Insulin pp 41-64 | Cite as

Mutant Human Insulins and Insulin Structure-Function Relationships

  • H. S. Tager
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 92)


Studies based on heritable defects in human function (sometimes called inborn errors of metabolism) have long played an important role to increase our understanding of mammalian biology in areas as diverse as biochemistry, cell and organismal physiology, and clinical medicine. In fact, studies over very many years of the hemoglobinopathies have formed a paradigm for the analysis of changes in molecular structure which both arise from genetic mutation and lead to important physiological consequences. Early work in the general area emphasized, for technical reasons alone, the results of mutations leading to: (a) structural change in the most abundant blood proteins; and (b) the replacement of amino acid residues that would change the properties of those proteins with respect to charge and electrophoretic mobility. Exceptions (including those involving important intracellular enzymes) are easily identified, but analysis of human tissues for genetic changes that result in concomitantly changed protein structure remained difficult for an extended period. Recent technical and methodological advances (including high performance liquid chromatography, instrumentation for ultramicro protein analysis, and the vast approaches of recombinant DNA analysis), however, have instilled renewed ability and interest to the field. The benefits that afford the study of genetic mutation in humans and of corresponding abnormal proteins are clear. They include determination of the genetic causes and implications of human disease and the importance of detailed protein structure in the attainment of correct protein, cellular, and organismal function. In many ways the analysis of human gene mutations helps to identify genes, proteins, and protein domains of special importance to normal and abnormal mammalian physiology.


Human Insulin Insulin Analog Insulin Gene Amino Acid Replacement Abnormal Insulin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Assoian RK, Thomas NE, Kaiser ET, Tager HS (1982) [LeuB25]insulin and [AlaB24]insulin: altered structures and cellular processing of B24-substituted insulin analogs. Proc Natl Acad Sci USA 79:5147–5151PubMedCrossRefGoogle Scholar
  2. Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM (1980) Sequence of the human insulin gene. Nature 284:26–32PubMedCrossRefGoogle Scholar
  3. Blundell T, Dodson G, Hodgkin D, Mercola D (1972) Insulin: the structure in the crystal and its reflection in chemistry and biology. Adv Protein Chem 26:279–402CrossRefGoogle Scholar
  4. Carroll RJ, Hammer RE, Chan SJ, Swift HH, Rubenstein AH, Steiner DF (1988) A mutant human proinsulin is secreted from islets of langerhans in increased amounts via an unregulated pathway. Proc Natl Acad Sci USA 85:8943–8947PubMedCrossRefGoogle Scholar
  5. Chan SJ, Keim P, Steiner DF (1976) Cell-free synthesis of rat preproinsulins: characterization and partial amino acid sequence determination. Proc Natl Acad Sci USA 73:1964–1968PubMedCrossRefGoogle Scholar
  6. Chan SJ, Seino SU, Gruppuso PA, Schwartz R, Steiner DF (1987) A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. Proc Natl Acad Sci USA 84:2194–2197PubMedCrossRefGoogle Scholar
  7. Chothia C, Lesk AM, Dodson G, Hodgkin DC (1983) Transmission of conformational change in insulin. Nature 302:500–505PubMedCrossRefGoogle Scholar
  8. Cosmatos A, Cheng K, Okada Y, Katsoyannis PG (1978) The chemical synthesis and biological evaluation of [1-L-alanine-A]-and [l-D-alanine-A]insulins. J Biol Chem 253:6586–6590PubMedGoogle Scholar
