Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Mar 1;99(5):1044–1056. doi: 10.1172/JCI119232

Comparison of the direct and indirect effects of epinephrine on hepatic glucose production.

C A Chu 1, D K Sindelar 1, D W Neal 1, E J Allen 1, E P Donahue 1, A D Cherrington 1
PMCID: PMC507913  PMID: 9062363

Abstract

To determine the extent to which the effect of a physiologic increment in epinephrine (EPI) on glucose production (GP) arises indirectly from its action on peripheral tissues (muscle and adipose tissue), epinephrine was infused intraportally (EPI po) or peripherally (EPI pe) into 18-h-fasted conscious dogs maintained on a pancreatic clamp. Arterial EPI levels in EPI po and EPI pe groups rose from 97 +/- 29 to 107 +/- 37 and 42 +/- 12 to 1,064 +/- 144 pg/ml, respectively. Hepatic sinusoidal EPI levels in EPI po and EPI pe were indistinguishable (561 +/- 84 and 568 +/- 75 pg/ml, respectively). During peripheral epinephrine infusion, GP increased from 2.2 +/- 0.1 to 5.1 +/- 0.2 mg/kg x min (10 min). In the presence of the same rise in sinusoidal EPI, but with no rise in arterial EPI (during portal EPI infusion), GP increased from 2.1 +/- 0.1 to 3.8 +/- 0.6 mg/kg x min. Peripheral EPI infusion increased the maximal gluconeogenic rate from 0.7 +/- 0.4 to 1.8 +/- 0.5 mg/ kg x min. Portal EPI infusion did not change the maximal gluconeogenic rate. The estimated initial increase in glycogenolysis was approximately 1.7 and 2.3 mg/kg x min in the EPI pe and EPI po groups, respectively. Gluconeogenesis was responsible for 60% of the overall increase in glucose production stimulated by the increase in plasma epinephrine (EPI pe). Elevation of sinusoidal EPI per se had no direct gluconeogenic effect on the liver, thus its effect on glucose production was solely attributable to an increase in glycogenolysis. Lastly, the gluconeogenic effects of EPI markedly decreased (60-80%) its overall glycogenolytic action on the liver.

Full Text

The Full Text of this article is available as a PDF (302.8 KB).

