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. 1991 Jun 1;88(11):4728–4730. doi: 10.1073/pnas.88.11.4728

Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients.

L Mosthaf 1, B Vogt 1, H U Häring 1, A Ullrich 1
PMCID: PMC51739  PMID: 1711209

Abstract

The human insulin receptor exists in two isoforms, HIR-A and HIR-B, which are generated by alternative splicing of a primary gene transcript and differ by a 12-amino acid insertion sequence in the alpha-subunit. The two receptor isoforms bind insulin with different affinities and are differentially expressed in human tissues. We report here a tissue-specific alteration of the insulin receptor RNA splice pattern in non-insulin-dependent diabetes mellitus (NIDDM) patients. Whereas skeletal muscle of healthy individuals contains exclusively high-affinity HIR-A-encoding RNA, we consistently find low-affinity HIR-B RNA expression in NIDDM muscle tissue at levels similar to HIR-A.

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Selected References

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  1. Accili D., Frapier C., Mosthaf L., McKeon C., Elbein S. C., Permutt M. A., Ramos E., Lander E., Ullrich A., Taylor S. I. A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes. EMBO J. 1989 Sep;8(9):2509–2517. doi: 10.1002/j.1460-2075.1989.tb08388.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arner P., Pollare T., Lithell H., Livingston J. N. Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1987 Jun;30(6):437–440. doi: 10.1007/BF00292549. [DOI] [PubMed] [Google Scholar]
  3. Caro J. F., Ittoop O., Pories W. J., Meelheim D., Flickinger E. G., Thomas F., Jenquin M., Silverman J. F., Khazanie P. G., Sinha M. K. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest. 1986 Jul;78(1):249–258. doi: 10.1172/JCI112558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. DeFronzo R. A., Ferrannini E., Koivisto V. New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med. 1983 Jan 17;74(1A):52–81. doi: 10.1016/0002-9343(83)90654-x. [DOI] [PubMed] [Google Scholar]
  6. Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E., Ou J. H., Masiarz F., Kan Y. W., Goldfine I. D. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985 Apr;40(4):747–758. doi: 10.1016/0092-8674(85)90334-4. [DOI] [PubMed] [Google Scholar]
  7. Freidenberg G. R., Henry R. R., Klein H. H., Reichart D. R., Olefsky J. M. Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. J Clin Invest. 1987 Jan;79(1):240–250. doi: 10.1172/JCI112789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kadowaki T., Bevins C. L., Cama A., Ojamaa K., Marcus-Samuels B., Kadowaki H., Beitz L., McKeon C., Taylor S. I. Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. Science. 1988 May 6;240(4853):787–790. doi: 10.1126/science.2834824. [DOI] [PubMed] [Google Scholar]
  9. Kahn C. R., White M. F. The insulin receptor and the molecular mechanism of insulin action. J Clin Invest. 1988 Oct;82(4):1151–1156. doi: 10.1172/JCI113711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Klinkhamer M. P., Groen N. A., van der Zon G. C., Lindhout D., Sandkuyl L. A., Krans H. M., Möller W., Maassen J. A. A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance. EMBO J. 1989 Sep;8(9):2503–2507. doi: 10.1002/j.1460-2075.1989.tb08387.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lockwood D. H., Amatruda J. M. Cellular alterations responsible for insulin resistance in obesity and type II diabetes mellitus. Am J Med. 1983 Nov 30;75(5B):23–31. doi: 10.1016/0002-9343(83)90250-4. [DOI] [PubMed] [Google Scholar]
  12. Moller D. E., Yokota A., Caro J. F., Flier J. S. Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. Mol Endocrinol. 1989 Aug;3(8):1263–1269. doi: 10.1210/mend-3-8-1263. [DOI] [PubMed] [Google Scholar]
  13. Moller D. E., Yokota A., Flier J. S. Normal insulin-receptor cDNA sequence in Pima Indians with NIDDM. Diabetes. 1989 Nov;38(11):1496–1500. doi: 10.2337/diab.38.11.1496. [DOI] [PubMed] [Google Scholar]