  9. DeMeyts P, van Obberghen E, Roth J, Wollmer A, Brandenburg D (1978) Mapping of the residues responsible for the negative cooperativity of the receptor-binding region of insulin. Nature 273:504–509PubMedCrossRefGoogle Scholar
  10. Dodson EJ, Dodson GG, Hodgkin DC, Reynolds CD (1979) Structural relationships in the two-zinc insulin hexamer. Can J Biochem 57:469–479PubMedCrossRefGoogle Scholar
  11. Dodson EJ, Dodson GG, Hubbard RE, Reynolds CD (1983) Insulin’s structural behavior and its relationship to activity. Biopolymers 22:281–291PubMedCrossRefGoogle Scholar
  12. Elliott RB, O’Brien D, Roy CC (1966) An abnormal insulin in juvenile diabetes mellitus. Diabetes 14:780–787Google Scholar
  13. Gabbay KH, DeLuca K, Fisher NJ Jr, Mako ME, Rubenstein AH (1976) Familial hyperproinsulinemia: an autosomal dominant defect. N Engl J Med 249:911–915CrossRefGoogle Scholar
  14. Gabbay KH, Bergenstal RM, Wolff J, Mako ME, Rubenstein AH (1979) Familial hyper-proinsulinemia: partial characterization of circulating proinsulin-like material. Proc Natl Acad Sci USA 76:2882–2885CrossRefGoogle Scholar
  15. Gammeltoft S (1984) Insulin structure and function. Physiol Rev 64:1321–1378PubMedGoogle Scholar
  16. Given BD, Mako ME, Tager HS, Baldwin D, Markese J, Rubenstein AH, Olefsky J et al. (1980) Diabetes due to secretion of an abnormal insulin. N Engl J Med 302:129–135PubMedCrossRefGoogle Scholar
  17. Given BD, Cohen RM, Shoelson SE, Frank BH, Rubenstein AH, Tager HS (1985) Biochemical and clinical implications of proinsulin conversion intermediates. J Clin Invest 76:1398–1405PubMedCrossRefGoogle Scholar
  18. Gruppuso PA, Gorden P, Kahn RC, Cornblath M, Zeller WP, Schwartz R (1984) Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin. N Engl J Med 311:629–634PubMedCrossRefGoogle Scholar
  19. Haneda M, Chan SJ, Kwok SCM, Rubenstein AH, Steiner DF (1983) Studies on mutant insulin genes: identification and sequence analysis of a gene encoding [SerB24]insulin. Proc Natl Acad Sci USA 80:6366–6370PubMedCrossRefGoogle Scholar
  20. Haneda M, Polonsky KS, Bergenstal RM, Jaspan JB, Shoelson SE, Blix PM, Chan SJ et al. (1984) Familial hyperinsulinemia due to a structurally abnormal insulin: definition of an emerging new clinical syndrome. N Engl J Med 310:1288–1294PubMedCrossRefGoogle Scholar
  21. Haneda M, Kobayashi M, Maegawa H, Watanabe N, Takata Y, Ishibashi O, Shigeta Y, Inouye K (1985) Decreased biological activity and degradation of human [SerB24]insulin, a second mutant insulin. Diabetes 34:568–573PubMedCrossRefGoogle Scholar
  22. Inouye K, Watanabe K, Morihara K, Tochino Y, Kanaya T, Emura J, Sakakibara S (1979) Enzyme-assisted semisynthesis of human insulin. J Am Chem Soc 101:751–752CrossRefGoogle Scholar
  23. Inouye K, Watanabe K, Tochino Y, Kobayashi M, Shigeta Y (1981) Semosynthesis and properties of some insulin analogs. Biopolymers 20:1845–1858PubMedCrossRefGoogle Scholar
  24. Iwamoto Y, Sakura H, Yui R, Fujita T, Sakamoto Y, Matsuda A, Kuzuya T (1986a) Identification and characterization of a mutant insulin isolated from the pancreas of a patient with abnormal insulinemia. Diabetes [Suppl 1] 35:77 ACrossRefGoogle Scholar
  25. Iwamoto Y, Sakura H, Ishii Y, Yamamoto R, Kumakura S, Sakamoto Y, Masuda A, Kuzuya T (1986b) Radioreceptor assay for serum insulin as a useful method for detection of abnormal insulin with a description of a new family of abnormal insulinemia. Diabetes 35:1237–1242PubMedCrossRefGoogle Scholar
  26. Kimmel JR, Pollack HG (1967) Studies of human insulin from nondiabetic and diabetic pancreas. Diabetes 16:687–694PubMedGoogle Scholar
