Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Jan;75(1):251–257. doi: 10.1172/JCI111681

Hyperuricemia in glycogen storage disease type I. Contributions by hypoglycemia and hyperglucagonemia to increased urate production.

J L Cohen, A Vinik, J Faller, I H Fox
PMCID: PMC423433  PMID: 2856925

Abstract

Studies were performed to determine whether hypoglycemia or the glucagon response to hypoglycemia increases uric acid production in glycogen storage disease type I (glucose-6-phosphatase deficiency). Three adults with this disease had hyperuricemia (serum urate, 11.3-12.4 mg/dl) and reduced renal clearance of urate (renal urate clearance, 1.1-3.1 ml/min). These abnormalities were improved in one patient by intravenous glucose infusion for 1 mo, suggesting a role for hypoglycemia and its attendant effects on urate metabolism and excretion. A pharmacologic dose of glucagon caused a rise in serum urate from 11.4 to 13.0 mg/dl, a ninefold increase in urinary excretion of oxypurines, a 65% increase in urinary radioactivity derived from radioactively labeled adenine nucleotides, and a 90% increase in urinary uric acid excretion. These changes indicate that intravenous glucagon increases ATP breakdown to its degradation products and thereby stimulates uric acid production. To observe whether physiologic changes in serum glucagon modulate ATP degradation, uric acid production was compared during saline and somatostatin infusions. Serum urate, urinary oxypurine, radioactivity, and uric acid excretion increased during saline infusion as patients became hypoglycemic. Infusion of somatostatin suppressed these increases despite hypoglycemia and decreased the elevated plasma glucagon levels from a mean of 81.3 to 52.2 pg/ml. These data suggest that hypoglycemia can stimulate uric acid synthesis in glucose-6-phosphatase deficiency. Glucagon contributes to this response by activating ATP degradation to uric acid.

