Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1981 Mar;67(3):673–680. doi: 10.1172/JCI110082

Increased Clearance and Degradation of [3H]Insulin in Streptozotocin Diabetic Rats

ROLE OF THE INSULIN-RECEPTOR COMPARTMENT

Jacques Philippe 1,2, Philippe A Halban 1,2, Asllan Gjinovci 1,2, William C Duckworth 1,2, Jurek Estreicher 1,2, Albert E Renold 1,2
PMCID: PMC370616  PMID: 6451633

Abstract

The role of the insulin-receptor compartment in the pharmacokinetics of intravenously injected insulin in rats was studied. Since streptozotocin-diabetes in rats results in increased insulin binding to tissues in vitro, insulin pharmacokinetics in streptozotocin-diabetic rats were compared to controls, using semisynthetic [3H]insulin as the tracer. The initial distribution volume for [3H]insulin was elevated by 60% in diabetic rats. By contrast, no difference in initial distribution volume for [14C]inulin was observed, and the absolute values were lower than those found for [3H]insulin. The metabolic clearance rate of [3H]insulin was elevated by 44% in diabetic rats. That these differences were the result of increased binding of insulin to a specific receptor compartment in diabetic rats was shown by three additional experiments. The first involved receptor saturation by injection of 10 U native insulin 2 min before the tracer injection, resulting in identical [3H]insulin disappearance rates in the two groups of rats. The second consisted of displacing [3H]insulin from receptors by injecting 10 U unlabeled insulin 6 min after the tracer injection. Displacement of intact [3H]insulin from receptors and subsequent reappearance in the circulation occurred in both control and diabetic animals; however, such displacement was 25% greater in the diabetic rats. Finally, treatment of diabetic rats with insulin for 8 d normalized [3H]insulin clearance even though the tracer was injected at a time when the animals were again hyperglycemic and hypoinsulinemic. This suggests that down-regulation of insulin receptors had occurred during insulin therapy. These results confirm that a specific compartment for insulin exists (the insulin-receptor compartment) and that this compartment plays an important role in insulin clearance.