  27. Kitagawa K, Ogawa H, Burke GT, Chanley JD, Katsoyanis PG (1984a) Critical role of the A2 amino acid residue in the biological activity of insulin. Biochemistry 23:1405–1413PubMedCrossRefGoogle Scholar
  28. Kitagawa K, Ogawa H, Burke GT, Chanley JD, Katsoyanis PG (1984b) Interaction between the A2 and A19 amino acid residues is of critical importance for high biological activity in insulin. Biochemistry 23:4444–4448PubMedCrossRefGoogle Scholar
  29. Kobayashi M, Ohgaku S, Iwasaki M, Maegawa H, Shigeta Y, Inouye K (1982a) Characterization of [LeuB24]-and [LeuB25]insulin analogs. Biochem J 206:597–603PubMedGoogle Scholar
  30. Kobayashi M, Ohgaku S, Iwasaki M, Maegawa H, Shigeta Y, Inouye K (1982b) Supernormal insulin: [D-PheB24]insulin with increased affinity for insulin receptors. Biochem Biophys Res Commun 107:329–336PubMedCrossRefGoogle Scholar
  31. Kobayashi M, Haneda M, Maegawa H, Watanabe N, Takato Y, Shigeta Y, Inouye K (1984a) Receptor binding and biological activity of [SerB24]insulin, an abnormal mutant insulin. Biochem Biophys Res Commun 119:49–57PubMedCrossRefGoogle Scholar
  32. Kobayashi M, Haneda M, Ishibashi O, Takata Y, Maegawa H, Watanabe N, Shigeta Y (1984b) Prolonged disappearance rate of a structurally abnormal mutant insulin from the blood. Diabetes [Suppl 1] 33:17 AGoogle Scholar
  33. Kobayashi M, Takata Y, Ishibashi O, Sasoka T, Iwasaki M, Shigeta Y, Inouye K (1986) Receptor binding and negative cooperativity of a mutant insulin [LeuA3]insulin. Biochem Biophys Res Commun 137:250–257PubMedCrossRefGoogle Scholar
  34. Kwok SCM, Chan SJ, Rubenstein AH, Poucher R, Steiner DF (1981) Loss of restriction endonuclease cleavage site in the gene of a structurally abnormal insulin. Biochem Biophys Res Commun 98:844–849PubMedCrossRefGoogle Scholar
  35. Kwok SCM, Steiner DF, Rubenstein AH, Tager HS (1983) Identification of the mutation giving rise to insulin Chicago. Diabetes 32:872–875PubMedCrossRefGoogle Scholar
  36. Mirmira RG, Tager HS (1989) Role of the phenylalanine B24 side chain in directing insulin interaction with its receptor. J Biol Chem 264:6349–6354PubMedGoogle Scholar
  37. Nakagawa SH, Tager HS (1986) Role of the phenylalanine B25 side chain in directing insulin interaction with its receptor. J Biol Chem 261:7332–7341PubMedGoogle Scholar
  38. Nakagawa S, Tager HS (1987) Role of the COOH-terminal B-chain domain in insulin-receptor interactions. J Biol Chem 262:12054–12058PubMedGoogle Scholar
  39. Nanjo K, Sanke T, Miyano M, Okai K, Sowa R, Kondo M, Nishimura S et al. (1986a) Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). J Clin Invest 77:514–519PubMedCrossRefGoogle Scholar
  40. Nanjo K, Given B, Sänke T, Kondo M, Miyano M, Okai K, Miyama K et al. (1986b) Pancreatic function in the mutant insulin syndrome. Diabetes [Suppl 1] 35:77 AGoogle Scholar
  41. Orci L, Ravazzola M, Amherdt M, Madsen O, Vassaili J-D, Perrelet A (1985) Direct identification of prohormone conversion site in insulin-secreting cells. Cell 42:671–681PubMedCrossRefGoogle Scholar
  42. 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. J Biol Chem 26:13989–13994Google Scholar
  43. Robbins DC, Blix PM, Rubenstein AH, Kanazawa Y, Kosaka K, Tager HS (1981) A human proinsulin variant at arginine 65. Nature 291:679–681PubMedCrossRefGoogle Scholar
  44. Robbins DC, Shoelson SE, Rubenstein AH, Tager HS (1984) Familial hyperproinsulinemia: two cohorts secreting indistinguishable type II intermediates of proinsulin conversion. J Clin Invest 73:714–719PubMedCrossRefGoogle Scholar
