Evidence for a catabolic role of glucagon during an amino acid load.

Charlton, Michael; Adey, Deborah; Nair, K. Sreekumaran

doi:10.1172/jci118782

Cited by 107 publications

(92 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lactate, 3-hydroxybutyrate and NEFA were analysed as described previously [3], as was circulating epinephrine [18]. Plasma insulin and growth hormone were measured using a chemiluminescent sandwich assay (Sanofi Diagnostics, Chaska, MN, USA) and glucagon and cortisol were measured with radioimmunoassays (Diagnostic Products, Los Angeles, CA, USA).…”

Section: Study Protocolmentioning

confidence: 99%

Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis: The aim of this study was to test the hypothesis that type 1 diabetes alters renal amino acid, glucose and fatty acid metabolism. Materials and methods: We studied five C-peptide-negative, type 1 diabetic subjects during insulin replacement (glucose 5.6 mmol/l) and insulin deprivation (glucose 15.5 mmol/l) and compared them with six non-diabetic subjects. Leucine, phenylalanine, tyrosine, glucose and palmitate tracers were infused after an overnight fast and samples were obtained from the renal vein, femoral vein and femoral artery. Results: Insulin deprivation significantly increased wholebody fluxes (20-25%) of phenylalanine, tyrosine and leucine, and leucine oxidation (50%). Kidney contributed 5-10% to the whole-body leucine and phenylalanine flux. A net uptake of phenylalanine, conversion of phenylalanine to tyrosine (5 μmol/min) and net release of tyrosine (∼5 μmol/min) occurred across the kidney. Whole-body (three-fold) and leg (two-fold) leucine transamination increased but amino acid metabolism in the kidney did not alter with diabetes or insulin deprivation. Insulin deprivation doubled endogenous glucose production, renal glucose production was unaltered by insulin deprivation and diabetes (ranging between 100 and 140 μmol/min).Renal palmitate exchange was unaltered by insulin deprivation. Conclusions/interpretation: In conclusion, kidney postabsorptively accounts for 5-10% of whole-body protein turnover, 15-20% of leucine transamination and 10-15% of endogenous glucose production, and actively converts phenylalanine to tyrosine. During insulin deprivation, leg becomes a major site for leucine transamination but insulin deprivation does not affect renal phenylalanine, leucine, palmitate or glucose metabolism. Despite its key metabolic role, insulin deprivation in type 1 diabetic patients does not alter many of these metabolic functions.

show abstract

Section: Study Protocolmentioning

confidence: 99%

Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Interestingly, the catabolic response is not specific to individual AA and the capacity for degradation of the deficient AA is also elevated (Keene and Austic 2001). Glucagon appears to be the signal responsible for the up-regulation of hepatic expression of enzymes for essential AA catabolism when circulating AA concentrations are high (Charlton et al 1996;O'Sullivan et al 2000). In cattle infused postruminally with mixtures of AA, plasma glucagon is typically elevated (Cohick et al 1986;Choung and Chamberlain 1995), especially when single essential AA are missing from the infusate (Luimes, P.H., Cant, J.P, Weekes, T.L.…”

Section: Coordination Of Amino Acid Utilizationmentioning

confidence: 99%

Responses of the bovine mammary glands to absorptive supply of single amino acids

Cant¹,

Berthiaume²,

Lapierre³

et al. 2003

Can. J. Anim. Sci.

View full text Add to dashboard Cite

Responses of the bovine mammary glands to absorptive supply of single amino acids. Can. J. Anim. Sci. 83: [341][342][343][344][345][346][347][348][349][350][351][352][353][354][355]. In this review, we discuss the mechanisms of responses of various tissues of the lactating dairy cow, particularly the mammary glands, to perturbations in supply of single amino acids that result in observed milk protein yields. Additions of methionine, lysine, histidine or leucine to the absorptive supply cause arterial concentrations of these amino acids to increase, mammary extractions to drop and mammary blood flow to decrease. Single subtractions of essential amino acids have the opposite effect. Changes in mammary blood flow that have been recorded can be explained as attempts by the mammary glands to restore intracellular ATP balance in the face of altered concentrations of energy metabolites in the general circulation. In a quantitative sense, milk protein yield is relatively insensitive to fluctuations in arterial amino acid concentrations but can be stimulated by any one of a number of amino acids. In this context, it is suggested that the designation of a limiting amino acid is not appropriate to the purpose of predicting milk protein yield. Rather, milk protein synthesis appears to operate at a predetermined rate set by external communications of milk withdrawal rate, physiological state and overall nutritional status. Utilization of amino acids (AA) by splanchnic and peripheral tissues, in coordination with the mammary setpoint, offsets imperfections in the dietary AA supply. How strongly an individual AA influences the mammary setpoint, arterial concentrations of energy metabolites, and mammary AA transport capacity will determine the magnitude of the milk protein yield response when its absorptive supply is changed. Dans cet article, les auteurs examinent comment certains tissus de la vache laitière en lactation, principalement la glande mammaire, réagissent à une modification de l'apport de certains acides aminés entraînant un changement du rendement du lait en protéines. L'addition de méthionine, de lysine, d'histidine ou de leucine aux acides aminés absorbés augmente leur concentration dans le sang artériel et la diminue dans les sécrétions et le sang de la glande mammaire. La soustraction d'un de ces acides aminés a l'effet contraire. On explique les variations observées au niveau de la circulation sanguine dans la glande mammaire par les efforts que cette dernière déploie pour rétablir l'équilibre de l'ATP après modification de la quantité de métabolites porteurs d'énergie dans la circulation générale. Sur le plan quantitatif, le rendement du lait en protéines est relativement insensible aux fluctuations de la concentration d'acides aminés dans le sang artériel, mais il est stimulé par plusieurs acides aminés. On estime qu'il est impossible de prévoir le rendement du lait en protéines à partir d'un acide aminé limitant. En effet, les protéines laitières semblent être synthétisées à un taux préétabli par les rappo...