Full text

PDF
673

Selected References

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

  1. Berger M., Halban P. A., Assal J. P., Offord R. E., Vranic M., Renold A. E. Pharmacokinetics of subcutaneously injected tritiated insulin: effects of exercise. Diabetes. 1979 Jan;28 (Suppl 1):53–57. doi: 10.2337/diab.28.1.s53. [DOI] [PubMed] [Google Scholar]
  2. Berger M., Halban P. A., Girardier L., Seydoux J., Offord R. E., Renold A. E. Absorption kinetics of subcutaneously injected insulin. Evidence for degradation at the injection site. Diabetologia. 1979 Aug;17(2):97–99. doi: 10.1007/BF01222209. [DOI] [PubMed] [Google Scholar]
  3. Berger M., Halban P. A., Muller W. A., Offord R. E., Renold A. E., Vranic M. Mobilization of subcutaneously injected tritiated insulin in rats: effects of muscular exercise. Diabetologia. 1978 Aug;15(2):133–140. doi: 10.1007/BF00422259. [DOI] [PubMed] [Google Scholar]
  4. CONSTABLE B. J. Changes in blood volume and blood picture during the life of the rat and guinea-pig from birth to maturity. J Physiol. 1963 Jul;167:229–238. doi: 10.1113/jphysiol.1963.sp007143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davidson M. B., Kaplan S. A. Increased insulin binding by hepatic plasma membranes from diabetic rats: normalization by insulin therapy. J Clin Invest. 1977 Jan;59(1):22–30. doi: 10.1172/JCI108618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Duckworth W. C., Gifford D., Kitabchi A. E., Runyan K., Solomon S. S. Insulin binding and degradation by muscles from streptozotocin-diabetic rats. Diabetes. 1979 Aug;28(8):746–748. doi: 10.2337/diab.28.8.746. [DOI] [PubMed] [Google Scholar]
  7. Estreicher J., Revillard C., Scherrer J. R. Compartmental analysis--I: LINDE, a program using an analytical method of integration with constituent matrices. Comput Biol Med. 1979;9(1):49–65. doi: 10.1016/0010-4825(79)90022-2. [DOI] [PubMed] [Google Scholar]
  8. Frayn K. N. Disappearance of 125I-labelled and unlabelled insulins from blood in normal and injured rats. Clin Sci Mol Med. 1976 May;50(5):385–392. doi: 10.1042/cs0500385. [DOI] [PubMed] [Google Scholar]
  9. Gavin J. R., 3rd, Roth J., Neville D. M., Jr, de Meyts P., Buell D. N. Insulin-dependent regulation of insulin receptor concentrations: a direct demonstration in cell culture. Proc Natl Acad Sci U S A. 1974 Jan;71(1):84–88. doi: 10.1073/pnas.71.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Gliemann J., Sonne O., Linde S., Hansen B. Biological potency and binding affinity of monoiodoinsulin with iodine in tyrosine A14 or tyrosine A19. Biochem Biophys Res Commun. 1979 Apr 27;87(4):1183–1190. doi: 10.1016/s0006-291x(79)80032-7. [DOI] [PubMed] [Google Scholar]
  12. Gorden P., Carpentier J. L., Freychet P., LeCam A., Orci L. Intracellular translocation of iodine-125-labeled insulin: direct demonstration in isolated hepatocytes. Science. 1978 May 19;200(4343):782–785. doi: 10.1126/science.644321. [DOI] [PubMed] [Google Scholar]
  13. Halban P. A., Berger M., Offord R. E. Distribution and metabolism of intravenously injected tritiated insulin in rats. Metabolism. 1979 Nov;28(11):1097–1104. doi: 10.1016/0026-0495(79)90147-1. [DOI] [PubMed] [Google Scholar]
  14. Halban P. A., Karakash C., Davies J. G., Offord R. E. The degradation of semisynthetic tritiated insulin by perfused mouse livers. Biochem J. 1976 Nov 15;160(2):409–412. doi: 10.1042/bj1600409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Halban P. A., Offord R. E. The preparation of a semisynthetic tritiated insulin with a specific radioactivity of up to 20 Curies per millimole. Biochem J. 1975 Nov;151(2):219–225. doi: 10.1042/bj1510219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Herbert V., Lau K. S., Gottlieb C. W., Bleicher S. J. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965 Oct;25(10):1375–1384. doi: 10.1210/jcem-25-10-1375. [DOI] [PubMed] [Google Scholar]
  17. Insel J. R., Kolterman O. G., Saekow M., Olefsky J. M. Short-term regulation of insulin receptor affinity in man. Diabetes. 1980 Feb;29(2):132–139. doi: 10.2337/diab.29.2.132. [DOI] [PubMed] [Google Scholar]
  18. Izzo J. L., Bartlett J. W., Roncone A., Izzo M. J., Bale W. F. Physiological processes and dynamics in the disposition of small and large doses of biologically active and inactive 131-I-insulins in the rat. J Biol Chem. 1967 May 25;242(10):2343–2355. [PubMed] [Google Scholar]
