Summary
Insulin, biosynthetic human proinsulin and 2 human proinsulin conversion intermediates, des (64, 65) human proinsulin and des (31, 32) human proinsulin, were labelled with 123 I and the derivatives monosubstituted on Tyr A14 were purified by reverse phase high performance liquid chromatography. The four tracers were injected into anaesthetized rats via a jugular or a portal vein and time activity curves were generated for the liver and kidneys using a gamma camera and an online computer. Liver extraction coefficients varied in the order insulin (38%), des (64, 65) human proinsulin (11.7%), des (31, 32) human proinsulin (3.2%), human proinsulin (1.6%); whereas half-life of hepatic activity varied in the reverse order, from 6 min for insulin, to 45 min for human proinsulin. As expected for a non-receptor mediated process, kidney extraction varied conversely to liver extraction, being highest for human proinsulin and lowest for insulin. It is concluded that the kinetics of human proinsulin conversion intermediates depends upon the site of cleavage and deletion and is intermediate between those of insulin and intact human proinsulin.
Article PDF
Similar content being viewed by others
References
Kemmler W, Steiner DF, Borg J (1973) Studies on the conversion of proinsulin to insulin. III. Studies in vitro with a crude secretion granule fraction isolated from rat islets of Langerhans. J Biol Chem 248: 4544–4551
Fletcher DJ, Quigley JP, Bauer GE, Noe BD (1981) Characterization of proinsulin- and proglucagon-converting activities in isolated islet secretory granules. J Cell Biol 90: 312–322
Docherty K, Carroll RJ, Steiner DF (1982) Conversion of proinsulin to insulin: involvement of a 31,500 molecular weight thiol protease. Proc Natl Acad Sci USA 79: 4613–4617
Rhodes CJ, Davidson HW, Zumbrunn A, Shaw E, Hutton JC (1988) Proinsulin to insulin conversion is mediated by two distinct site specific endopeptidases that are regulated by Ca+ + and pH. Diabetologia 31: 535 A
de Haën C, Little SA, May JM, Williams RH (1978) Characterization of proinsulin-insulin intermediates in human plasma. J Clin Invest 62: 727–737
Creutzfeldt C, Track NS, Creuzfeldt W (1973) In vitro studies of the rate of proinsulin and insulin turnover in seven human insulinomas. Eur J Clin Invest 3: 371–384
Gutman RA, Lazarus NR, Penhos JC, Fajans S, Recant L (1971) Circulating proinsulin-like material in patients with functioning insulinomas. N Engl J Med 284: 1003–1008
Sherman BM, Pek S, Fajans SS, Floyd JC Jr, Conn JW (1972) Plasma proinsulin in patients with functioning pancreatic islet cell tumors. J Clin Endocrinol Metab 3: 271–280
Gabbay KH, Bergenstal RM, Wolff J, Mako ME, Rubenstein AH (1979) Familial hyperproinsulinemia: partial characterization of circulating proinsulin-like material. Proc Natl Acad Sci USA 76: 2881–2885
Robbins DC, Blix PM, Rubenstein AH, Kanazawa Y, Kosaka K, Tager HS (1981) A human proinsulin variant at arginine 65. Nature 291: 679–681
Robbins DC, Shoelson SE, Rubenstein AH, Tager HS (1984) Familial hyperproinsulinemia: two families secreting indistinguishable type II intermediates of proinsulin conversion. J Clin Invest 73: 714–719
Given BD, Cohen RM, Shoelson SE, Frank BH, Rubenstein AH, Tager HS (1985) Biochemical and clinical implications of proinsulin conversion intermediates. J Clin Invest 76: 1398–1405
Freychet P (1974) The interactions of proinsulin with insulin receptors on the plasma membrane of the liver. J Clin Invest 54: 1020–1031
Revers RR, Henry R, Schmeiser L, Kolterman O, Cohen R, Bergenstahl R, Polonsky K, Jaspan J, Rubenstein AH, Frank B, Galloway J, Olefsky JM (1984) The effects of biosynthetic human proinsulin on carbohydrate metabolism. Diabetes 33: 762–770
Henry R, Schmeiser L, Kolterman O, Cohen R, Rubenstein A, Frank B, Galloway J, Olefsky JM (1984) Biosynthetic human insulin and proinsulin have additive but not synergistic effects on total body glucose disposal. J Clin Endocrinol Metab 58: 1094–1098
