Free amino acid levels in muscle and liver of a patient with glucagonoma syndrome

Roth, Erich; Mühlbacher, F.; Karner, J.; Hamilton, Gerhard; Funovics, J.

doi:10.1016/0026-0495(87)90055-2

Cited by 47 publications

(22 citation statements)

References 20 publications

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“…Enhanced clearances, as well as the higher ratio of intracellular to plasma leucine rates of appearance, also suggest a relative intracellular amino acid accumulation in glucagonoma. In a previous report the reduction of amino acid concentrations was less pronounced in the liver and skeletal muscle than in plasma in a glucagonoma patient [9], and relatively higher intracellular amino acids are in keeping with the known glucagon-dependent stimulation of amino acid inward transport across the cell membrane [4].…”

Section: Discussionsupporting

confidence: 53%

Protein metabolism in glucagonoma

et al. 1999

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Patients with glucagon-producing pancreatic tumours exhibit profound metabolic disturbances, leading to the typical glucagonoma syndrome [1]. In particular, weight loss, muscle mass reduction and hypoaminoacidaemia suggest a sustained protein catabolism probably due, at least in part, to glucagon excess. Indeed, acute hyperglucagonaemia in healthy humans reduced plasma amino acid concentration [2] and enhanced essential amino acid catabolism [3,4], although no effects on whole-body proteolysis were detected in the presence of basal insulin concentrations [3,4]. Rather surprisingly, when leucine and protein kinetics were studied in a patient with glucagonoma, only a slight increase of leucine oxidation was reported, and protein breakdown was normal [5]. This patient had been treated, however, with i. v. octreotide and amino acids, which might have influenced protein turnover during the study [6]. Therefore, the mechanisms leading to protein wasting in glucagonoma are still not completely understood. To investigate this issue, postabsorptive leucine, phenylalanine and tyrosine kinetics were studied in two glucagonoma patients prior to treatment, and compared with normal control subjects values. Diabetologia (1999) Plasma leucine, phenylalanine and tyrosine rates of appearance in patients with glucagonoma were similar to values in the control subjects, except leucine rate of appearence in the female patient with glucagonoma ( + &30 %, d > 2 SD). In contrast, the intracellular leucine rate of appearence, reflecting protein degradation, was considerably increased in both patients ( + 60±80 %, d > 2 SD). Phenylalanine hydroxylation was moderately higher only in the male patient with glucagonoma ( + &30 %, d > 2 SD). Leucine, phenylalanine and tyrosine clearances ( + 100±300 %), as well as phenylalanine hydroxylative clearance ( + 75±100 %) were also increased in the patients. In conclusion, whole-body protein breakdown is enhanced in patients with glucagonoma compared with healthy control subjects. Phenylalanine hydroxylative clearance is also higher. Reduced plasma amino acid concentrations are probably due, at least in part, to their increased clearance. These alterations could contribute to the determination of the catabolic state of the glucagonoma syndrome. [Diabetologia (1999) 42: 326±329]

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Section: Discussionsupporting

confidence: 53%

Protein metabolism in glucagonoma

et al. 1999

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“…Hormones with hepatic receptors such as glucagon are tentative factors. An increased hepatic extraction of glutamine and an increased release of glutamate from the liver have been reported in a patient with glucagonoma, who displayed several AA abnormalities and weight loss (Roth et al 1987). Future studies are required to clarify whether the increased glutamate and IGFBP-1 levels are due to increased levels of a common stimulator.…”

Section: Discussionmentioning

confidence: 95%

Glutamate concentration in plasma, erythrocyte and muscle in relation to plasma levels of insulin-like growth factor (IGF)-I, IGF binding protein-1 and insulin in patients on haemodialysis

Filho

Hazel²,

Fürst³

et al. 1998

Journal of Endocrinology

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Elevated insulin-like growth factor binding protein (IGFBP) levels, including IGFBP-1, occur in renal failure, and may contribute towards reduced IGF bioactivity in uraemia. The reduced IGF bioactivity may, in turn, contribute towards the disturbances in protein metabolism present in renal failure. In this study, the relationships between intra-and extracellular amino acid (AA) levels and IGF-I and/or IGFBP-1 levels were studied in 30 adult patients (aged 24-70 years) on haemodialysis who had no clinical signs of malnutrition. Blood samples (n=30) and muscle biopsies (n=13) were collected for determination of free AA in erythrocytes (RBC), plasma and muscle by reverse-phase HPLC while IGFBP-1, IGF-I and insulin plasma levels were determined by radioimmunoassay.The patients on haemodialysis had elevated glutamate concentrations in RBC and plasma compared with healthy controls (524 26 vs 448 17 µmol/l, P<0·05 and 45 4 vs 32 4 µmol/l, P<0·01 respectively), although glutamate levels in muscle were within the normal range. The mean IGF-I level was slightly increased (.. score +0·74 0·30) but insulin levels were within the normal range. IGFBP-1 levels, which were inversely correlated to insulin (r= 0·40, P<0·02), were elevated threefold compared with controls. No plasma AA level displayed a significant correlation with IGF-I, IGFBP-1 or insulin levels. However, glutamate concentrations in RBC were positively correlated to IGFBP-1 (r=0·51, P<0·01) and inversely correlated to IGF-I (r= 0·46, P<0·01), although unrelated to insulin. Muscle glutamate, which was inversely related to RBC glutamate, displayed an opposite pattern with an inverse relation to IGFBP-1 levels (r= 0·73, P<0·01) and a positive correlation to IGF-I levels (r=0·64, P<0·02). Glutamate was the only AA to display an inverse correlation between RBC and muscle (r= 0·65, P<0·02, n=12).These findings lead us to propose that, in uraemia, the elevated IGFBP-1 levels, which reduce the bioavailability of IGFs, are linked to glutamate uptake in muscle, resulting in accumulation of RBC glutamate. Whether there is a causal relationship or the correlation is due to some common regulator is not clarified in the present study.

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“…In patients with glucagonoma, in which glucose metabolism is only minimally disturbed, there is marked muscle wasting, skin atrophy, and hypoaminocidemia (6). In these patients there is a reduction of free intracellular branched-chain amino acids (BCAA) in liver and muscle (7). It has been postulated that accelerated oxidation of BCAA is a cause of their decreased intracellular concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…After isotope boluses had been administered and continuous infusion of l - [1][2][3][4][5][6][7][8][9][10][11][12][13] C]leucine at a rate of 7.5 mol/kg/h had begun, an infusion of normal saline at a rate of 1.5 ml/kg/h was initiated for the first 2 h of each study. After 2 h of each study, one of the following five infusion protocols was begun and continued for 4 h until completion of the study.…”

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confidence: 99%

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

Charlton¹,

Adey²,

Nair³

1996

J. Clin. Invest.

108

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Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations. ( J. Clin. Invest. 1996. 98:90-99.)

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Free amino acid levels in muscle and liver of a patient with glucagonoma syndrome

Cited by 47 publications

References 20 publications

Protein metabolism in glucagonoma

Protein metabolism in glucagonoma

Glutamate concentration in plasma, erythrocyte and muscle in relation to plasma levels of insulin-like growth factor (IGF)-I, IGF binding protein-1 and insulin in patients on haemodialysis

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

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