Applied Microbiology and Biotechnology

, Volume 67, Issue 2, pp 151–159 | Cite as

Therapeutic insulins and their large-scale manufacture

  • Gary WalshEmail author


Biotechnological innovations over the past 25 years have underpinned the rapid development of a thriving biopharmaceutical sector. Therapeutic insulin remains one of the most commonly used products of pharmaceutical biotechnology and insulin-based products command annual global sales in excess of $4.5 billion. Innovations in its method of production and in particular the advent of engineered insulin analogues provide a fascinating insight into how scientific and technological advances have impacted upon the pharmaceutical biotechnology sector as a whole. Current insulin-based diabetes research is increasingly focused not on the insulin molecule per se, but upon areas such as the development of non-parenteral insulin delivery systems, as well as organ-/cell-based and gene therapy-based approaches to controlling the disease.


Human Insulin Insulin Glargine Proinsulin Insulin Analogue Insulin Lispro 
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.


  1. Aventis (2003) Aventis 2003 annual report. Available at
  2. Banting F, Best C (1922) The internal secretions of the pancreas. J Lab Clin Med 7:251–266Google Scholar
  3. Bliss M (1993) The history of insulin. Diabetes Care 16(3):4–7Google Scholar
  4. Blundell T, Dodson G, Hodgkin D, Mercola D (1972) Insulin: the structure in the crystal and its reflection in chemistry and biology. Adv Prot Chem 26:279–402Google Scholar
  5. Brange J, Ribel J, Hansen JF, Dodson G, Hansen MT, Havelund S, Melberg SG, Norris K, Norris L, Snel L, Sorensen AR, Voigt HO (1988) Monomeric insulins obtained by protein engineering and their medical implications. Nature 333:679–682CrossRefPubMedGoogle Scholar
  6. Brange J, Owens DR, Kang S, Volund A (1990) Monomeric insulins and their experimental and clinical implications. Diabetes Care 13(9):923–954PubMedGoogle Scholar
  7. Carino G, Mathiowitz E (1999) Oral insulin delivery. Adv Drug Del Rev 35:249–257CrossRefGoogle Scholar
  8. Cefalu WT (2004) Concepts, strategies and feasibility of noninvasive insulin delivery. Diabetes Care 27(1):239–246PubMedGoogle Scholar
  9. Chance R, Frank B (1993) Research, development production and safety of biosynthetic human insulin. Diabetes Care 16(3):133–142Google Scholar
  10. Chance R, Glazer N, Wishner K (1999) Insulin Lispro (Humalog). In: Walsh G, Murphy B (eds) Biopharmaceuticals, an industrial perspective. Kluwer, Dordrecht pp 149–172Google Scholar
  11. Ciszak E, Beals M, Frank BH (1995) Role of C-terminal B chain residues in insulin assembly: the structure of hexameric LysB28 ProB29 human insulin. Structure 3:615–622CrossRefPubMedGoogle Scholar
  12. Clement S, Dandona P, Still JG, Kosutic G (2004) Oral modified insulin (HIM2) in patients with type 1 diabetes mellitus: results from a phase I/II clinical trial. Metabolism 53(1):54–58CrossRefPubMedGoogle Scholar
  13. Efrat S (2004) Generation of insulin producing cells from stem cells for cell replacement therapy of type 1 diabetes. Isr Med Assoc J 6(5):265–267PubMedGoogle Scholar
  14. Frank B (1981) The production of human proinsulin and its transformation to human insulin and C peptide. In: Rich D, Gross E (eds) Proceedings of the seventh American peptide symposium on peptidases: synthesis-structure-function. Pierce Chemical, Rockford, USA, pp 729–738Google Scholar
