Abstract
Although the hypercortisolism-induced impairment of protein homeostasis is object of several studies, a detailed evaluation of the complete amino acid profile of patients with Cushing’s syndrome (CS) has never been performed. The aim of the current open transversal controlled study was to evaluate serum and urinary concentrations as well as renal clearance of the complete series of natural amino acids and their relationship with glucose tolerance in patients with Cushing’s disease (CD). Twenty patients with CD (10 active and 10 cured) and 20 sex- and age-matched healthy controls entered the study. Measurement of serum and urinary levels of the complete series of natural amino acids was performed in all patients analyzed by cationic exchange high performance liquid cromatography (HPLC) after 2 weeks of a standardized protein intake regimen. The renal clearance (renal excretion rate) of each amino acid was calculated on the basis of the serum and urinary concentrations of creatinine and the specific amino acid. Fasting glucose and insulin levels, glucose and insulin response to standard glucose load, insulinogenic and homeostasis model insulin resistance (Homa-R) indexes were also evaluated and correlated to the circulating levels and renal clearances of each amino acid. Significantly higher serum (p<0.01) and urinary (p<0.05) levels of alanine and cystine, lower serum and higher urinary levels of leucine, isoleucine and valine (p<0.05) and higher renal excretion rates of leucine, isoleucine and valine (p<0.01) were found in patients with active CD than in patients cured from the disease and in controls. No difference was found between cured patients and controls. Creatinine clearance was similar in active and cured patients and in controls. In patients with active CD, urinary cortisol levels were significantly correlated to urinary cystine levels (r=0.85; p<0.01) and renal excretion rate of leucine (r=−0.76; p<0.05), isoleucine (r=−0.76; p<0.05) and valine (r=−0.66; p<0.05). Fasting blood glucose levels were significantly correlated to serum alanine levels (r=0.70; p<0.05). Although Homa-R was significantly correlated to BMI in active patients (r=0.74 p<0.05), it was not correlated to amino acid levels. In conclusion, the results of the current study demonstrate that patients with CD have significant changes in serum and urinary concentration of several amino acids and changes in renal clearance of some specific amino acids. Normalization of cortisol levels restored the amino acid profile.
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References
Orth D.N., Kovacs W.J., De Bold C.R. The adrenal cortex. In: Wilson J.D., Foster D.W., Kronenberg H.M., Larsen P.R. (Eds.), Williams Textbook of Endocrinology. W.B. Saunders, Philadelphia, 1998, p. 517.
Aron D.C., Findling J.W., Tyrrel J.B. Cushing’s disease. Endocrinol. Metab. Clin. North Am. 1987, 16: 705–730.
Wise J.K., Hendler R., Felig P. Influence of glucocorticoids on glucagon secretion and plasma amino acid concentrations in man. J. Clin. Invest. 1973, 52: 2774–2782.
Simmons P.S., Miles J.M., Gerich J.E., Haymond M.W. Increased proteolysis: an effect of increases in plasma cortisol within the physiologic range. J. Clin. Invest. 1984, 73: 412–420.
Beaufree B., Horber F.F., Schwenk W.F., et al. Glucocorticosteroids increase leucine oxidation and impair leucine balance in humans. Am. Physiol. Soc. 1989, 257: E712–E721.
Clerc D., Wick H., Keller U. Acute cortisol excess results in unimpaired insulin action on lipolysis and branched chain amino acids, but not on glucose kinetics and C-peptide concentration in men. Metabolism 1986, 35: 404–410.
Tessari P., Inchiostro S., Biolo G., et al. Leucine kinetics and effects of hyperinsulinemia in patients with Cushing’s syndrome. J. Clin. Endocrinol. Metab. 1989, 68: 256–262.
Bowes S.B., Benn J.J., Scobie I.N., et al. Leucine metabolism in patients with Cushing’s syndrome before and after successful treatment. Clin. Endocrinol. 1993, 39: 591–598.
Reinartz G., Angermaier A., Buchfelder M., Fahlbusch R., Georgieff M. Pre- and postoperative investigations of hepatic glucose production and leucine turnover in Cushing’s disease utilizing stable isotope techniques. Horm. Metab. Res. 1995, 27: 425–431.
Castellino P., Luzi L., Simonson D.C., Haymond M., De Fronzo R.A. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. J. Clin. Invest. 1987, 80: 1784–1793.
Colao A., Pivonello R., Spiezia S., et al. Persistence of increased cardiovascular risk in patients with Cushing’s disease after 5 years of Cushing’s disease utilizing stable isotope techniques. J. Clin. Endocrinol. Metab. 1999, 84: 2664–2672.
Russel-Jones D.L., Weissberger A.J., Bowes S.B., et al. Protein metabolism in growth hormone deficiency, and effects of growth hormone replacement therapy. Acta Endocrinol. 1993, 128: 44–47.
Growth Hormone Research Society (GRS). Consensus guidelines for diagnosis and treatment of adults with GH deficiency. Porth Stephens Workshop. J. Clin. Endocrinol. Metab. 1998, 83: 379–385.
Colao A., Cerbone G., Pivonello R., et al. The growth hormone (GH) response to arginine plus GH-releasing hormone test is correlated to the severity of lipid profile abnormalities in adult patients with GH deficiency. J. Clin. Endocrinol. Metab. 1999, 84: 1277–1282.
American Diabetes Association: Expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1999, 22: 5–19.
Matthews D.R., Hosker J.P., Rudeski A.S., et al. Homeostasis model assessment: insulin resistance and B-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28: 412–419.
Kosaka K., Kuzuya T., Yoshinaga H., Hagura R. A prospective study of health check examinees for the development of non-insulin-dependent diabetes mellitus: relationship of the incidence of diabetes with the initial insulinogenic index and degree of obesity. Diabet. Med. 1996, 13: S120–S126.
Bauer J.H., Brooks C.S., Burch R.N. Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am. J. Kidney Dis. 1982, 2: 337–346.
Claris-Appiani A., Ardissino G., Tirelli A.S., et al. Metabolic factors in the renal response to amino acid infusion. Am. J. Nephrol. 1998, 18: 359–366.
Snell K. Muscle alanine synthesis and hepatic gluconeogenesis. Biochem. Soc. Trans. 1980, 8: 205–213.
Felig P. The glucose-alanine cycle. Metabolism 1973, 22: 179–207.
Robert J.J., Bier D.M., Zhao X.H., Matthews D.E., Young V.R. Glucose and insulin effects on de novo amino acid synthesis in young men: studies with stable isotope alanine, glycine, leucine and lysine. Metabolism 1982, 31: 1210–1218.
Stipanuk M.H. Metabolism of sulfur-containing amino acids. Ann. Rev. Nut. 1986, 6: 179–209.
Tudhope G.R. Endocrine diseases. Clin. Haematol. 1972, 1: 475–506.
Savage D.G., Ogundipe A., Allen R.H., Stabler S.P., Lindenbaum J. Etiology and diagnostic evaluation of macrocytosis. Am. J. Med. Sci. 2000, 319: 343–352.
Fleck C. Renal transport of endogenous amino acids. II. Influence of treatment with triiodothyronine or dexamethasone in immature and adult rats. Ren. Physiol. Biochem. 1992, 15: 266–276.
Souba W.W., Pacitti, A.J. How amino acids get into cells: mechanisms, models, menus, and mediators. J. Parent. Ent. Nut. 1992, 16: 569–578.
Palacín M., Estévez R., Bertran J., Zorzano A. Molecular biology of mammalian plasma membrane amino acid transporters. Am. Physiol. Soc. 1998, 78: 969–1054.
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Faggiano, A., Pivonello, R., Melis, D. et al. Evaluation of circulating levels and renal clearance of natural amino acids in patients with Cushing’s disease. J Endocrinol Invest 25, 142–151 (2002). https://doi.org/10.1007/BF03343978
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DOI: https://doi.org/10.1007/BF03343978