in the ratios of ATP/ADP, NADH/NAD, and acetyl-CoA/CoA within the mitochondria.As for the citric acid cycle, enhanced citrate synthesis from acetyl-CoA and oxaloacetate was supported by the rapid drop in the concentration of the inhibitor of citrate synthesis, LCA. In contrast to that, the concentration of succinyl-CoA, an inhibitor of the enzyme in vitro, remained practically ...

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Glucagon and Insulin Control of Gluconeogenesis in the Perfused Isolated Rat Liver. Effects on Cellular Metabolite Distribution

Cited by 50 publications

References 41 publications

The role of glucagon in weight loss‐mediated metabolic improvement: a systematic review and meta‐analysis

The role of glucagon in weight loss‐mediated metabolic improvement: a systematic review and meta‐analysis

Actions of glucagon on flux rates in perfused rat liver

Rapid Conversion by Insulin of Hepatic Intermediary Metabolism from Glucose Production to Glucose Utilization in the Liver of Alloxan-diabetic Rats

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