  15. Frank B (1991) Manupilation of the position of proline in the B chain produced monomeric insulins. Diabetes 40[Suppl 1]:423AGoogle Scholar
  16. Frank B, Baker J, Bakaysa D (1995) Lys B28 Pro B29 human insulin (insulin lispro): solution properties of a rapid acting insulin. Diabetologia 38[Suppl 1]:A189Google Scholar
  17. Galloway JA, Chance RE (1994) Improving insulin therapy: achievements and challenges. Horm Metab Res 26(12):591–598PubMedGoogle Scholar
  18. Generex (2004) Oralin product information. Available at
  19. Ghilzai NM (2003) New developments in insulin delivery. Drug Dev Ind Pharm 29(3):253–265CrossRefPubMedGoogle Scholar
  20. Havelund S, Plum A, Ribel U, Jonassen I, Volund A, Markussen J, Kurtzhals P (2004) The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res 21(8):1498–1504CrossRefPubMedGoogle Scholar
  21. Heise T, Nosek L, Ronn B, Endhal L, Heinemann L, Kapitza C (2004) Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 53(6):1614–1620PubMedGoogle Scholar
  22. Hinchcliffe M, Illum L (1999) Intranasal insulin delivery and therapy. Adv Drug Del Rev 35:199–234CrossRefGoogle Scholar
  23. Homandberg GA, Mattis J, Llaskowski M (1978) Synthesis of peptide bonds by proteinases. Addition of organic solvents shifts peptide bond equilibria towards synthesis. Biochemistry 17:5220–5227PubMedGoogle Scholar
  24. Kang S, Owens DR, Vora JP, Brange J (1990) Comparison of insulin analog B9ASPB27GLU and soluble human insulin in insulin-treated diabetics. Lancet 335:303–306CrossRefPubMedGoogle Scholar
  25. Kang S, Creagh F, Peters J, Brange J, Volund A, Owens D (1991) Comparison of subcutaneous soluble human insulin and insulin analogues on meal-related plasma glucose excursions in type-1 diabetic subjects. Diabetes Care 14:571–577PubMedGoogle Scholar
  26. Kapitza C, Hompesch M, Scharling B, Heise T, (2004) Intrasubject variability of inhaled insulin in type 1 diabetes: a comparison with subcutaneous insulin. Diabetes Technol Ther 6(4):466–472CrossRefPubMedGoogle Scholar
  27. Kjeldsen T (2000) Yeast secretory expression of insulin precursors. Appl Microbiol Biotechnol 54:277–286CrossRefPubMedGoogle Scholar
  28. Kjeldsen T, Ludvigsen S, Diers I, Balschmidt P, Sorensen A, Kaarsholm N (2002) Engineering-enhanced protein secretory expression in yeast with application to insulin. J Biol Chem 277(21):18245–18248CrossRefPubMedGoogle Scholar
  29. Kost J, Langer R (1991) Responsive polymeric delivery systems. Adv Drug Del Rev 6:19–50CrossRefGoogle Scholar
  30. Kurtzhals P, Havelund S, Jonassen S, Markussen J (1997) Effect of fatty acids and selected drugs on the albumin binding of a long acting, acylated insulin analogue. J Pharm Sci 86(12):1365–1368CrossRefPubMedGoogle Scholar
  31. Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, Trub T, (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49(6):999–1005PubMedGoogle Scholar
  32. Lee MK, Bae YH (2000) Cell transplantation for endocrine disorders. Adv Drug Del Rev 42:103–120CrossRefGoogle Scholar
  33. Levene F, Leibowitz G (1999) Towards gene therapy of diabetes mellitus. Mol Med Today 5:165–171CrossRefPubMedGoogle Scholar
  34. Lilly (2003) Lilly 2003 annual report. Available at
  35. Markussen J (1980) Process for preparing insulin esters. United Kingdom patent application GB 2069502 AGoogle Scholar
  36. Markussen J, Jorgensen K, Thim L, Damgaard U, Sorensen E, Dodson G, Chawdhury F (1981) Human monocomponent insulin: chemistry and characteristics of human insulin. Diabetologia 21:302Google Scholar
