Role of the direct and indirect pathways for glycogen synthesis in rat liver in the postprandial state.

Huang, Minghui; Veech, Richard L.

doi:10.1172/jci113397

Cited by 57 publications

(29 citation statements)

References 26 publications

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“…Thus, this tracer will determine an underestimation of the direct pathway that is in direct proportion to the rate of the pentose phosphate cycle. Because the pentose phosphate cycle has been shown to be negligible in these experimental conditions (24) and, perhaps more importantly, it has been reported to be normal or decreased in diabetic animals (57,72) Our results confirm that in the postabsorptive state the indirect pathway ofhepatic glycogen repletion plays a predominant role (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). In control rats, the per cent contribution of the direct pathway to hepatic glycogen repletion was 13% and 51% during the euglycemic and the +5.5 mM hyperglycemic insulin clamp studies respectively, in close agreement with previous results obtained, under identical experimental conditions, by nuclear magnetic resonance spectroscopy (7).…”

Section: Discussionsupporting

confidence: 72%

“…Over the last several years, numerous studies have suggested that, when a glucose load is administered to animals (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) or humans (21-24), a large portion ofthe liver glycogen is repleted by the indirect pathway. This issue has been addressed by several isotopic approaches, mainly based upon the detritiation ofglucose in the indirect pathway, or the determination of the randomization of labeling carbons in UDPglucose (extracted from urine glycoconjugates) or glucosyl units in glycogen.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is now well established, that, after glucose administration, in both animals (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and humans (21)(22)(23)(24), a significant portion of liver glycogen is not repleted through the classi-cose -glycogen. Several studies suggest that in non-insulindependent diabetes mellitus (NIDDM), the contribution ofgluconeogenesis to hepatic glucose output is increased, and plays a major role in the augmented plasma glucose concentration and hepatic glucose production during the postabsorptive state (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

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Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats.

Giaccari¹,

Rossetti²

1992

J. Clin. Invest.

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Liver glycogen formation can occur via the direct (glucose glucose-6-phosphate -v glycogen) or indirect (glucose -. C3 compounds --glucose-6-phosphate -3 glycogen) pathways. In the present study we have examined the effect of hyperglycemia on the pathways of hepatic glycogenesis, estimated from liver uridine diphosphoglucose (UDPglucose) specific activities, and on peripheral (muscle) glucose metabolism in awake, unstressed control and 90% pancreatectomized, diabetic rats.Under identical conditions of hyperinsulinemia (-550 gsU/ ml), 2-h euglycemic (6 mM) and hyperglycemic (+5.5 mM and +11 mM) clamp studies were performed in combination with 13-3H,U-`4Cjglucose, 16-3H,U-14Cjglucose, or 13-3Hjglucose and IU-14Cllactate infusions under postabsorptive conditions. Total body glucose uptake and muscle glycogen synthesis were decreased in diabetic vs. control rats during all the clamp studies, whereas glycolytic rates were similar. By contrast, hyperglycemia determined similar rates of liver glycogen synthesis in both groups. Nevertheless, in diabetic rats, the contribution of the direct pathway to hepatic glycogen repletion was severely decreased, whereas the indirect pathway was markedly increased. After hyperglycemia, hepatic glucose-6-phosphate concentrations were increased in both groups, whereas UDPglucose concentrations were reduced only in the control group. These results indicate that in the diabetic state, under hyperinsulinemic conditions, hyperglycemia normally stimulates liver glycogen synthesis through a marked increase in the indirect pathway, which in turn may compensate for the reduction in the direct pathway. The increase in the hepatic concentrations of both glucose-6-phosphate and UDPglucose suggests the presence, in this diabetic rat model, of a compensatory "push" mechanism for liver glycogen repletion. (J. Clin. Invest. 1992.89:36-45.)

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats.

Giaccari¹,

Rossetti²

1992

J. Clin. Invest.

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“…Huang and Veech (10) and in other studies as evidence for a negligible contribution of an indirect path. Indirect Path.…”

Section: Methodsmentioning

confidence: 57%

Determination of pathways of glycogen synthesis and the dilution of the three-carbon pool with [U-13C]glucose.

Katz

Wals

Lee

1991

Proc. Natl. Acad. Sci. U.S.A.

