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. 1991 Aug;88(2):578–587. doi: 10.1172/JCI115342

Sources of carbon for hepatic glycogen synthesis in the conscious dog.

M C Moore 1, A D Cherrington 1, G Cline 1, M J Pagliassotti 1, E M Jones 1, D W Neal 1, C Badet 1, G I Shulman 1
PMCID: PMC295390  PMID: 1864968

Abstract

To identify the source(s) of carbon for the indirect pathway of hepatic glycogen synthesis, we studied nine 42-h fasted conscious dogs given a continuous intraduodenal infusion of glucose, labeled with [1-13C]glucose and [3-3H]glucose, at 8 mg.kg-1.min-1 for 240 min. Glycogen formation by the direct pathway was measured by 13C-NMR. Net hepatic balances of glucose, gluconeogenic amino acids, lactate, and glycerol were determined using the arteriovenous difference technique. During the steady-state period (the final hour of the infusion), 81% of the glucose infused was absorbed as glucose. Net gut output of lactate and alanine accounted for 5% and 3% of the glucose infused, respectively. The cumulative net hepatic uptakes were: glucose, 15.5 +/- 3.8 g; gluconeogenic amino acids, 32.2 +/- 2.2 mmol (2.9 +/- 0.2 g of glucose equivalents); and glycerol, 6.1 +/- 0.9 mmol (0.6 +/- 0.1 g of glucose equivalents). The liver produced a net of 29.2 +/- 9.6 mmol of lactate (2.6 +/- 0.8 g of glucose equivalents). Net hepatic glycogen synthesis totaled 9.3 +/- 2.5 g (1.8 +/- 0.4 g/100 g liver), with the direct pathway being responsible for 57 +/- 10%. Thus, net hepatic glucose uptake was sufficient to account for all glycogen formed by both the direct and indirect pathways. Total net hepatic uptake of gluconeogenic precursors (gluconeogenic amino acids, glycerol, and lactate) was able to account for only 20% of net glycogen synthesis by the indirect pathway. In a net sense, our data are consistent with an intrahepatic origin for most of the three-carbon precursors used for indirect glycogen synthesis.

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Selected References

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  1. Abumrad N. N., Cherrington A. D., Williams P. E., Lacy W. W., Rabin D. Absorption and disposition of a glucose load in the conscious dog. Am J Physiol. 1982 Jun;242(6):E398–E406. doi: 10.1152/ajpendo.1982.242.6.E398. [DOI] [PubMed] [Google Scholar]
  2. Adkins-Marshall B. A., Myers S. R., Hendrick G. K., Williams P. E., Triebwasser K., Floyd B., Cherrington A. D. Interaction between insulin and glucose-delivery route in regulation of net hepatic glucose uptake in conscious dogs. Diabetes. 1990 Jan;39(1):87–95. doi: 10.2337/diacare.39.1.87. [DOI] [PubMed] [Google Scholar]
  3. Aguilar-Parada E., Eisentraut A. M., Unger R. H. Pancreatic glucagon secretion in normal and diabetic subjects. Am J Med Sci. 1969 Jun;257(6):415–419. doi: 10.1097/00000441-196906000-00008. [DOI] [PubMed] [Google Scholar]
  4. BISHOP J. S., STEELE R., ALTSZULER N., DUNN A., BJERKNES C., DEBODO R. C. EFFECTS OF INSULIN ON LIVER GLYCOGEN SYNTHESIS AND BREAKDOWN IN THE DOG. Am J Physiol. 1965 Feb;208:307–316. doi: 10.1152/ajplegacy.1965.208.2.307. [DOI] [PubMed] [Google Scholar]
  5. Barrett E. J., Ferrannini E., Gusberg R., Bevilacqua S., DeFronzo R. A. Hepatic and extrahepatic splanchnic glucose metabolism in the postabsorptive and glucose fed dog. Metabolism. 1985 May;34(5):410–420. doi: 10.1016/0026-0495(85)90205-7. [DOI] [PubMed] [Google Scholar]
  6. Bergman R. N., Beir J. R., Hourigan P. M. Intraportal glucose infusion matched to oral glucose absorption. Lack of evidence for "gut factor" involvement in hepatic glucose storage. Diabetes. 1982 Jan;31(1):27–35. doi: 10.2337/diab.31.1.27. [DOI] [PubMed] [Google Scholar]
  7. Bidlingmeyer B. A., Cohen S. A., Tarvin T. L. Rapid analysis of amino acids using pre-column derivatization. J Chromatogr. 1984 Dec 7;336(1):93–104. doi: 10.1016/s0378-4347(00)85133-6. [DOI] [PubMed] [Google Scholar]
  8. Bratusch-Marrain P. R., Waldhäusl W. K., Gasić S., Korn A., Nowotny P. Oral glucose tolerance test: effect of different glucose loads on splanchnic carbohydrate and substrate metabolism in healthy man. Metabolism. 1980 Mar;29(3):289–295. doi: 10.1016/0026-0495(80)90071-2. [DOI] [PubMed] [Google Scholar]
  9. CAHILL G. F., Jr, HASTINGS A. B., ASHMORE J., ZOTTU S. Studies on carbohydrate metabolism in rat liver slices. X. Factors in the regulation of pathways of glucose metabolism. J Biol Chem. 1958 Jan;230(1):125–135. [PubMed] [Google Scholar]
  10. Cherrington A. D., Chiasson J. L., Liljenquist J. E., Jennings A. S., Keller U., Lacy W. W. The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog. J Clin Invest. 1976 Dec;58(6):1407–1418. doi: 10.1172/JCI108596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Elwyn D. H., Launder W. J., Parikh H. C., Wise E. M., Jr Roles of plasma and erythrocytes in interorgan transport of amino acids in dogs. Am J Physiol. 1972 May;222(5):1333–1342. doi: 10.1152/ajplegacy.1972.222.5.1333. [DOI] [PubMed] [Google Scholar]
  12. Elwyn D. H., Parikh H. C., Shoemaker W. C. Amino acid movements between gut, liver, and periphery in unanesthetized dogs. Am J Physiol. 1968 Nov;215(5):1260–1275. doi: 10.1152/ajplegacy.1968.215.5.1260. [DOI] [PubMed] [Google Scholar]
  13. Ferrannini E., Bjorkman O., Reichard G. A., Jr, Pilo A., Olsson M., Wahren J., DeFronzo R. A. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes. 1985 Jun;34(6):580–588. doi: 10.2337/diab.34.6.580. [DOI] [PubMed] [Google Scholar]
  14. Frayn K. N., Coppack S. W., Humphreys S. M., Whyte P. L. Metabolic characteristics of human adipose tissue in vivo. Clin Sci (Lond) 1989 May;76(5):509–516. doi: 10.1042/cs0760509. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Gottesman I., Mandarino L., Gerich J. Use of glucose uptake and glucose clearance for the evaluation of insulin action in vivo. Diabetes. 1984 Feb;33(2):184–191. doi: 10.2337/diab.33.2.184. [DOI] [PubMed] [Google Scholar]
  17. Hartley C. J., Cole J. S. An ultrasonic pulsed Doppler system for measuring blood flow in small vessels. J Appl Physiol. 1974 Oct;37(4):626–629. doi: 10.1152/jappl.1974.37.4.626. [DOI] [PubMed] [Google Scholar]
  18. Heinrikson R. L., Meredith S. C. Amino acid analysis by reverse-phase high-performance liquid chromatography: precolumn derivatization with phenylisothiocyanate. Anal Biochem. 1984 Jan;136(1):65–74. doi: 10.1016/0003-2697(84)90307-5. [DOI] [PubMed] [Google Scholar]
  19. Hendrick G. K., Frizzell R. T., Williams P. E., Cherrington A. D. Effect of hyperglucagonemia on hepatic glycogenolysis and gluconeogenesis after a prolonged fast. Am J Physiol. 1990 May;258(5 Pt 1):E841–E849. doi: 10.1152/ajpendo.1990.258.5.E841. [DOI] [PubMed] [Google Scholar]
  20. Jackson R. A., Hamling J. B., Sim B. M., Hawa M. I., Blix P. M., Nabarro J. D. Peripheral lactate and oxygen metabolism in man: the influence of oral glucose loading. Metabolism. 1987 Feb;36(2):144–150. doi: 10.1016/0026-0495(87)90008-4. [DOI] [PubMed] [Google Scholar]
  21. Jacot E., Defronzo R. A., Jéquier E., Maeder E., Felber J. P. The effect of hyperglycemia, hyperinsulinemia, and route of glucose administration on glucose oxidation and glucose storage. Metabolism. 1982 Sep;31(9):922–930. doi: 10.1016/0026-0495(82)90183-4. [DOI] [PubMed] [Google Scholar]
  22. Johnson J. L., Bagby G. J. Gluconeogenic pathway in liver and muscle glycogen synthesis after exercise. J Appl Physiol (1985) 1988 Apr;64(4):1591–1599. doi: 10.1152/jappl.1988.64.4.1591. [DOI] [PubMed] [Google Scholar]
  23. Jungermann K. Metabolic zonation of liver parenchyma. Semin Liver Dis. 1988 Nov;8(4):329–341. doi: 10.1055/s-2008-1040554. [DOI] [PubMed] [Google Scholar]
  24. Kalderon B., Gopher A., Lapidot A. Metabolic pathways leading to liver glycogen repletion in vivo, studied by GC-MS and NMR. FEBS Lett. 1986 Aug 11;204(1):29–32. doi: 10.1016/0014-5793(86)81381-3. [DOI] [PubMed] [Google Scholar]
  25. Kurland I. J., Pilkis S. J. Indirect versus direct routes of hepatic glycogen synthesis. FASEB J. 1989 Sep;3(11):2277–2281. doi: 10.1096/fasebj.3.11.2673899. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. Mitrakou A., Jones R., Okuda Y., Pena J., Nurjhan N., Field J. B., Gerich J. E. Pathway and carbon sources for hepatic glycogen repletion in dogs. Am J Physiol. 1991 Feb;260(2 Pt 1):E194–E202. doi: 10.1152/ajpendo.1991.260.2.E194. [DOI] [PubMed] [Google Scholar]
  29. Mitrakou A., Milde J., Michenfelder J., Gerich J. Rates of lactate appearance and disappearance and brain lactate balance after oral glucose in the dog. Horm Metab Res. 1989 May;21(5):236–239. doi: 10.1055/s-2007-1009202. [DOI] [PubMed] [Google Scholar]
  30. Mårin P., Rebuffé-Scrive M., Smith U., Björntorp P. Glucose uptake in human adipose tissue. Metabolism. 1987 Dec;36(12):1154–1160. doi: 10.1016/0026-0495(87)90242-3. [DOI] [PubMed] [Google Scholar]
  31. Newgard C. B., Hirsch L. J., Foster D. W., McGarry J. D. Studies on the mechanism by which exogenous glucose is converted into liver glycogen in the rat. A direct or an indirect pathway? J Biol Chem. 1983 Jul 10;258(13):8046–8052. [PubMed] [Google Scholar]
  32. Nilsson L. H., Hultman E. Liver and muscle glycogen in man after glucose and fructose infusion. Scand J Clin Lab Invest. 1974 Feb;33(1):5–10. doi: 10.3109/00365517409114190. [DOI] [PubMed] [Google Scholar]
  33. Olefsky J. M., Reaven G. M. Insulin and glucose responses to identical oral glucose tolerance tests performed forty-eight hours apart. Diabetes. 1974 May;23(5):449–453. doi: 10.2337/diab.23.5.449. [DOI] [PubMed] [Google Scholar]
  34. Radziuk J., McDonald T. J., Rubenstein D., Dupre J. Initial splanchnic extraction of ingested glucose in normal man. Metabolism. 1978 Jun;27(6):657–669. doi: 10.1016/0026-0495(78)90003-3. [DOI] [PubMed] [Google Scholar]
  35. Reaven G. M., Olefsky J. M. Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes. Diabetologia. 1977 May;13(3):201–206. doi: 10.1007/BF01219700. [DOI] [PubMed] [Google Scholar]
  36. SHOEMAKER W. C., WALKER W. F., VAN ITALLIE T. B., MOORE F. D. A method for simultaneous catheterization of major hepatic vessels in a chronic canine preparation. Am J Physiol. 1959 Feb;196(2):311–314. doi: 10.1152/ajplegacy.1959.196.2.311. [DOI] [PubMed] [Google Scholar]
  37. Shulman G. I., Cline G., Schumann W. C., Chandramouli V., Kumaran K., Landau B. R. Quantitative comparison of pathways of hepatic glycogen repletion in fed and fasted humans. Am J Physiol. 1990 Sep;259(3 Pt 1):E335–E341. doi: 10.1152/ajpendo.1990.259.3.E335. [DOI] [PubMed] [Google Scholar]
  38. Shulman G. I., Rothman D. L., Jue T., Stein P., DeFronzo R. A., Shulman R. G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990 Jan 25;322(4):223–228. doi: 10.1056/NEJM199001253220403. [DOI] [PubMed] [Google Scholar]
  39. Shulman G. I., Rothman D. L., Smith D., Johnson C. M., Blair J. B., Shulman R. G., DeFronzo R. A. Mechanism of liver glycogen repletion in vivo by nuclear magnetic resonance spectroscopy. J Clin Invest. 1985 Sep;76(3):1229–1236. doi: 10.1172/JCI112078. [DOI] [PMC free article] [PubMed] [Google Scholar]

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