Stoll RW, Touber JL, Winterscheid LC, Ensinck JW, Williams RH (1971) Hypoglycemic activity and immunological half-life of porcine insulin and proinsulin in baboons and swine. Endocrinology 88: 714–717
Starr JI, Rubenstein AH (1974) Metabolism of endogenous proinsulin and insulin in man. J Clin Endocrinol Metab 38: 305–308
Peavy DE, Brunner MR, Duckworth WC, Hooker CS, Frank BH (1985) Receptor binding and biological potency of several split forms (conversion intermediates) of human proinsulin. Studies in cultured IM9 lymphocytes and in vivo and in vitro in rats. J Biol Chem 260: 13989–13994
Sodoyez JC, Sodoyez-Goffaux F, Guillaume M, Merchie G (1983) 123-I-insulin metabolism in normal rats and humans: external detection by a scintillation camera. Science 219: 865–867
Verdin EM, Marathos-Flier E, Kahn CR, Sodoyez JC, Sodoyez-Goffaux F, De Vos CJ, Lynn SP, Fields BN (1987) Visualization of viral clearance in the living animal. Science 236: 439–442
Frank BH, Pettee JM, Zimmerman RE, Burck PJ (1981) Peptides, structure and function. Pierce Chemical Company, Illinois, pp 729–738
Sodoyez JC, Sodoyez-Goffaux F (1988) Studies of insulin receptors in vivo, using 123-I-insulin and scintillation scanning. In: Kahn CR, Harrison LC (eds.) Insulin receptors. Part B: Clinical assessment, biological responses and comparison to the IGF-1 Receptor. Alan R Liss, New York, pp 135–151
Dixon WJ, Brown MB (eds) (1981) BMDP Biomedical Computer Programs. University of California Press, Berkley Los Angeles London
Linde S, Hansen B, Sonne O, Holst JJ, Gliemann J (1981) Tyrosine A14 125 I monoiodoinsulin preparation, biologic properties and long term stability. Diabetes 30: 1–8
Frank BH, Peavy DE, Hooker CS, Duckworth W (1983) Receptor binding properties of monoiodotyrosyl insulin isomers purified by high performance liquid chromatography. Diabetes 32: 705–711
Jorgensen KH, Moody AJ, Christensen MC (1982) Evidence that monoiodo-(A14)-insulin is more potent than insulin in the rat free fat cell assay. Abstract 11th Congress IDF, Nairobi
Sherwin RS, Kramer KJ, Tobin JD, Insel PA, Liljenquist JE, Berman M, Andres R (1974) A model of the kinetics of insulin in man. J Clin Invest 53: 1481–1492
Terris S, Steiner DF (1976) Retention and degradation of 125-I-insulin by perfused livers from diabetic rats. J Clin Invest 57: 885–896
Ferrannini E, Pilo A (1979) Pattern of insulin delivery after intravenous glucose injection in man and its relation to plasma glucose disappearance. J Clin Invest 64: 243–254
Cockram CS, Jones RH, Boroujerdi MA, Sönksen PH (1984) Evidence for separate handling in vivo of different regions of the insulin molecule using A14- and B1-labeled insulin tracers. Diabetes 33: 721–727
Sodoyez JC, Sodoyez-Goffaux F, Von Frenckell R, De Vos CJ, Treves S, Kahn CR (1985) Differing effects of antiinsulin serum and antiinsulin receptor serum on 123-I-insulin metabolism in rats. J Clin Invest 75: 1455–1462
Sodoyez JC, Sodoyez-Goffaux FR, Moris YM (1980) 125 I-insulin. Kinetics of interaction with its receptors and rate of degradation in vivo. Am J Physiol 239: E3-E11
Katz AI, Rubenstein AH (1973) Metabolism of proinsulin, insulin, and C-peptide in the rat. J Clin Invest 52: 1113–1121
Rubenstein AH, Pottenger LA, Mako M, Getz GS, Steiner DF (1972) The metabolism of proinsulin and insulin by the liver. J Clin Invest 51: 912–921
Rabkin R, Ross BD, Mako ME, Rubenstein AH (1978) The handling of insulin, proinsulin, and C-peptide by the isolated rat kidney. Diabetes 27 [Suppl.1]: 192–196
Podlecki DA, Frank BH, Olefsky JM (1984) In vitro characterization of biosynthetic human proinsulin. Diabetes 33: 111–118
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sodoyez-Goffaux, F., Sodoyez, J.C., Koch, M. et al. Scintigraphic distribution of 123 I labelled proinsulin, split conversion intermediates and insulin in rats. Diabetologia 31, 848–854 (1988). https://doi.org/10.1007/BF00277489
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00277489