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Determination of pathways of glycogen synthesis and the dilution of the three-carbon pool with [U-13C] The enrichment of 13C and the specific activity of 14C in glycogen formed by the indirect path were 20-25% of glycogen formed directly from glucose. The dilution is of two kinds: (i) an exchange of labeled carbon with unlabeled carbon in the tricarboxylic acid cycle and (ii) dilution by unlabeled nonglucose carbon. Methods to calculate the two types of dilution are presented. In control rats the dilution factor by exchange in the tricarboxylic acid cycle is 1.4, and the dilution by unlabeled carbon is 2.5-to 3.0-fold, with the overall dilution about 4-fold. In rats preinjected with glucagon, the dilution through the tricarboxylic acid cycle was unaffected but that by nonglucose carbon was decreased.It is now generally realized that only a part of liver glycogen is derived from intact glucose (1). However, there still prevails confusion as to what the direct path represents and how its contribution to glycogen may be determined. Very little attention has been paid to the indirect path, the synthesis of glycogen from three-carbon compounds. We have previously described (2, 3) the application of gas chromatography/mass spectroscopy (GC/MS) with [U-13C] and three rats were not treated. At the end of the infusion, portal and arterial blood was sampled and liver was homogenized in 6% (vol/vol) perchloric acid, and glucose and glycogen were isolated. Arterial blood glucose at sacrifice (165 min after start of infusion) averaged 6.5 ,umol/g of blood, and portal blood glucose was 9.5 ,tmol/g of blood, but '3C enrichment and specific activities in portal and arterial blood were virtually the same. Liver glycogen content averaged 85Armol/g. Glycogen content of fasted rats was very low, from 0.7 to 1.3 ,umol/g (n = 3), and no correction for initial glycogen content was applied. GC/MS analysis and corrections for natural abundance and 12C in [U-13C]glucose were as described (2-4). Spectrograms of the infusate, blood glucose, and glycogen have been published elsewhere (3).The total infused dose of [14C]-and [3H]glucose was 120 X 106 cpm each. Blood and glycogen glucose were degraded to obtain the specific activity of 14C in C-1 and C-6 of glucose. C-1 of glucose was released enzymatically as CO2. The incubation mixture was 0.1 M Hepes'NaOH (pH 8), 8 mM NADP, 5 mM ATP, 10 mM MgCl2, hexokinase (5 units/ml), glucose-6-phosphate dehydrogenase (10 units/ml), and 0.6 unit of phosphogluconate dehydrogenase. Total volume was 5 ml containing 10 ,mol ofglucose. Incubation was overnight at room temperature. CO2 was released by acidification with H2SO4 and was trapped in 2 ml of 50% (wt/vol) phenethylamine. The activity of C-6 of glucose after periodate oxidation was obtained as the dimedon derivative of formaldehyde as described by Bloom (5 [U-_3C]glucose is 600%.) The conventional term for enrichment is atom percent excess (APE), equal to 61 mn/6 for glucose, a term not used by us. The term relative molar enrichment (or relative enric...

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“…After determining metabolite content in µmol/g wet weight tissue, the data were converted to µmol/ml total tissue water from the total water content of the tissue. Intracellular tissue ion concentrations were determined using the equation: (13). Hepatic vascular space was determined by incubating erythrocytes with Na 2 51 CrO 4 and infusing the labeled cells into the jugular vein followed by a saline flush.…”

Section: Methodsmentioning

confidence: 99%

The Energetics of Ion Distribution: The Origin of the Resting Electric Potential of Cells

Veech¹,

Kashiwaya²,

Gates³

et al. 2002

IUBMB Life

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SummaryThe relation between the energies of ion movement and ATP hydrolysis is unknown in tissues with widely varying electric potentials. Consequently, we measured the concentration of the nine major inorganic ions in the extra-and intracellular phases in heart, liver, and red cells with resting electrical potentials, E N , of −86, −28, and −6 mV, respectively, under six different physiological conditions. We calculated the Nernst electric potential and the energy of ion movement between the phases. We found that the energy of ATP hydrolysis was essentially constant, between −54 and −58 kJ/mol, in all tissues and conditions. In contrast, as E N decreased, the energies of the Na + and K + gradients decreased, with slopes approximating their valence. The difference between the energies of Na + and K + gradients remained constant at 17 kJ/mol, which is approximately one third of the energy of ATP hydrolysis, demonstrating near-equilibrium of the Na + /K + ATPase in all tissues under all conditions. All cations, except K + , were pumped out of cells and all anions, except Cl − in liver and red cell, were pumped into cells. We conclude that the energy of ATP was expressed in Na + /K + ATPase and its linked inorganic ion transporters to create a Gibbs-Donnan near-equilibrium system, an inherent part of which was the electric potential.

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Role of the direct and indirect pathways for glycogen synthesis in rat liver in the postprandial state.

Cited by 57 publications

References 26 publications

Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats.

Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats.

Determination of pathways of glycogen synthesis and the dilution of the three-carbon pool with [U-13C]glucose.

The Energetics of Ion Distribution: The Origin of the Resting Electric Potential of Cells

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