show abstract

“…In contrast, few studies have examined the effects of the hormone on protein metabolism. Reports suggest that in vivo glucagon has an overall catabolic effect on protein metabolism, although the mechanisms through which it acts are unclear (2)(3)(4)(5). Studies using a perfused rat liver preparation show that glucagon stimulates protein degradation, inhibits protein synthesis, and prevents completely the stimulation of protein synthesis induced by elevated levels of perfusate amino acid concentration (6).…”

mentioning

confidence: 99%

Glucagon Represses Signaling through the Mammalian Target of Rapamycin in Rat Liver by Activating AMP-activated Protein Kinase

Kimball

Siegfried

Jefferson

2004

Journal of Biological Chemistry

120

104

View full text Add to dashboard Cite

The opposing actions of glucagon and insulin on glucose metabolism within the liver are essential mechanisms for maintaining plasma glucose concentrations within narrow limits. Less well studied are the counterregulatory actions of glucagon on protein metabolism. In the present study, the effect of glucagon on amino acid-induced signaling through the mammalian target of rapamycin (mTOR), an important controller of the mRNA binding step in translation initiation, was examined using the perfused rat liver as an experimental model. The results show that amino acids enhance signaling through mTOR resulting in phosphorylation of eukaryotic initiation factor 4E-binding protein (4E-BP)1, the 70-kDa ribosomal protein (rp)S6 kinase, S6K1, and rpS6. In contrast, glucagon repressed both basal and amino acid-induced signaling through mTOR, as assessed by changes in the phosphorylation of 4E-BP1 and S6K1. The repression was associated with the activation of protein kinase A and enhanced phosphorylation of LKB1 and the AMP-activated protein kinase (AMPK). Surprisingly, the phosphorylation of two S6K1 substrates, rpS6 and eukaryotic initiation factor 4B, was not repressed but instead was increased by glucagon treatment, regardless of the amino acid concentration. The latter finding could be explained by the glucagoninduced phosphorylation of the ERK1 and the 90-kDa rpS6 kinase p90 rsk . Thus, glucagon represses phosphorylation of 4E-BP1 and S6K1 through the activation of a protein kinase A-LKB-AMPK-mTOR signaling pathway, while simultaneously enhancing phosphorylation of other downstream effectors of mTOR through the activation of the extracellular signal-regulated protein kinase 1-p90 rsk signaling pathway. Amino acids also enhance AMPK phosphorylation, although to a lesser extent than glucagon and amino acids combined.The counter-regulatory action of glucagon on insulin-stimulated glucose metabolism is well documented in the literature (1). In contrast, few studies have examined the effects of the hormone on protein metabolism. Reports suggest that in vivo glucagon has an overall catabolic effect on protein metabolism, although the mechanisms through which it acts are unclear (2-5). Studies using a perfused rat liver preparation show that glucagon stimulates protein degradation, inhibits protein synthesis, and prevents completely the stimulation of protein synthesis induced by elevated levels of perfusate amino acid concentration (6). Studies using rat hepatocytes show that glucagon attenuates the stimulatory effect of epidermal growth factor on phosphorylation of the ribosomal protein (rp) 1 S6 kinase S6K1 (7).In rat liver, the stimulation of S6K1 phosphorylation by hormones and nutrients is regulated through a signal transduction pathway involving a protein kinase referred to as the mammalian target of rapamycin (mTOR). Phosphorylation activates S6K1, which then phosphorylates rpS6 (8) and eukaryotic initiation factor (eIF)4B (9), resulting in an enhanced translation of subsets of mRNA such as those containing an oligopyri...

show abstract

Evidence for a catabolic role of glucagon during an amino acid load.

Cited by 107 publications

References 57 publications

Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

Responses of the bovine mammary glands to absorptive supply of single amino acids

Glucagon Represses Signaling through the Mammalian Target of Rapamycin in Rat Liver by Activating AMP-activated Protein Kinase

Contact Info

Product

Resources

About