  45. Sanz N, Karam JH, Horita S, Bell GI (1985) DNA screening for insulin gene mutations in non-insulin-dependent diabetes mellitus (NIDDM). Diabetes [Suppl 1] 34:85 AGoogle Scholar
  46. Schwartz GP, Burke GT, Katsoyanis PG (1987) A superactive insulin: [B10-aspartic acid]insulin (human). Proc Natl Acad Sci USA 84:6408–6411PubMedCrossRefGoogle Scholar
  47. Schwartz TW, Witteis B, Tager HS (1983) Hormone precursor processing in the pancreatic islet. In: Hruby VJ, Rich DH (eds) Peptides: structure and function. Pierce Chemical Company, Rockford, pp 229–238Google Scholar
  48. Shibasaki Y, Kawakami T, Kanazawa Y, Akamura Y, Takaku T (1985) Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulmemia. J Clin Invest 76:378–380PubMedCrossRefGoogle Scholar
  49. Shoelson S, Haneda M, Blix P, Nanjo K, Sanke T, Inouye K, Steiner D et al. (1983a) Three mutant insulins in man. Nature 302:540–543PubMedCrossRefGoogle Scholar
  50. Shoelson S, Fickova M, Haneda M, Nahum A, Musso G, Kaiser ET, Rubenstein AH, Tager HS (1983b) Identification of a mutant insulin predicted to contain a serine-forphenylalanine substitution. Proc Natl Acad Sci USA 80:7390–7394PubMedCrossRefGoogle Scholar
  51. Shoelson SE, Polonsky KS, Zeidler A, Rubenstein AH, Tager HS (1984) Human insulin (Phe→Ser): secretion and metabolic clearance of the abnormal insulin in man and in a dog model. J Clin Invest 73:1351–1358PubMedCrossRefGoogle Scholar
  52. Smith GD, Swenson DC, Dodson EJ, Dodson GG, Reynolds CD (1984) Structural stability in the 4-zinc human insulin hexamer. Proc Natl Acad Sci USA 81.7093–7097PubMedCrossRefGoogle Scholar
  53. Steiner DF (1977) Insulin today. Diabetes 26:322–340PubMedGoogle Scholar
  54. Steiner DF, Cunningham DD, Spigelman S, Aten B (1967) Insulin biosynthesis: evidence for a precursor. Science 157:697–700PubMedCrossRefGoogle Scholar
  55. Steiner DF, Clark JL, Nolan C, Rubenstein AH, Margoliash E, Aten B, Oyer PE (1969) Proinsulin and the biosynthesis of insulin. Recent Prog Horm Res 25:207–282PubMedGoogle Scholar
  56. Steiner DF, Quinn PS, Chan SJ, Marsh J, Tager HS (1980) Processing mechanisms in the biosynthesis of proteins. Ann NY Acad Sci 343:1–16PubMedCrossRefGoogle Scholar
  57. Tager HS, Given B, Baldwin D, Mako M, Markese J, Rubenstein AH, Olefsky J et al. (1979) A structurally abnormal insulin causing human diabetes. Nature 281:122–125PubMedCrossRefGoogle Scholar
  58. Tager HS, Palzelt C, Assoian RK, Chan SJ, Duguid JR, Steiner DF (1980a) Biosynthesis of islet cell hormones. Ann NY Acad Sci 343:133–147PubMedCrossRefGoogle Scholar
  59. Tager HS, Thomas N, Assoian R, Rubenstein A, Saekow M, Olefsky J, Kaiser ET (1980b) Semisynthesis and biological activity of porcine [LeuB24]insulin and [LeuB25]insulin. Proc Natl Acad Sci USA 77:3181–3185PubMedCrossRefGoogle Scholar
  60. Terris S, Steiner DF (1975) Binding and degradation of 125I-insulin by rat hepatocytes. J Biol Chem 250:8389–8398PubMedGoogle Scholar
  61. Terris S, Steiner DF (1976) Retention and degradation of 125I-insulin by perfused livers from diabetic rats. J Clin Invest 57:885–896PubMedCrossRefGoogle Scholar
  62. Ullrich A, Dull TJ, Gray A, Brosius J, Sives I (1980) Genetic variation in the human insulin gene. Science 209:612–615PubMedCrossRefGoogle Scholar
  63. Wollmer A, Strassburger W, Glatler V, Dodson GG, McCall M, Danho W, Brandenburg D et al. (1981) Two mutant forms of human insulin: structural consequences of the substitution of invariant B24 or B25 by leucine. Hoppe Seylers Z Physiol Chem 362:581–592PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • H. S. Tager

There are no affiliations available

Personalised recommendations