Full text

PDF
257

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alepa F. P., Howell R. R., Klinenberg J. R., Seegmiller J. E. Relationships between glycogen storage disease and tophaceous gout. Am J Med. 1967 Jan;42(1):58–66. doi: 10.1016/0002-9343(67)90006-x. [DOI] [PubMed] [Google Scholar]
  2. Benke P. J., Gold S. Uric acid metabolism in therapy of glycogen storage disease type I. Pediatr Res. 1978 Mar;12(3):204–206. doi: 10.1203/00006450-197803000-00008. [DOI] [PubMed] [Google Scholar]
  3. Bondar R. J., Mead D. C. Evaluation of glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides in the hexokinase method for determining glucose in serum. Clin Chem. 1974 May;20(5):586–590. [PubMed] [Google Scholar]
  4. Clarke W. L., Santiago J. V., Thomas L., Ben-Galim E., Haymond M. W., Cryer P. E. Adrenergic mechanisms in recovery from hypoglycemia in man: adrenergic blockade. Am J Physiol. 1979 Feb;236(2):E147–E152. doi: 10.1152/ajpendo.1979.236.2.E147. [DOI] [PubMed] [Google Scholar]
  5. Crigler J. F., Jr, Folkman J. Glycogen storage disease: new approaches to therapy. Ciba Found Symp. 1977;(55):331–351. doi: 10.1002/9780470720363.ch17. [DOI] [PubMed] [Google Scholar]
  6. Edwards N. L., Recker D., Fox I. H. Overproduction of uric acid in hypoxanthine-guanine phosphoribosyltransferase deficiency. Contribution by impaired purine salvage. J Clin Invest. 1979 May;63(5):922–930. doi: 10.1172/JCI109392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ehrlich R. M., Robinson B. H., Freedman M. H., Howard N. J. Nocturnal intragastric infusion of glucose in management of defective gluconeogenesis with hypoglycemia. Am J Dis Child. 1978 Mar;132(3):241–243. doi: 10.1001/archpedi.1978.02120280025005. [DOI] [PubMed] [Google Scholar]
  8. Exton J. H., Mallette L. E., Jefferson L. S., Wong E. H., Friedmann N., Miller T. B., Jr, Park C. R. The hormonal control of hepatic gluconeogenesis. Recent Prog Horm Res. 1970;26:411–461. doi: 10.1016/b978-0-12-571126-5.50014-5. [DOI] [PubMed] [Google Scholar]
  9. Exton J. H., Robison G. A., Sutherland E. W., Park C. R. Studies on the role of adenosine 3',5'-monophosphate in the hepatic actions of glucagon and catecholamines. J Biol Chem. 1971 Oct 25;246(20):6166–6177. [PubMed] [Google Scholar]
  10. Faller J., Fox I. H. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med. 1982 Dec 23;307(26):1598–1602. doi: 10.1056/NEJM198212233072602. [DOI] [PubMed] [Google Scholar]
  11. Fine R. N., Strauss J., Donnell G. N. Hyperuricemia in glycogen-storage disease type 1. Am J Dis Child. 1966 Dec;112(6):572–576. doi: 10.1001/archpedi.1966.02090150116013. [DOI] [PubMed] [Google Scholar]
  12. Fox I. H., Kelley W. N. Studies on the mechanism of fructose-induced hyperuricemia in man. Metabolism. 1972 Aug;21(8):713–721. doi: 10.1016/0026-0495(72)90120-5. [DOI] [PubMed] [Google Scholar]
  13. Fox I. H. Metabolic basis for disorders of purine nucleotide degradation. Metabolism. 1981 Jun;30(6):616–634. doi: 10.1016/0026-0495(81)90142-6. [DOI] [PubMed] [Google Scholar]
  14. GLICK S. M., ROTH J., YALOW R. S., BERSON S. A. IMMUNOASSAY OF HUMAN GROWTH HORMONE IN PLASMA. Nature. 1963 Aug 24;199:784–787. doi: 10.1038/199784a0. [DOI] [PubMed] [Google Scholar]
  15. Garber A. J., Cryer P. E., Santiago J. V., Haymond M. W., Pagliara A. S., Kipnis D. M. The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man. J Clin Invest. 1976 Jul;58(1):7–15. doi: 10.1172/JCI108460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gerich J. E., Schneider V., Dippe S. E., Langlois M., Noacco C., Karam J. H., Forsham P. H. Characterization of the glucagon response to hypoglycemia in man. J Clin Endocrinol Metab. 1974 Jan;38(1):77–82. doi: 10.1210/jcem-38-1-77. [DOI] [PubMed] [Google Scholar]
  17. Gerich J., Davis J., Lorenzi M., Rizza R., Bohannon N., Karam J., Lewis S., Kaplan R., Schultz T., Cryer P. Hormonal mechanisms of recovery from insulin-induced hypoglycemia in man. Am J Physiol. 1979 Apr;236(4):E380–E385. doi: 10.1152/ajpendo.1979.236.4.E380. [DOI] [PubMed] [Google Scholar]
  18. Greene H. L., Slonim A. E., Burr I. M., Moran J. R. Type I glycogen storage disease: five years of management with nocturnal intragastric feeding. J Pediatr. 1980 Mar;96(3 Pt 2):590–595. doi: 10.1016/s0022-3476(80)80871-7. [DOI] [PubMed] [Google Scholar]
  19. Greene H. L., Slonim A. E., O'Neill J. A., Jr, Burr I. M. Continuous nocturnal intragastric feeding for management of type 1 glycogen-storage disease. N Engl J Med. 1976 Feb 19;294(8):423–425. doi: 10.1056/NEJM197602192940805. [DOI] [PubMed] [Google Scholar]
  20. Greene H. L., Wilson F. A., Hefferan P., Terry A. B., Moran J. R., Slonim A. E., Claus T. H., Burr I. M. ATP depletion, a possible role in the pathogenesis of hyperuricemia in glycogen storage disease type I. J Clin Invest. 1978 Aug;62(2):321–328. doi: 10.1172/JCI109132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. HOWELL R. R., ASHTON D. M., WYNGAARDEN J. B. Glucose-6-phosphatase deficiency glycogen storage disease. Studies on the interrelationships of carbohydrate, lipid, and purine abnormalities. Pediatrics. 1962 Apr;29:553–565. [PubMed] [Google Scholar]
  22. Hayashi M., Floyd J. C., Jr, Pek S., Fajans S. S. Insulin, proinsulin, glucagon and gastrin in pancreatic tumors and in plasma of patients with organic hyperinsulinism. J Clin Endocrinol Metab. 1977 Apr;44(4):681–694. doi: 10.1210/jcem-44-4-681. [DOI] [PubMed] [Google Scholar]
  23. Hers H. G., Van Den Berghe G. Enzyme defect in primary gout. Lancet. 1979 Mar 17;1(8116):585–586. doi: 10.1016/s0140-6736(79)91010-9. [DOI] [PubMed] [Google Scholar]
  24. Howell R. R. The interrelationship of glycogen storage disease and gout. Arthritis Rheum. 1965 Oct;8(5):780–785. doi: 10.1002/art.1780080441. [DOI] [PubMed] [Google Scholar]
  25. JEANDET J., LESTRADET H. [Hyperlactacidemia, probable cause of hyperuricemia, in hepatic glycogenosis]. Rev Fr Etud Clin Biol. 1961 Jan;6:71–72. [PubMed] [Google Scholar]
  26. JEUNE M., CHARRAT A., BERTRAND J. Polycorie hépatique, hypéruricemie et goutte. Arch Fr Pediatr. 1957;14(9):897–909. [PubMed] [Google Scholar]
  27. JEUNE M., FRANCOIS R., JARLOT B. Contribution à l'étude des polycories glycogéniques du foie. Rev Int Hepatol. 1959;9(1):1–33. [PubMed] [Google Scholar]
  28. Jakovcic S., Sorensen L. B. Studies of uric acid metabolism in glycogen storage disease associated with gouty arthritis. Arthritis Rheum. 1967 Apr;10(2):129–134. doi: 10.1002/art.1780100207. [DOI] [PubMed] [Google Scholar]
  29. KOLB F. O., DE LALLA O. F., GOFMAN J. W. The hyperlipemias in disorders of carbohydrate metabolism: serial lipoprotein studies in diabetic acidosis with xanthomatosis and in glycogen storage disease. Metabolism. 1955 Jul;4(4):310–317. [PubMed] [Google Scholar]
  30. Kelley W. N., Rosenbloom F. M., Seegmiller J. E., Howell R. R. Excessive production of uric acid in type I glycogen storage disease. J Pediatr. 1968 Apr;72(4):488–496. doi: 10.1016/s0022-3476(68)80339-7. [DOI] [PubMed] [Google Scholar]
  31. Klinenberg J. R., Goldfinger S., Bradley K. H., Seegmiller J. E. An enzymatic spectrophotometric method for the determination of xanthine and hypoxanthine. Clin Chem. 1967 Oct;13(10):834–846. [PubMed] [Google Scholar]
  32. LIDDLE L., SEEGMILLER J. E., LASTER L. The enzymatic spectrophotometric method for determination of uric acid. J Lab Clin Med. 1959 Dec;54:903–913. [PubMed] [Google Scholar]
  33. Okada S., Seino Y., Kodama H., Yutaka T., Inui K., Ishida M., Yabuuchi H., Seino Y. Insulin and glucagon secretion in hepatic glycogenoses. Acta Paediatr Scand. 1979 Sep;68(5):735–738. doi: 10.1111/j.1651-2227.1979.tb18448.x. [DOI] [PubMed] [Google Scholar]
  34. Palmer J. P., Henry D. P., Benson J. W., Johnson D. G., Ensinck J. W. Glucagon response to hypoglycemia in sympathectomized man. J Clin Invest. 1976 Feb;57(2):522–525. doi: 10.1172/JCI108305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pek S., Fajans S. S., Floyd J. C., Jr, Knopf R. F., Conn J. W. Failure of sulfonylureas to suppress plasma glucagon in man. Diabetes. 1972 Apr;21(4):216–223. doi: 10.2337/diab.21.4.216. [DOI] [PubMed] [Google Scholar]
  36. Perheentupa J., Raivio K. Fructose-induced hyperuricaemia. Lancet. 1967 Sep 9;2(7515):528–531. doi: 10.1016/s0140-6736(67)90494-1. [DOI] [PubMed] [Google Scholar]
  37. Perlman M., Aker M., Slonim A. E. Successful treatment of severe type I glycogen storage disease with neonatal presentation by nocturnal intragastric feeding. J Pediatr. 1979 May;94(5):772–774. doi: 10.1016/s0022-3476(79)80153-5. [DOI] [PubMed] [Google Scholar]
  38. Raivio K. O., Becker 7. A., Meyer L. J., Greene M. L., Nuki G., Seegmiller J. E. Stimulation of human purine synthesis de novo by fructose infusion. Metabolism. 1975 Jul;24(7):861–869. doi: 10.1016/0026-0495(75)90133-x. [DOI] [PubMed] [Google Scholar]
  39. Rizza R. A., Cryer P. E., Gerich J. E. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia. J Clin Invest. 1979 Jul;64(1):62–71. doi: 10.1172/JCI109464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Roe T. F., Kogut M. D. The pathogenesis of hyperuricemia in glycogen storage disease, type I. Pediatr Res. 1977 May;11(5):664–669. doi: 10.1203/00006450-197705000-00008. [DOI] [PubMed] [Google Scholar]
  41. SEEGMILLER J. E., GRAYZEL A. I., LASTER L., LIDDLE L. Uric acid production in gout. J Clin Invest. 1961 Jul;40:1304–1314. doi: 10.1172/JCI104360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Slonim A. E., Lacy W. W., Terry A., Greene H. L., Burr I. M. Nocturnal intragastric therapy in type I glycogen storage disease: effect on hormonal and amino acid metabolism. Metabolism. 1979 Jul;28(7):707–715. doi: 10.1016/0026-0495(79)90175-6. [DOI] [PubMed] [Google Scholar]
  43. Sutton J. R., Toews C. J., Ward G. R., Fox I. H. Purine metabolism during strenuous muscular exercise in man. Metabolism. 1980 Mar;29(3):254–260. doi: 10.1016/0026-0495(80)90067-0. [DOI] [PubMed] [Google Scholar]
  44. Woods H. F., Eggleston L. V., Krebs H. A. The cause of hepatic accumulation of fructose 1-phosphate on fructose loading. Biochem J. 1970 Sep;119(3):501–510. doi: 10.1042/bj1190501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Woolliscroft J. O., Colfer H., Fox I. H. Hyperuricemia in acute illness: a poor prognostic sign. Am J Med. 1982 Jan;72(1):58–62. doi: 10.1016/0002-9343(82)90578-2. [DOI] [PubMed] [Google Scholar]
  46. Young J. B., Landsberg L. Catecholamines and intermediary metabolism. Clin Endocrinol Metab. 1977 Nov;6(3):599–631. doi: 10.1016/s0300-595x(77)80073-x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES