Explore the vast range of titles available.

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11 beta-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11 beta-HSD-1) may function as an 11 beta-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11 beta-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11 beta-HSD-1 -/- mice were found to resist hyperglycemia provoked by obesity or stress. Attenuation of hepatic 11 beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis

The aim of this review was to elaborate a conceptual framework of the most important aspects of the main biochemical processes of synthesis and breakdown of energy substrates that human and pig foetuses and newborns can use during the transition from foetus to newborn. Under normal physiological conditions, the growth and development of the foetus depends upon nutrients such as glucose, lipids and amino acids. In addition to the maternal and foetal status, genetic factors are also reported to play a role. The main function of the placenta in all species is to promote the selective transport of nutrients and waste products between mother and foetus. This transport is facilitated by the close proximity of the maternal and foetal vascular systems in the placenta. The foetus depends on the placental supply of nutrients, which regulates energy reserves by means of glycogen storage. Also, the synthesis of foetal hepatic glycogen guarantees energy reserves during perinatal asphyxia or maternal hypoglycaemia. However, the foetus can also obtain energy from other resources, such as gluconeogenesis from the intermediary metabolism of the Krebs cycle and most amino acids. Later, when the placental glucose contribution ends during the transition to the postnatal period, the maturation of biological systems and essential metabolic adaptations for survival and growth is required. The maintenance of normoglycaemia depends on the conditions that determine nutrient status throughout life: the adequacy of glycogen stores, the maturation of the glycogenolytic and gluconeogenic pathway, and an integrated endocrine response.

Glucose production by liver is a major physiological function, which is required to prevent development of hypoglycemia in the postprandial and fasted states. The mechanism of glucose release from hepatocytes has not been studied in detail but was assumed instead to depend on facilitated diffusion through the glucose transporter GLUT2. Here, we demonstrate that in the absence of GLUT2 no other transporter isoforms were overexpressed in liver and only marginally significant facilitated diffusion across the hepatocyte plasma membrane was detectable. However, the rate of hepatic glucose output was normal. This was evidenced by (i) the hyperglycemic response to i.p. glucagon injection; (ii) the in vivo measurement of glucose turnover rate; and (iii) the rate of release of neosynthesized glucose from isolated hepatocytes. These observations therefore indicated the existence of an alternative pathway for hepatic glucose output. Using a [14C]-pyruvate pulse-labeling protocol to quantitate neosynthesis and release of [14C]glucose, we demonstrated that this pathway was sensitive to low temperature (12 degrees C). It was not inhibited by cytochalasin B nor by the intracellular traffic inhibitors brefeldin A and monensin but was blocked by progesterone, an inhibitor of cholesterol and caveolae traffic from the endoplasmic reticulum to the plasma membrane. Our observations thus demonstrate that hepatic glucose release does not require the presence of GLUT2 nor of any plasma membrane glucose facilitative diffusion mechanism. This implies the existence of an as yet unsuspected pathway for glucose release that may be based on a membrane traffic mechanism

Excised maize (Zea mays L.) root tips were used to study the early metabolic effects of glucose (Glc) starvation. Root tips were prelabeled with [1-13C]Glc so that carbohydrates and metabolic intermediates were close to steady-state labeling, but lipids and proteins were scarcely labeled. They were then incubated in a sugar-deprived medium for carbon starvation. Changes in the level of soluble sugars, the respiratory quotient, and the 13C enrichment of intermediates, as measured by 13C and 1H nuclear magnetic resonance, were studied to detect changes in carbon fluxes through glycolysis and the tricarboxylic acid cycle. Labeling of glutamate carbons revealed two major changes in carbon input into the tricarboxylic acid cycle: (a) the phosphoenolpyruvate carboxylase flux stopped early after the start of Glc starvation, and (b) the contribution of glycolysis as the source of acetyl-coenzyme A for respiration decreased progressively, indicating an increasing contribution of the catabolism of protein amino acids, fatty acids, or both. The enrichment of glutamate carbons gave no evidence for proteolysis in the early steps of starvation, indicating that the catabolism of proteins was delayed compared with that of fatty acids. Labeling of carbohydrates showed that sucrose turnover continues during sugar starvation, but gave no indication for any significant flux through gluconeogenesis

The aim of this work was to assess the extent to which mitochondria control the gluconeogenic flux in cucumber (Cucumis sativus L.) cotyledons, by quantifying the distribution of control of succinate oxidation by cotyledon mitochondria. The methods of metabolic control analysis were applied under state 3 and state 4 conditions and in the presence of cell-free extracts in order to simulate in-vivo conditions. Oxygen uptake by isolated cotyledon mitochondria oxidising succinate under state 3 conditions was examined using inhibitor titrations. During lipid mobilization in light-grown cotyledons (3-4 d post-imbibition), control was shared between the adenine-nucleotide translocator (flux-control coefficient, C= 0.25-0.28) and the dicarboxylate-uptake system (C = 0.69-0.72). The dicarboxylate-uptake system was also important in dark-grown cotyledons at this stage (C = 0.55-0.57). In the photosynthetic phase of development (more than 5 d post-imbibition) control rested with the respiratory chain. Application of an external ATP demand provided either by cell-free extracts of cucumber cotyledons or a glucose/hexokinase ADP-regenerating system showed that the reactions outside the mitochondria exert control (C = 0.45-0.54 and C = 0.24-0.38, for cytosolic extract and glucose/hexokinase, respectively). The adenine-nucleotide translocator was a controlling step of both oxygen uptake (C = 0.11-0.32) and the flux between succinate and hexose phosphates (C = 0.28). Other mitochondrial steps made a significant contribution to control. Control of oxygen uptake was dependent on both the nature of the external load and on the rate of phosphorylation. A potential role for mitochondrial membrane-transport processes, including the adenine-nucleotide translocator, is proposed for the integration of lipid breakdown and gluconeogenesis in vivo.

Acute stress induced alterations in the activity levels of rate limiting enzymes and concentration of intermediates of different pathways of carbohydrate metabolism have been studied. Adult male Wistar rats were restrained (RS) for 1 h and after an interval of 4 h they were subjected to forced swimming (FS) exercise and appropriate controls were maintained. Five rats were killed before the commencement of the experiment (initial controls), 5 control and equal number of stressed rats were killed 2 h after RS and remaining 5 rats in each group were killed 4 h after FS. There was a significant increase in the adrenal 3β- hydroxy steroid dehydrogenase activity following RS, which showed further increase after FS compared to controls and thereby indicated stress response of rats. There was a significant increase in the blood glucose levels following RS which showed further increase and reached hyperglycemic condition after FS. The hyperglycemic condition due to stress was accompanied by significant increases in the activities of glutamate- pyruvate transaminase, glutamate- oxaloacetate transaminase, glucose -6- phosphatase and lactate dehydrogenase and significant decrease in the glucose -6- phosphate dehydrogenase and pyruvate dehydrogenase activities, whereas pyruvate kinase activity did not show any alteration compared to controls. Further, the glycogen and total protein contents of the liver were decreased whereas those of pyruvate and lactate showed significant increase compared to controls after RS as well as FS. The results put together indicate that acute stress induced hyperglycemia results due to increased gluconeogenesis and glycogenolysis without alteration in glycolysis. The study first time reveals that after first acute stress exposure, the subsequent stressful experience augments metabolic stress response leading to hyperglycemia. The results have relevance to human health as human beings are exposed to several stressors in a day and such an experience might lead to insulin resistance because prolonged hyperglycemic condition is known to cause insulin resistance.

Cette étude a comme objectif d'évaluer la capacité gluconéogénique chez le dromadaire. Six dromadaires males âgés de 3 ans et de poids moyen de 300 kg ont été utilisés. Deux types de tests dynamiques ont été réalisés ; en intraveineuse et par voie orale. La perfusion a concerné quelques précurseurs de la gluconéogenèse comme le propionate et le propylene glycol et à moindre degré, l'acétate. L'administration orale a intéressé, le glucose, le fructose et le saccharose. Les résultats obtenus montrent que durant les deux types d'épreuves, la glycémie s'élève et se maintient à une valeur élevée durant une période plus importante comparée aux autres ruminants conventionnels (bovins, ovins, caprins).

The intermediary metabolism in hepatocytes isolated from diabetic rats has been studied. The incubation medium is a Krebs-Henseleit buffer containing albumin-bound oleate (1 mmol/1). The high rates of gluconeogenesis, ureogenesis and ketogenesis were consistent with the diabetic state of the rats. Insulin (8 × 10⁻⁷ mol/1) decreased glucose and urea productions from alanine (10 mmol/1) by 30%; β-hydroxybutyrate production, oleate utilization and malate efflux (calculated) from mitochondria were also decreased. No effect of insulin was found with lactate (10 mmol/1) as gluconeogenic substrate. The glycogen content of cells was constant during the time of incubation (4 h). These data suggest that the oxidationreduction state of mitochondria and the cytoplasmic oxaloacetate concentration could be important factors in the action of insulin. Les hépatocytes de rats diabétiques (streptozotocine 90 mg/kg) ayant adhéré à un film de collagène sont incubés dans un milieu de Krebs-Henseleit (pH 7,4) contenant 1 mmol/1 d'oléate de sodium lié à de l'albumine. Les productions importantes de glucose, d'urée et de corps cétoniques reflètent in vitro l'état diabétique des animaux. L'insuline (8 × 10⁻⁷ mol/1) diminue d'un tiers les productions d'urée et de glucose à partir de l'alanine (10 mmol/1) et l'efîlux de malate des mitochondries (calculé) est ralenti; la production de β-hydroxybutyrate et la consommation d'oléate sont diminuées. Avec le lactate (10 mmol/1) comme substrat glucoformateur, aucun effet de l'insuline n'est observé. La teneur en glycogène des hépatocytes (0,02 μmol de Glc/10⁶ hépatocytes) ne varie pas au cours des 4 h d'incubation. Ces résultats suggèrent que l'état d'oxydoréduction du secteur mitochondrial et la concentration cytoplasmique en oxaloacétate pourraient être des facteurs importants de l'action de l'insuline.