Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Mar;73(3):714–719. doi: 10.1172/JCI111264

Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.

D C Robbins, S E Shoelson, A H Rubenstein, H S Tager
PMCID: PMC425073  PMID: 6368587

Abstract

Familial hyperproinsulinemia, a hereditary syndrome in which individuals secrete high amounts of 9,000-mol wt proinsulin-like material, has been identified in two unrelated cohorts. Separate analysis of the material from each of the two cohorts had suggested that the proinsulin-like peptide was a conversion intermediate in which the C-peptide remained attached to the insulin B-chain in one case, whereas it was a conversion intermediate in which the C-peptide remained attached to the insulin A-chain in the other. To reinvestigate this apparent discrepancy, we have now used chemical, biochemical, immunochemical, and physical techniques to compare in parallel the structures of the immunoaffinity chromatography-purified, proinsulin-like peptides isolated from the serum of members of both families. Our results show that affected individuals in both cohorts secrete two-chained intermediates of proinsulin conversion in which the COOH-terminus of the C-peptide is extended by the insulin A-chain and from which the insulin B-chain is released by oxidative sulfitolysis. Analysis of the conversion intermediates by reverse-phase high-performance liquid chromatography using two different buffer systems showed that the proinsulin-related peptides from both families elute at a single position very near that of the normal intermediate des-Arg31, Arg32-proinsulin. Further, treatment of these peptides with acetic anhydride prevented trypsin-catalyzed cleavage of the C-peptide from the insulin A-chain, a result demonstrating the presence of Lys64 and the absence of Arg65 in both abnormal forms. We conclude that individuals from both cohorts with familial hyperproinsulinemia secret very similar or identical intermediates of proinsulin conversion in which the C-peptide remains attached to the insulin A chain and in which Arg65 has been replaced by another amino acid residue.

Full text

PDF
714

Selected References

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

  1. Abdo Y., Rousseaux J., Dautrevaux M. Proalbumin Lille, a new variant of human serum albumin. FEBS Lett. 1981 Aug 31;131(2):286–288. doi: 10.1016/0014-5793(81)80386-9. [DOI] [PubMed] [Google Scholar]
  2. Bell G. I., Pictet R. L., Rutter W. J., Cordell B., Tischer E., Goodman H. M. Sequence of the human insulin gene. Nature. 1980 Mar 6;284(5751):26–32. doi: 10.1038/284026a0. [DOI] [PubMed] [Google Scholar]
  3. Brennan S. O., Carrell R. W. A circulating variant of human proalbumin. Nature. 1978 Aug 31;274(5674):908–909. doi: 10.1038/274908a0. [DOI] [PubMed] [Google Scholar]
  4. DAVIS B. J. DISC ELECTROPHORESIS. II. METHOD AND APPLICATION TO HUMAN SERUM PROTEINS. Ann N Y Acad Sci. 1964 Dec 28;121:404–427. doi: 10.1111/j.1749-6632.1964.tb14213.x. [DOI] [PubMed] [Google Scholar]
  5. Faber O. K., Binder C., Markussen J., Heding L. G., Naithani V. K., Kuzuya H., Blix P., Horwitz D. L., Rubenstein A. H. Characterization of seven C-peptide antisera. Diabetes. 1978;27 (Suppl 1):170–177. doi: 10.2337/diab.27.1.s170. [DOI] [PubMed] [Google Scholar]
  6. Gabbay K. H., Bergenstal R. M., Wolff J., Mako M. E., Rubenstein A. H. Familial hyperproinsulinemia: partial characterization of circulating proinsulin-like material. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2881–2885. doi: 10.1073/pnas.76.6.2881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gabbay K. H., DeLuca K., Fisher J. N., Jr, Mako M. E., Rubenstein A. H. Familial hyperproinsulinemia. An autosomal dominant defect. N Engl J Med. 1976 Apr 22;294(17):911–915. doi: 10.1056/NEJM197604222941701. [DOI] [PubMed] [Google Scholar]
  8. Given B. D., Mako M. E., Tager H. S., Baldwin D., Markese J., Rubenstein A. H., Olefsky J., Kobayashi M., Kolterman O., Poucher R. Diabetes due to secretion of an abnormal insulin. N Engl J Med. 1980 Jan 17;302(3):129–135. doi: 10.1056/NEJM198001173020301. [DOI] [PubMed] [Google Scholar]
  9. Haneda M., Chan S. J., Kwok S. C., Rubenstein A. H., Steiner D. F. Studies on mutant human insulin genes: identification and sequence analysis of a gene encoding [SerB24]insulin. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6366–6370. doi: 10.1073/pnas.80.20.6366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kuzuya H., Blix P. M., Horwitz D. L., Steiner D. F., Rubenstein A. H. Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes. 1977 Jan;26(1):22–29. doi: 10.2337/diab.26.1.22. [DOI] [PubMed] [Google Scholar]
  11. Kwok S. C., Steiner D. F., Rubenstein A. H., Tager H. S. Identification of a point mutation in the human insulin gene giving rise to a structurally abnormal insulin (insulin Chicago). Diabetes. 1983 Sep;32(9):872–875. doi: 10.2337/diab.32.9.872. [DOI] [PubMed] [Google Scholar]
  12. Robbins D. C., Blix P. M., Rubenstein A. H., Kanazawa Y., Kosaka K., Tager H. S. A human proinsulin variant at arginine 65. Nature. 1981 Jun 25;291(5817):679–681. doi: 10.1038/291679a0. [DOI] [PubMed] [Google Scholar]
  13. Shoelson S., Fickova M., Haneda M., Nahum A., Musso G., Kaiser E. T., Rubenstein A. H., Tager H. Identification of a mutant human insulin predicted to contain a serine-for-phenylalanine substitution. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7390–7394. doi: 10.1073/pnas.80.24.7390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Shoelson S., Haneda M., Blix P., Nanjo A., Sanke T., Inouye K., Steiner D., Rubenstein A., Tager H. Three mutant insulins in man. Nature. 1983 Apr 7;302(5908):540–543. doi: 10.1038/302540a0. [DOI] [PubMed] [Google Scholar]
  15. Steiner D. F., Cho S., Oyer P. E., Terris S., Peterson J. D., Rubenstein A. H. Isolation and characterization of proinsulin C-peptide from bovine pancreas. J Biol Chem. 1971 Mar 10;246(5):1365–1374. [PubMed] [Google Scholar]
  16. Tager H., Given B., Baldwin D., Mako M., Markese J., Rubenstein A., Olefsky J., Kobayashi M., Kolterman O., Poucher R. A structurally abnormal insulin causing human diabetes. Nature. 1979 Sep 13;281(5727):122–125. doi: 10.1038/281122a0. [DOI] [PubMed] [Google Scholar]
  17. Varandani P. T. Studies on the nature of antigenicity of A and B chains of bovine insulin. Biochemistry. 1967 Jan;6(1):100–104. doi: 10.1021/bi00853a017. [DOI] [PubMed] [Google Scholar]
  18. Yu S. S., Kitbachi A. E. Biological activity of proinsulin and related polypeptides in the fat tissue. J Biol Chem. 1973 Jun 10;248(11):3753–3761. [PubMed] [Google Scholar]

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

RESOURCES