Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Mar 15;97(6):1497–1503. doi: 10.1172/JCI118572

Transendothelial insulin transport is not saturable in vivo. No evidence for a receptor-mediated process.

G M Steil 1, M Ader 1, D M Moore 1, K Rebrin 1, R N Bergman 1
PMCID: PMC507210  PMID: 8617883

Abstract

In vitro, insulin transport across endothelial cells has been reported to be saturable, suggesting that the transport process is receptor mediated. In the present study, the transport of insulin across capillary endothelial cells was investigated in vivo. Euglycemic glucose clamps were performed in anesthetized dogs (n = 16) in which insulin was infused to achieve concentrations in the physiological range (1.0 mU/kg per min + 5 mU/kg priming bolus; n = 8) or pharmacologic range (18 mU/kg per min + 325 mU/kg priming bolus; n = 8). Insulin concentrations were measured in plasma and hindlimb lymph derived from interstitial fluid (ISF) surrounding muscle. Basal plasma insulin concentrations were twice the basal ISF insulin concentrations and were not different between the physiologic and pharmacologic infusion groups (plasma/ISF ratio 2.05 +/- 0.22 vs 2.05 +/- 0.23; p = 0.0003). The plasma/ISF gradient was, however, significantly reduced at steady-state pharmacologic insulin concentrations (1.37 +/- 0.25 vs 1.98 +/- 0.21; P = 0.0003). The reduced gradient is opposite to that expected if transendothelial insulin transport were saturable. Insulin transport into muscle ISF tended to increase with pharmacologic compared with physiologic changes in insulin concentration (41% increase; 1.37 +/- 0.18 10(-2) to 1.93 +/- 0.24 10(-2) min-1; P = 0.088), while at the same time insulin clearance out of the muscle ISF compartment was unaltered (2.53 +/- 0.26 10(-2) vs 2.34 +/- 0.28 10(-2) min-1; P = 0.62). Thus, the reduced plasma/ISF gradient at pharmacologic insulin was due to enhanced transendothelial insulin transport rather than changes in ISF insulin clearance. We conclude that insulin transport is not saturable in vivo and thus not receptor mediated. The increase in transport efficiency with saturating insulin is likely due to an increase in diffusionary capacity resulting from capillary dilation or recruitment.

Full Text

The Full Text of this article is available as a PDF (231.5 KB).

Selected References

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

  1. Adair T. H., Moffatt D. S., Paulsen A. W., Guyton A. C. Quantitation of changes in lymph protein concentration during lymph node transit. Am J Physiol. 1982 Sep;243(3):H351–H359. doi: 10.1152/ajpheart.1982.243.3.H351. [DOI] [PubMed] [Google Scholar]
  2. Andersen L., Dinesen B., Jørgensen P. N., Poulsen F., Røder M. E. Enzyme immunoassay for intact human insulin in serum or plasma. Clin Chem. 1993 Apr;39(4):578–582. [PubMed] [Google Scholar]
  3. Bar R. S., Boes M., Sandra A. Vascular transport of insulin to rat cardiac muscle. Central role of the capillary endothelium. J Clin Invest. 1988 Apr;81(4):1225–1233. doi: 10.1172/JCI113439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bar R. S., Hoak J. C., Peacock M. L. Insulin receptors in human endothelial cells: identification and characterization. J Clin Endocrinol Metab. 1978 Sep;47(3):699–702. doi: 10.1210/jcem-47-3-699. [DOI] [PubMed] [Google Scholar]
  5. Baron A. D. Hemodynamic actions of insulin. Am J Physiol. 1994 Aug;267(2 Pt 1):E187–E202. doi: 10.1152/ajpendo.1994.267.2.E187. [DOI] [PubMed] [Google Scholar]
  6. Baura G. D., Foster D. M., Porte D., Jr, Kahn S. E., Bergman R. N., Cobelli C., Schwartz M. W. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest. 1993 Oct;92(4):1824–1830. doi: 10.1172/JCI116773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bradley D. C., Poulin R. A., Bergman R. N. Dynamics of hepatic and peripheral insulin effects suggest common rate-limiting step in vivo. Diabetes. 1993 Feb;42(2):296–306. doi: 10.2337/diab.42.2.296. [DOI] [PubMed] [Google Scholar]
  8. Bundgaard M. Vesicular transport in capillary endothelium: does it occur? Fed Proc. 1983 May 15;42(8):2425–2430. [PubMed] [Google Scholar]
  9. Genuth S. M. Metabolic clearance of insulin in man. Diabetes. 1972 Oct;21(10):1003–1012. doi: 10.2337/diab.21.10.1003. [DOI] [PubMed] [Google Scholar]
  10. Ghitescu L., Fixman A., Simionescu M., Simionescu N. Specific binding sites for albumin restricted to plasmalemmal vesicles of continuous capillary endothelium: receptor-mediated transcytosis. J Cell Biol. 1986 Apr;102(4):1304–1311. doi: 10.1083/jcb.102.4.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. IZZO J. L., RONCONE A., IZZO M. J., BALE W. F. RELATIONSHIP BETWEEN DEGREE OF IODINATION OF INSULIN AND ITS BIOLOGICAL, ELECTROPHORETIC, AND IMMUNOCHEMICAL PROPERTIES. J Biol Chem. 1964 Nov;239:3749–3754. [PubMed] [Google Scholar]
  12. Jansson P. A., Fowelin J. P., von Schenck H. P., Smith U. P., Lönnroth P. N. Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid. Importance of the endothelial barrier for insulin. Diabetes. 1993 Oct;42(10):1469–1473. doi: 10.2337/diab.42.10.1469. [DOI] [PubMed] [Google Scholar]
  13. King G. L., Johnson S. M. Receptor-mediated transport of insulin across endothelial cells. Science. 1985 Mar 29;227(4694):1583–1586. doi: 10.1126/science.3883490. [DOI] [PubMed] [Google Scholar]
  14. Laakso M., Edelman S. V., Brechtel G., Baron A. D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844–1852. doi: 10.1172/JCI114644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Poulin R. A., Steil G. M., Moore D. M., Ader M., Bergman R. N. Dynamics of glucose production and uptake are more closely related to insulin in hindlimb lymph than in thoracic duct lymph. Diabetes. 1994 Feb;43(2):180–190. doi: 10.2337/diab.43.2.180. [DOI] [PubMed] [Google Scholar]
  16. Rasio E. A., Hampers C. L., Soeldner J. S., Cahill G. F., Jr Diffusion of glucose, insulin, inulin, and Evans blue protein into thoracic duct lymph of man. J Clin Invest. 1967 Jun;46(6):903–910. doi: 10.1172/JCI105596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rasio E. A., Mack E., Egdahl R. H., Herrera M. G. Passage of insulin and inulin across vascular membranes in the dog. Diabetes. 1968 Nov;17(11):668–672. doi: 10.2337/diab.17.11.668. [DOI] [PubMed] [Google Scholar]
  18. Rasio E. The capillary barrier to circulating insulin. Diabetes Care. 1982 May-Jun;5(3):158–161. doi: 10.2337/diacare.5.3.158. [DOI] [PubMed] [Google Scholar]
  19. Schaeffer R. C., Jr, Gong F., Bitrick M. S., Jr Restricted diffusion of macromolecules by endothelial monolayers and small-pore filters. Am J Physiol. 1992 Jul;263(1 Pt 1):L27–L36. doi: 10.1152/ajplung.1992.263.1.L27. [DOI] [PubMed] [Google Scholar]
  20. Schwartz M. W., Bergman R. N., Kahn S. E., Taborsky G. J., Jr, Fisher L. D., Sipols A. J., Woods S. C., Steil G. M., Porte D., Jr Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport. J Clin Invest. 1991 Oct;88(4):1272–1281. doi: 10.1172/JCI115431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sonksen P. H., McCormick J. R., Egdahl R. H., Soeldner J. S. Distribution and binding of insulin in the dog hindlimb. Am J Physiol. 1971 Dec;221(6):1672–1680. doi: 10.1152/ajplegacy.1971.221.6.1672. [DOI] [PubMed] [Google Scholar]
  22. Steil G. M., Meador M. A., Bergman R. N. Thoracic duct lymph. Relative contribution from splanchnic and muscle tissue. Diabetes. 1993 May;42(5):720–731. doi: 10.2337/diab.42.5.720. [DOI] [PubMed] [Google Scholar]
  23. White M. F., Kahn C. R. The insulin signaling system. J Biol Chem. 1994 Jan 7;269(1):1–4. [PubMed] [Google Scholar]
  24. Yang Y. J., Hope I. D., Ader M., Bergman R. N. Insulin transport across capillaries is rate limiting for insulin action in dogs. J Clin Invest. 1989 Nov;84(5):1620–1628. doi: 10.1172/JCI114339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yang Y. J., Hope I., Ader M., Poulin R. A., Bergman R. N. Dose-response relationship between lymph insulin and glucose uptake reveals enhanced insulin sensitivity of peripheral tissues. Diabetes. 1992 Feb;41(2):241–253. doi: 10.2337/diabetes.41.2.241. [DOI] [PubMed] [Google Scholar]

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

RESOURCES