  37. Markussen J, Damgaard U, Diers I, Fiil N, Hansen M, Lassen P, Norris F, Norris P, Schou O, Snel L, Thim L, Voigt H (1986) Biosynthesis of human insulin in yeast via single chain precursors. Diabetologia 29:568A–569AGoogle Scholar
  38. Morihara K, Oka T, Tsuzukih H (1979) Semi synthesis of human insulin by trypsin-catalyzed replacement of Ala-B30 by Thr in porcine insulin. Nature 280:412–413PubMedGoogle Scholar
  39. Nett PC, Sollinger HW, Alam T (2003) Hepatic insulin gene therapy in insulin-dependent diabetes mellitus. Am J Transplant 3(10):1197–1203CrossRefPubMedGoogle Scholar
  40. Nicol S, Smith M (1960) Amino acid sequence of human insulin. Nature 187:483–485PubMedGoogle Scholar
  41. Novo (2003) Novo nordisk 2003 annual report. Available at
  42. Owens DR, Vora JP, Dolben J (1991) Human insulin and beyond: semisynthesis and recombinant DNA technology reviewed. In: Pickup JC (ed) Biotechnology of insulin therapy. Blackwell, Oxford, pp 24–41Google Scholar
  43. Owens DR, Zinman B, Bolli G (2001) Insulins today and beyond. Lancet 358:739–746CrossRefPubMedGoogle Scholar
  44. Owens DR, Zinman B, Bolli G (2003). Alternative routes of insulin delivery. Diabet Med 20(11):886–898CrossRefPubMedGoogle Scholar
  45. Patton J (1996) Mechanisms of macromolecule absorption by the lungs. Adv Drug Del Rev 19:3–36CrossRefGoogle Scholar
  46. Patton J, Bukar J, Nagarajan S (1999) Inhaled insulin. Adv Drug Del Rev 35:235–247CrossRefGoogle Scholar
  47. Peck AB, Ramiya V (2004) In vitro generation of surrogate islets from adult stem cells. Transpl Immunol 12(3–4):259–272CrossRefPubMedGoogle Scholar
  48. Pillai O, Panchagnula R (2001) Insulin therapies—past, present and future. Drug Discov Today 20(6):1056–1061CrossRefGoogle Scholar
  49. Roche E, Sepulcre MP, Ensenat-Waser R, Maestre I, Reig JA, Soria B (2003) Bio-engineering insulin-secreting cells from embryonic stem cells: a review of progress. Med Biol Eng Comput 41(4):384–391PubMedGoogle Scholar
  50. Scott D (1934) Crystalline insulin. Biochem J 28(II):1592–1602Google Scholar
  51. Sieber P, Kamber B, Hartmann A, Johl A, Riniker B, Rittel W (1974) Total synthese von human insulin unter gezielter bildung der disulfid bindungen. Helv Chim Acta 57:2617–2621PubMedGoogle Scholar
  52. Steil GM, Panteleon AE, Rebrin K (2004) Cloosed-loop insulin delivery—the path to physiological glucose control. Adv Drug Del Rev 56(2):125–144CrossRefGoogle Scholar
  53. Sutcliffe J, Duin N (1992) A history of medicine. Barnes and Noble, USA, pp 104–105Google Scholar
  54. Thim L, Hansen MT, Norris K, Hoegh I, Boel E, Forstrom J, Ammerer G, Fiil NP (1986) Secretion and processing of insulin precursors in yeast. PNAS 83:6766–6770PubMedGoogle Scholar
  55. Vora JP, Owens DR, Dolben J, Atiea TA, Dean JD, Kang S, Burch A, Brange J (1988) Recombinant DNA derived monomeric insulin analogue. Comparison with soluble human insulin in normal subjects. Br Med J 297:1236–1239Google Scholar
  56. Walsh G (1998) Biopharmaceuticals: biochemistry and biotechnology. Wiley, ChichesterGoogle Scholar
  57. WHO (2004) Diabetes action report. Available at
  58. Yoon JW, Jun HS (2002) Recent advances in gene therapy for type 1 diabetes. Trends Mol Med 8(2):62–68CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Industrial Biochemistry ProgramUniversity of LimerickLimerick CityIreland

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