  14. Moller D. E., Yokota A., Ginsberg-Fellner F., Flier J. S. Functional properties of a naturally occurring Trp1200----Ser1200 mutation of the insulin receptor. Mol Endocrinol. 1990 Aug;4(8):1183–1191. doi: 10.1210/mend-4-8-1183. [DOI] [PubMed] [Google Scholar]
  15. Moller D. E., Yokota A., White M. F., Pazianos A. G., Flier J. S. A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. J Biol Chem. 1990 Sep 5;265(25):14979–14985. [PubMed] [Google Scholar]
  16. Mosthaf L., Grako K., Dull T. J., Coussens L., Ullrich A., McClain D. A. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J. 1990 Aug;9(8):2409–2413. doi: 10.1002/j.1460-2075.1990.tb07416.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Obermaier-Kusser B., White M. F., Pongratz D. E., Su Z., Ermel B., Muhlbacher C., Haring H. U. A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus. J Biol Chem. 1989 Jun 5;264(16):9497–9504. [PubMed] [Google Scholar]
  18. Ojamaa K., Hedo J. A., Roberts C. T., Jr, Moncada V. Y., Gorden P., Ullrich A., Taylor S. I. Defects in human insulin receptor gene expression. Mol Endocrinol. 1988 Mar;2(3):242–247. doi: 10.1210/mend-2-3-242. [DOI] [PubMed] [Google Scholar]
  19. Olefsky J. M., Ciaraldi T. P., Kolterman O. G. Mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. Am J Med. 1985 Sep 20;79(3B):12–22. doi: 10.1016/s0002-9343(85)80003-6. [DOI] [PubMed] [Google Scholar]
  20. Olefsky J. M. LIlly lecture 1980. Insulin resistance and insulin action. An in vitro and in vivo perspective. Diabetes. 1981 Feb;30(2):148–162. doi: 10.2337/diab.30.2.148. [DOI] [PubMed] [Google Scholar]
  21. Pfeifer M. A., Halter J. B., Porte D., Jr Insulin secretion in diabetes mellitus. Am J Med. 1981 Mar;70(3):579–588. doi: 10.1016/0002-9343(81)90579-9. [DOI] [PubMed] [Google Scholar]
  22. Reaven G. M., Chen Y. I., Coulston A. M., Greenfield M. S., Hollenbeck C., Lardinois C., Liu G., Schwartz H. Insulin secretion and action in noninsulin-dependent diabetes mellitus. Is insulin resistance secondary to hypoinsulinemia? Am J Med. 1983 Nov 30;75(5B):85–93. doi: 10.1016/0002-9343(83)90258-9. [DOI] [PubMed] [Google Scholar]
  23. Seino S., Bell G. I. Alternative splicing of human insulin receptor messenger RNA. Biochem Biophys Res Commun. 1989 Feb 28;159(1):312–316. doi: 10.1016/0006-291x(89)92439-x. [DOI] [PubMed] [Google Scholar]
  24. Taylor S. I., Roth J., Blizzard R. M., Elders M. J. Qualitative abnormalities in insulin binding in a patient with extreme insulin resistance: decreased sensitivity to alterations in temperature and pH. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7157–7161. doi: 10.1073/pnas.78.11.7157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ullrich A., Bell J. R., Chen E. Y., Herrera R., Petruzzelli L. M., Dull T. J., Gray A., Coussens L., Liao Y. C., Tsubokawa M. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. 1985 Feb 28-Mar 6Nature. 313(6005):756–761. doi: 10.1038/313756a0. [DOI] [PubMed] [Google Scholar]
  26. Ullrich A., Shine J., Chirgwin J., Pictet R., Tischer E., Rutter W. J., Goodman H. M. Rat insulin genes: construction of plasmids containing the coding sequences. Science. 1977 Jun 17;196(4296):1313–1319. doi: 10.1126/science.325648. [DOI] [PubMed] [Google Scholar]
  27. Yamamoto-Honda R., Koshio O., Tobe K., Shibasaki Y., Momomura K., Odawara M., Kadowaki T., Takaku F., Akanuma Y., Kasuga M. Phosphorylation state and biological function of a mutant human insulin receptor Val996. J Biol Chem. 1990 Sep 5;265(25):14777–14783. [PubMed] [Google Scholar]
  28. Yarden Y., Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–478. doi: 10.1146/annurev.bi.57.070188.002303. [DOI] [PubMed] [Google Scholar]
  29. Yoshimasa Y., Seino S., Whittaker J., Kakehi T., Kosaki A., Kuzuya H., Imura H., Bell G. I., Steiner D. F. Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing. Science. 1988 May 6;240(4853):784–787. doi: 10.1126/science.3283938. [DOI] [PubMed] [Google Scholar]

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