Selected References

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

  1. Cherrington A. D., Lacy W. W., Chiasson J. L. Effect of glucagon on glucose production during insulin deficiency in the dog. J Clin Invest. 1978 Sep;62(3):664–677. doi: 10.1172/JCI109174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chiasson J. L., Liljenquist J. E., Lacy W. W., Jennings A. S., Cherrington A. D. Gluconeogenesis: methodological approaches in vivo. Fed Proc. 1977 Feb;36(2):229–235. [PubMed] [Google Scholar]
  3. Chu C. A., Sindelar D. K., Neal D. W., Cherrington A. D. Direct effects of catecholamines on hepatic glucose production in conscious dog are due to glycogenolysis. Am J Physiol. 1996 Jul;271(1 Pt 1):E127–E137. doi: 10.1152/ajpendo.1996.271.1.E127. [DOI] [PubMed] [Google Scholar]
  4. Clore J. N., Glickman P. S., Nestler J. E., Blackard W. G. In vivo evidence for hepatic autoregulation during FFA-stimulated gluconeogenesis in normal humans. Am J Physiol. 1991 Oct;261(4 Pt 1):E425–E429. doi: 10.1152/ajpendo.1991.261.4.E425. [DOI] [PubMed] [Google Scholar]
  5. Clutter W. E., Bier D. M., Shah S. D., Cryer P. E. Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest. 1980 Jul;66(1):94–101. doi: 10.1172/JCI109840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Connolly C. C., Steiner K. E., Stevenson R. W., Neal D. W., Williams P. E., Alberti K. G., Cherrington A. D. Regulation of glucose metabolism by norepinephrine in conscious dogs. Am J Physiol. 1991 Dec;261(6 Pt 1):E764–E772. doi: 10.1152/ajpendo.1991.261.6.E764. [DOI] [PubMed] [Google Scholar]
  7. Connolly C. C., Stevenson R. W., Neal D. W., Wasserman D. H., Cherrington A. D. The effects of lactate loading on alanine and glucose metabolism in the conscious dog. Metabolism. 1993 Feb;42(2):154–161. doi: 10.1016/0026-0495(93)90029-n. [DOI] [PubMed] [Google Scholar]
  8. Corbin J. D., Beebe S. J., Blackmore P. F. cAMP-dependent protein kinase activation lowers hepatocyte cAMP. J Biol Chem. 1985 Jul 25;260(15):8731–8735. [PubMed] [Google Scholar]
  9. DEBODO R. C., STEELE R., ALTSZULER N., DUNN A., BISHOP J. S. ON THE HORMONAL REGULATION OF CARBOHYDRATE METABOLISM; STUDIES WITH C14 GLUCOSE. Recent Prog Horm Res. 1963;19:445–488. [PubMed] [Google Scholar]
  10. Diamond M. P., Rollings R. C., Steiner K. E., Williams P. E., Lacy W. W., Cherrington A. D. Effect of alanine concentration independent of changes in insulin and glucagon on alanine and glucose homeostasis in the conscious dog. Metabolism. 1988 Jan;37(1):28–33. doi: 10.1016/0026-0495(88)90025-x. [DOI] [PubMed] [Google Scholar]
  11. Dobbins R. L., Davis S. N., Neal D. W., Cobelli C., Cherrington A. D. Pulsatility does not alter the response to a physiological increment in glucagon in the conscious dog. Am J Physiol. 1994 Mar;266(3 Pt 1):E467–E478. doi: 10.1152/ajpendo.1994.266.3.E467. [DOI] [PubMed] [Google Scholar]
  12. Exton J. H. Mechanisms of hormonal regulation of hepatic glucose metabolism. Diabetes Metab Rev. 1987 Jan;3(1):163–183. doi: 10.1002/dmr.5610030108. [DOI] [PubMed] [Google Scholar]
  13. Giaccari A., Rossetti L. Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats. J Clin Invest. 1992 Jan;89(1):36–45. doi: 10.1172/JCI115583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Goresky C. A., Bach G. G., Nadeau B. E. Red cell carriage of label: its limiting effect on the exchange of materials in the liver. Circ Res. 1975 Feb;36(2):328–351. doi: 10.1161/01.res.36.2.328. [DOI] [PubMed] [Google Scholar]
  15. Hamilton K. S., Gibbons F. K., Bracy D. P., Lacy D. B., Cherrington A. D., Wasserman D. H. Effect of prior exercise on the partitioning of an intestinal glucose load between splanchnic bed and skeletal muscle. J Clin Invest. 1996 Jul 1;98(1):125–135. doi: 10.1172/JCI118756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ishida T., Lewis R. M., Hartley C. J., Entman M. L., Field J. B. Comparison of hepatic extraction of insulin and glucagon in conscious and anesthetized dogs. Endocrinology. 1983 Mar;112(3):1098–1109. doi: 10.1210/endo-112-3-1098. [DOI] [PubMed] [Google Scholar]
  17. Jahoor F., Peters E. J., Wolfe R. R. The relationship between gluconeogenic substrate supply and glucose production in humans. Am J Physiol. 1990 Feb;258(2 Pt 1):E288–E296. doi: 10.1152/ajpendo.1990.258.2.E288. [DOI] [PubMed] [Google Scholar]
  18. LEEVY C. M., MENDENHALL C. L., LESKO W., HOWARD M. M. Estimation of hepatic blood flow with indocyanine green. J Clin Invest. 1962 May;41:1169–1179. doi: 10.1172/JCI104570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lloyd B., Burrin J., Smythe P., Alberti K. G. Enzymic fluorometric continuous-flow assays for blood glucose, lactate, pyruvate, alanine, glycerol, and 3-hydroxybutyrate. Clin Chem. 1978 Oct;24(10):1724–1729. [PubMed] [Google Scholar]
  20. Mari A. Estimation of the rate of appearance in the non-steady state with a two-compartment model. Am J Physiol. 1992 Aug;263(2 Pt 1):E400–E415. doi: 10.1152/ajpendo.1992.263.2.E400. [DOI] [PubMed] [Google Scholar]
  21. McGuinness O. P., Fugiwara T., Murrell S., Bracy D., Neal D., O'Connor D., Cherrington A. D. Impact of chronic stress hormone infusion on hepatic carbohydrate metabolism in the conscious dog. Am J Physiol. 1993 Aug;265(2 Pt 1):E314–E322. doi: 10.1152/ajpendo.1993.265.2.E314. [DOI] [PubMed] [Google Scholar]
  22. Miles J. M., Nissen S. L., Gerich J. E., Haymond M. W. Effects of epinephrine infusion on leucine and alanine kinetics in humans. Am J Physiol. 1984 Aug;247(2 Pt 1):E166–E172. doi: 10.1152/ajpendo.1984.247.2.E166. [DOI] [PubMed] [Google Scholar]
  23. Moghimzadeh E., Nobin A., Rosengren E. Fluorescence microscopical and chemical characterization of the adrenergic innervation in mammalian liver tissue. Cell Tissue Res. 1983;230(3):605–613. doi: 10.1007/BF00216204. [DOI] [PubMed] [Google Scholar]
  24. Myers S. R., McGuinness O. P., Neal D. W., Cherrington A. D. Intraportal glucose delivery alters the relationship between net hepatic glucose uptake and the insulin concentration. J Clin Invest. 1991 Mar;87(3):930–939. doi: 10.1172/JCI115100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pagliassotti M. J., Holste L. C., Moore M. C., Neal D. W., Cherrington A. D. Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog. J Clin Invest. 1996 Jan 1;97(1):81–91. doi: 10.1172/JCI118410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Puhakainen I., Yki-Järvinen H. Inhibition of lipolysis decreases lipid oxidation and gluconeogenesis from lactate but not fasting hyperglycemia or total hepatic glucose production in NIDDM. Diabetes. 1993 Dec;42(12):1694–1699. doi: 10.2337/diab.42.12.1694. [DOI] [PubMed] [Google Scholar]
  27. Saccà L., Vigorito C., Cicala M., Corso G., Sherwin R. S. Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans. Am J Physiol. 1983 Sep;245(3):E294–E302. doi: 10.1152/ajpendo.1983.245.3.E294. [DOI] [PubMed] [Google Scholar]
  28. Steiner K. E., Stevenson R. W., Adkins-Marshall B. A., Cherrington A. D. The effects of epinephrine on ketogenesis in the dog after a prolonged fast. Metabolism. 1991 Oct;40(10):1057–1062. doi: 10.1016/0026-0495(91)90130-o. [DOI] [PubMed] [Google Scholar]
  29. Stevenson R. W., Steiner K. E., Connolly C. C., Fuchs H., Alberti K. G., Williams P. E., Cherrington A. D. Dose-related effects of epinephrine on glucose production in conscious dogs. Am J Physiol. 1991 Mar;260(3 Pt 1):E363–E370. doi: 10.1152/ajpendo.1991.260.3.E363. [DOI] [PubMed] [Google Scholar]
  30. Stevenson R. W., Steiner K. E., Davis M. A., Hendrick G. K., Williams P. E., Lacy W. W., Brown L., Donahue P., Lacy D. B., Cherrington A. D. Similar dose responsiveness of hepatic glycogenolysis and gluconeogenesis to glucagon in vivo. Diabetes. 1987 Mar;36(3):382–389. doi: 10.2337/diab.36.3.382. [DOI] [PubMed] [Google Scholar]
  31. Stumvoll M., Chintalapudi U., Perriello G., Welle S., Gutierrez O., Gerich J. Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. J Clin Invest. 1995 Nov;96(5):2528–2533. doi: 10.1172/JCI118314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Venkatakrishnan A., Abel M. J., Campbell R. A., Donahue E. P., Uselton T. C., Flakoll P. J. Whole blood analysis of gluconeogenic amino acids for estimation of de novo gluconeogenesis using pre-column o-phthalaldehyde derivatization and high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1996 Feb 9;676(1):1–6. doi: 10.1016/0378-4347(95)00403-3. [DOI] [PubMed] [Google Scholar]
  33. WALL J. S., STEELE R., DE BODO R. C., ALTSZULER N. Effect of insulin on utilization and production of circulating glucose. Am J Physiol. 1957 Apr;189(1):43–50. doi: 10.1152/ajplegacy.1957.189.1.43. [DOI] [PubMed] [Google Scholar]
  34. Wahren J., Felig P., Ahlborg G., Jorfeldt L. Glucose metabolism during leg exercise in man. J Clin Invest. 1971 Dec;50(12):2715–2725. doi: 10.1172/JCI106772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wasserman D. H., Geer R. J., Williams P. E., Becker T., Lacy D. B., Abumrad N. N. Interaction of gut and liver in nitrogen metabolism during exercise. Metabolism. 1991 Mar;40(3):307–314. doi: 10.1016/0026-0495(91)90115-d. [DOI] [PubMed] [Google Scholar]
  36. Watanabe Y., Püschel G. P., Gardemann A., Jungermann K. Presinusoidal and proximal intrasinusoidal confluence of hepatic artery and portal vein in rat liver: functional evidence by orthograde and retrograde bivascular perfusion. Hepatology. 1994 May;19(5):1198–1207. [PubMed] [Google Scholar]
  37. Williamson J. R., Kreisberg R. A., Felts P. W. Mechanism for the stimulation of gluconeogenesis by fatty acids in perfused rat liver. Proc Natl Acad Sci U S A. 1966 Jul;56(1):247–254. doi: 10.1073/pnas.56.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wolfe R. R., Jahoor F., Shaw J. H. Effect of alanine infusion on glucose and urea production in man. JPEN J Parenter Enteral Nutr. 1987 Mar-Apr;11(2):109–111. doi: 10.1177/0148607187011002109. [DOI] [PubMed] [Google Scholar]

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

RESOURCES