  19. Izzo J. L., Roncone A. M., Helton D. L., Izzo M. J. Disposition of 131I proinsulin in the rat. Comparisons with 131 I insulin. Diabetes. 1978 Apr;27(4):400–410. doi: 10.2337/diab.27.4.400. [DOI] [PubMed] [Google Scholar]
  20. Karakash C., Assimacopoulos-Jeannet F., Jeanrenaud B. An anomaly of insulin removal in perfused livers of obese-hyperglycemic (ob/ob) mice. J Clin Invest. 1976 May;57(5):1117–1124. doi: 10.1172/JCI108378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kobayashi M., Olefsky J. M. Effects of streptozotocin-induced diabetes on insulin binding, glucose transport, and intracellular glucose metabolism in isolated rat adipocytes. Diabetes. 1979 Feb;28(2):87–95. doi: 10.2337/diab.28.2.87. [DOI] [PubMed] [Google Scholar]
  22. Ladegaard-Pedersen H. J. Measurement of extracellular volume and renal clearance by a single injection of inulin. Scand J Clin Lab Invest. 1972 Apr;29(2):145–153. doi: 10.3109/00365517209081067. [DOI] [PubMed] [Google Scholar]
  23. Le Marchand-Brustel Y., Freychet P. Effect of fasting and streptozotocin diabetes on insulin binding and action in the isolated mouse soleus muscle. J Clin Invest. 1979 Nov;64(5):1505–1515. doi: 10.1172/JCI109609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nakagawa S., Nakayama H., Sasaki T., Yoshino K., Yu Y. Y. A simple method for the determination of serum free insulin levels in insulin-treated patients. Diabetes. 1973 Aug;22(8):590–600. doi: 10.2337/diab.22.8.590. [DOI] [PubMed] [Google Scholar]
  25. Navalesi R., Pilo A., Ferrannini E. Insulin kinetics after portal and peripheral injection of [125I] insulin: II. Experiments in the intact dog. Am J Physiol. 1976 Jun;230(6):1630–1636. doi: 10.1152/ajplegacy.1976.230.6.1630. [DOI] [PubMed] [Google Scholar]
  26. Navalesi R., Pilo A., Ferrannini E. Kinetic analysis of plasma insulin disappearance in nonketotic diabetic patients and in normal subjects. A tracer study with 125I-insulin. J Clin Invest. 1978 Jan;61(1):197–208. doi: 10.1172/JCI108918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Navalesi R., Pilo A., Lenzi S., Donato L. Insulin metabolism in chronic uremia and in the anephric state: effect of the dialytic treatment. J Clin Endocrinol Metab. 1975 Jan;40(1):70–85. doi: 10.1210/jcem-40-1-70. [DOI] [PubMed] [Google Scholar]
  28. Ooms H. A., Arnould Y., Rosa U., Pennisi G. F., Franckson J. R. Clearances métaboliques globales de l'insuline cristalline et d'insulines substituées au radioiode. Pathol Biol. 1968 Mar;16(5):241–245. [PubMed] [Google Scholar]
  29. Reaven G. M., Sageman W. S., Swenson R. S. Development of insulin resistance in normal dogs following alloxan-induced insulin deficiency. Diabetologia. 1977 Sep;13(5):459–462. doi: 10.1007/BF01234496. [DOI] [PubMed] [Google Scholar]
  30. Rudas B. Streptozotocin. Arzneimittelforschung. 1972 May;22(5):830–861. [PubMed] [Google Scholar]
  31. Sodoyez J. C., Sodoyez-Goffaux F. R., Moris Y. M. 125I-insulin: kinetics of interaction with its receptors and rate of degradation in vivo. Am J Physiol. 1980 Jul;239(1):E3–E8. doi: 10.1152/ajpendo.1980.239.1.E3. [DOI] [PubMed] [Google Scholar]
  32. Sodoyez J. C., Sodoyez-Goffaux F., Goff M. M., Zimmerman A. E., Arquilla E. R. [127-I]- or carrier-free [125-I]monoiodoinsulin. J Biol Chem. 1975 Jun 10;250(11):4268–4277. [PubMed] [Google Scholar]
  33. Soman V., Felig P. Glucagon binding and adenylate cyclase activity in liver membranes from untreated and insulin-treated diabetic rats. J Clin Invest. 1978 Mar;61(3):552–560. doi: 10.1172/JCI108966. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  34. Terris S., Steiner D. F. Binding and degradation of 125I-insulin by rat hepatocytes. J Biol Chem. 1975 Nov 10;250(21):8389–8398. [PubMed] [Google Scholar]
  35. Trimble E. R., Siegel E. G., Berthoud H. R., Renold A. E. Intraportal islet transplantation: functional assessment in conscious unrestrained rats. Endocrinology. 1980 Mar;106(3):791–797. doi: 10.1210/endo-106-3-791. [DOI] [PubMed] [Google Scholar]
  36. Zeleznik A. J., Roth J. Demonstration of the insulin receptor in vivo in rabbits and its possible role as a reservoir for the plasma hormone. J Clin Invest. 1978 May;61(5):1363–1374. doi: 10.1172/JCI109054. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES