Biphasic stimulation of amino acid uptake by glucagon in hepatocytes

Edmondson, James W.; Lumeng, Lawrence

doi:10.1016/0006-291x(80)91181-x

Cited by 48 publications

(26 citation statements)

References 11 publications

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“…We recently found that glucagon, the major counterregulatory hormone in healthy individuals, acutely increases the uptake of glutamine, but it does not increase its release with proteolysis or de novo synthesis, and it produces decrements in circulating glutamine and leucine (16). This finding is also supported by animal studies that found that both insulin and glucagon stimulate hepatic glutamine transport (43)(44)(45)(46). In contrast, glucagon increases whole-body proteolysis only with insulin deficiency (13), but it has a very small effect at postabsorptive insulinemia (9,14,16).…”

Section: A B Csupporting

confidence: 67%

Effect of hypoglycemia on amino acid and protein metabolism in healthy humans.

et al. 2000

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In response to hypoglycemia, healthy individuals rapidly antagonize insulin action on glucose and lipid metabolism, but the effects on protein metabolism are unclear. Because amino acids are an important substrate for gluconeogenesis and a fuel alternative to glucose for oxidation, we evaluated whether hypoglycemia antagonizes the hypoaminoacidemic and the antiproteolytic effects of insulin and changes the de novo synthesis of glutamine, a gluconeogenic amino acid. To this purpose, in 7 healthy subjects, we performed 2 studies, 3.5 h each, at similar insulin but different glucose concentrations (i.e., 4.9 ± 0.1 mmol/l [euglycemic clamp] or 2.9 ± 0.2 mmol/l [hypoglycemic clamp]). As expected, hypoglycemia antagonized the insulin suppression of glucose production achieved in euglycemia (from 21 ± 15 to 116 ± 12% of basal, P < 0.001), the stimulation of glucose uptake (from 207 ± 28 to 103 ± 7% of basal, P < 0.01) and the suppression of circulating free fatty acids (from 30 ± 5 to 80 ± 17% of basal, P < 0.001). In contrast, hypoglycemia increased the insulin suppression of circulating leucine (from 63 ± 1 to 46 ± 2% of basal, P < 0.001) and phenylalanine (from 79 ± 3 to 64 ± 3% of basal, P < 0.001) concentrations. Hypoglycemia did not change the insulin suppression of proteolysis (from 79 ± 2 to 82 ± 4% of basal, P < 0.001). However, hypoglycemia doubled the insulin suppression of the glutamine concentrations (from 84 ± 3 to 63 ± 3% of basal, P < 0.01) in the absence of significant changes in the glutamine rate of appearance, but it also caused an imbalance between glutamine uptake and release. This study demonstrates that successful counterregulation does not affect proteolysis. Moreover, it does not increase the availability of circulating amino acids by de novo synthesis. In contrast, despite the lower concentration of circulating amino acids, hypoglycemia increases the uptake of glutamine that can be used for gluconeogenesis and as a fuel alternative to glucose.

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Section: A B Csupporting

confidence: 67%

Effect of hypoglycemia on amino acid and protein metabolism in healthy humans.

et al. 2000

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“…Potter and his associates find that there is a lag period of 1 to 2 hr prior to any observable increase in AIB uptake by primary hepatocyte cultures . Others report that little or no lag period is observed for freshly isolated cells in suspension Edmondson & Lumeng, 1980). It is not clear at the present time if these differences are, in fact, due to culturing; however, rapid effects of glucagon are also seen in liver slices (Tews, Woodcock, Colosi & Harper, 1975) and perfused liver (Chambers et al, 1968 ;Kilberg & Neuhaus, 1977).…”

Section: Glucagonmentioning

confidence: 72%

“…The stimulation of transport by glucagon in freshly isolated hepatocytes in suspension is independent of de novo protein synthesis for the initial 15-30 min, whereas after 30 min cycloheximide completely abolishes any further enhancement by the hormone (Edmondson & Lumeng, 1980). The mechanism by which glucagon increases amino acid transport prior to the involvement of protein synthesis is still unclear.…”

Section: Glucagonmentioning

confidence: 95%

Amino acid transport in isolated rat hepatocytes

Kilberg

1982

J. Membrain Biol.

217

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Improvements in the collagenase perfusion techniques have made isolated rat hepatocytes a popular model in which to study hepatic function. Our knowledge of hepatic amino acid transport has been advanced as a result of this methodology. Translocation across the hepatocyte plasma membrane can, in some instances, represent the rate-limiting step in the overall metabolism of certain amino acids. Furthermore, regulation of amino acid uptake by hepatocytes appears to play a role in diabetes, and perhaps in malignant transformation. Comparisons between normal adult hepatocytes and several hepatoma cell lines show basic differences in amino acid transport. There are at least eight distinct systems in normal hepatocytes for transport of the hormones. Systems A and N exhibit enhanced uptake rates after the cells have been maintained in the absence of extracellular amino acids, a phenomenon termed adaptive control. Further studies using isolated hepatocytes will increase our basic understanding of membrane transport processes and their regulation.

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“…The K,,, values determined in this study agree well with those reported by others [3, 91. The increase in V,,, as well as the fact that the stimulation could be blocked by cycloheximide suggest that the hormonal induction (i. e. long-term regulation) of system N seems to depend on the synthesis of new transport molecules and their insertion into the plasma membrane as has been found for the hormonal induction of system A [28]. It is not known whether there exists also a short-term regulation by hormones via effects on membrane potential and the sodium gradient as described for system A [29].…”

Section: Discussionmentioning

confidence: 97%

Hormonal regulation of amino acid transport system N in primary cultures of rat hepatocytes

Gebhardt

Kleemann

1987

Eur J Biochem

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The transport of histidine and glutamine via system N in cultured hepatocytes was found to be subject to hormonal control. This long-term regulation showed the following characteristics.1. The transport capacity for histidine and glutamine (system N) increased slowly in response to the combination of dexamethasone and insulin to about 4-fold that of controls after 18-30 h. A similar time course was found for the stimulation of system N (2.5-fold) by dexamethasone and glucagon. In contrast the uptake of a-aminoisobutyric acid (system A) was rapidly stimulated 3-fold by dexamethasone and insulin and 5-fold by dexamethasone and glucagon within 3 -6 h but decreased towards control rates after 24 h of cultivation in minimal essential medium.2. Dexamethasone, insulin and glucagon each stimulated glutamine uptake about 2-fold in cultures maintained in W/AB 77 medium, while the combination of dexamethasone with either glucagon or insulin resulted in a 3 -4-fold increase.3. Dexamethasone was most effective at about 0.1 pM. Higher concentrations were less efficient. Insulin reached its optimal effect at concentrations above 1 pM.4. Kinetic analysis revealed that the increased capacity of glutamine transport in response to hormones was due to an increase in V,,,, while K,,, was essentially unchanged.5. The hormone-induced stimulation of system N was prevented by cycloheximide. 6. The induced uptake of glutamine was inhibited by excess amounts of asparagine and histidine but not of These results clearly differentiate the hormonal regulation of system N from that of system A.

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Biphasic stimulation of amino acid uptake by glucagon in hepatocytes

Cited by 48 publications

References 11 publications

Effect of hypoglycemia on amino acid and protein metabolism in healthy humans.

Effect of hypoglycemia on amino acid and protein metabolism in healthy humans.

Amino acid transport in isolated rat hepatocytes

Hormonal regulation of amino acid transport system N in primary cultures of rat hepatocytes

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