Applied Microbiology and Biotechnology

, Volume 103, Issue 21–22, pp 8737–8751 | Cite as

Insulin and its single-chain analogue

  • Ruifeng MaoEmail author
  • Yingying Chen
  • Zhenjing Chi
  • Yefu Wang


Insulin therapy remains the most effective method to treat diabetes mellitus (DM), and the demand for this valuable hormone has exceeded that of any other protein-based medicine as a result of the dramatic increase in the number of diabetic patients worldwide. Understanding the structure of insulin and the interaction with its receptor is important for developing proper formulations. As a result of the relatively low thermal stability of native insulin and its two-chain analogues, the application of single-chain insulin (SCI) analogues, which can be obtained relatively easily by recombinant DNA technology or chemical synthetic methods, represents a promising alternative approach. In this review, the basic knowledge of insulin (discovery, biosynthesis, and structure) and the current model of the interaction with its receptor are outlined. Furthermore, we outline the strategies for the design and production of various SCI analogues and their reported applications.


Diabetes mellitus Insulin Insulin receptor Single-chain insulin analogue 


Funding information

This study was supported by the National Natural Science Foundation of China (81803418), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (18KJD350001), and the Project for Youth Scholar of Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection (HSXT2-314).

Compliance with ethical standards

Ethical approval

This article does not contain studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abel JJ (1926) Crystalline insulin. Proc Natl Acad Sci U S A 12(2):132–136. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adamo M, Raizada MK, LeRoith D (1989) Insulin and insulin-like growth factor receptors in the nervous system. Mol Neurobiol 3(1):71–100. CrossRefPubMedGoogle Scholar
  3. Adams JP, Holder AL, Catchpole B (2014) Recombinant canine single chain insulin analogues: insulin receptor binding capacity and ability to stimulate glucose uptake. Vet J 202(3):436–442. CrossRefPubMedGoogle Scholar
  4. Alarcon C, Leahy JL, Schuppin GT, Rhodes CJ (1995) Increased secretory demand rather than a defect in the proinsulin conversion mechanism causes hyperproinsulinemia in a glucose-infusion rat model of non-insulin-dependent diabetes mellitus. J Clin Invest 95(3):1032–1039. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Baghban Taraghdari Z, Imani R, Mohabatpour F (2019) A review on bioengineering approaches to insulin delivery: a pharmaceutical and engineering perspective. Macromol Biosci 19(4):e1800458. CrossRefPubMedGoogle Scholar
  6. Baker EN, Blundell TL, Cutfield JF, Cutfield SM, Dodson EJ, Dodson GG, Hodgkin DM, Hubbard RE, Isaacs NW, Reynolds CD, Sakabe K, Sakabe N, Vijayan NM (1988) The structure of 2Zn pig insulin crystals at 1.5 A resolution. Philos Trans R Soc Lond B Biol Sci 319(1195):369–456. CrossRefPubMedGoogle Scholar
  7. Beckers CJ, Balch WE (1989) Calcium and GTP: essential components in vesicular trafficking between the endoplasmic reticulum and Golgi apparatus. J Cell Biol 108(4):1245–1256. CrossRefPubMedGoogle Scholar
  8. Berson SA, Yalow RS (1959) Species-specificity of human anti-beef, pork insulin serum. J Clin Invest 38(11):2017–2025. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Boder ET, Wittrup KD (1997) Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol 15(6):553–557. CrossRefPubMedGoogle Scholar
  10. Bott RF, Oliveira WP (2007) Storage conditions for stability testing of pharmaceuticals in hot and humid regions. Drug Dev Ind Pharm 33(4):393–401. CrossRefPubMedGoogle Scholar
  11. Brandenburg D (2008) History and diagnostic significance of C-peptide. Exp Diabetes Res 2008:576862. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Brandenburg D, Wollmer A (1973) The effect of a non-peptide interchain crosslink on the reoxidation of reduced insulin. Hoppe-Seylers Z Physiol Chem 354(6):613–627PubMedGoogle Scholar
  13. Brandenburg D, Gattner H-G, Schermutzki W, Schüttler A, Uschkoreit J, Weimann J, Wollmer A (1977) Crosslinked insulins: preparation, properties, and applications. In: Friedman M (ed) Protein crosslinking: biochemical and molecular aspects. Springer, Boston, pp 261–282Google Scholar
  14. Brandt J, Andersen AS, Kristensen C (2001) Dimeric fragment of the insulin receptor alpha-subunit binds insulin with full holoreceptor affinity. J Biol Chem 276(15):12378–12384. CrossRefPubMedGoogle Scholar
  15. Brange J, Langkjoer L (1993) Insulin structure and stability. Pharm Biotechnol 5:315–350PubMedGoogle Scholar
  16. Brems DN, Brown PL, Nakagawa SH, Tager HS (1991) The conformational stability and flexibility of insulin with an additional intramolecular cross-link. J Biol Chem 266(3):1611–1615PubMedGoogle Scholar
  17. Brown H, Sanger F, Kitai R (1955) The structure of pig and sheep insulins. Biochem J 60(4):556–565. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Cara JF, Mirmira RG, Nakagawa SH, Tager HS (1990) An insulin-like growth factor I/insulin hybrid exhibiting high potency for interaction with the type I insulin-like growth factor and insulin receptors of placental plasma membranes. J Biol Chem 265(29):17820–17825PubMedGoogle Scholar
  19. Chance RE, Frank BH (1993) Research, development, production, and safety of biosynthetic human insulin. Diabetes Care 16(Suppl 3):133–142PubMedGoogle Scholar
  20. Chance RE, Kroeff EP, Hoffmann JA, Frank BH (1981) Chemical, physical, and biologic properties of biosynthetic human insulin. Diabetes Care 4(2):147–154. CrossRefPubMedGoogle Scholar
  21. Chang SG, Kim DY, Choi KD, Shin JM, Shin HC (1998) Human insulin production from a novel mini-proinsulin which has high receptor-binding activity. Biochem J 329(Pt 3):631–635. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Conlon JM (2001) Evolution of the insulin molecule: insights into structure-activity and phylogenetic relationships. Peptides 22(7):1183–1193PubMedGoogle Scholar
  23. Crea R, Kraszewski A, Hirose T, Itakura K (1978) Chemical synthesis of genes for human insulin. Proc Natl Acad Sci U S A 75(12):5765–5769. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Cutfield J, Cutfield S, Dodson E, Dodson G, Hodgkin D, Reynolds C (1981) Evidence concerning insulin activity from the structure of a cross-linked derivative. Hoppe-Seylers Z Physiol Chem 362(6):755–761PubMedGoogle Scholar
  25. Das M, Kobayashi M, Yamada Y, Sreeramulu S, Ramakrishnan C, Wakatsuki S, Kato R, Varadarajan R (2007) Design of disulfide-linked thioredoxin dimers and multimers through analysis of crystal contacts. J Mol Biol 372:1278–1292. CrossRefPubMedGoogle Scholar
  26. De Meyts P (2004) Insulin and its receptor: structure, function and evolution. BioEssays 26(12):1351–1362. CrossRefPubMedGoogle Scholar
  27. De Meyts P (2015) Insulin/receptor binding: the last piece of the puzzle? What recent progress on the structure of the insulin/receptor complex tells us (or not) about negative cooperativity and activation. BioEssays 37(4):389–397. CrossRefPubMedGoogle Scholar
  28. Denley A, Bonython ER, Booker GW, Cosgrove LJ, Forbes BE, Ward CW, Wallace JC (2004) Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Mol Endocrinol 18(10):2502–2512. CrossRefPubMedGoogle Scholar
  29. Derewenda U, Derewenda Z, Dodson EJ, Dodson GG, Bing X, Markussen J (1991) X-ray analysis of the single chain B29-A1 peptide-linked insulin molecule. A completely inactive analogue. J Mol Biol 220(2):425–433. CrossRefPubMedGoogle Scholar
  30. Deshpande AD, Harris-Hayes M, Schootman M (2008) Epidemiology of diabetes and diabetes-related complications. Phys Ther 88(11):1254–1264. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Dodson G, Steiner D (1998) The role of assembly in insulin's biosynthesis. Curr Opin Struct Biol 8(2):189–194PubMedGoogle Scholar
  32. Du Vigneaud V, Jensen H, Wintersteiner O (1928) Studies on crystalline insulin III. Further observations on the crystallization of insulin and on the nature of the sulfur linkage. The isolation of cystine and tyrosine from hydrolyzed crystalline insulin. J Pharmacol Exp Ther 32(5):367–385Google Scholar
  33. Du YC, Zhang YS, Lu ZX, Tsou CL (1961) Resynthesis of insulin from its glycyl and phenyalanyl chains. Sci Sin 10:84–104PubMedGoogle Scholar
  34. Dunn MF (1993) The insulin story. Insulin, molecular biology to pathology: edited by Frances M. Ashcroft and Stephen J. H. Ashcroft, IRL Press at Oxford University Press, 1992. UK£25.00 (xxi + 421 pages) ISBN 0 19 963229 4. Trends Biotechnol 11(12):525–526. CrossRefGoogle Scholar
  35. Dunn MF (2005) Zinc-ligand interactions modulate assembly and stability of the insulin hexamer—a review. Biometals 18(4):295–303. CrossRefPubMedGoogle Scholar
  36. Duttaroy A, Kanakaraj P, Osborn BL, Schneider H, Pickeral OK, Chen C, Zhang G, Kaithamana S, Singh M, Schulingkamp R, Crossan D, Bock J, Kaufman TE, Reavey P, Carey-Barber M, Krishnan SR, Garcia A, Murphy K, Siskind JK, McLean MA, Cheng S, Ruben S, Birse CE, Blondel O (2005) Development of a long-acting insulin analog using albumin fusion technology. Diabetes 54(1):251–258. CrossRefPubMedGoogle Scholar
  37. Easa N, Alany RG, Carew M, Vangala A (2019) A review of non-invasive insulin delivery systems for diabetes therapy in clinical trials over the past decade. Drug Discovery Today 24(2):440–451. CrossRefPubMedGoogle Scholar
  38. Faria AM, Weiner HL (2006) Oral tolerance: therapeutic implications for autoimmune diseases. Clin Dev Immunol 13(2-4):143–157. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Frank BH, Chance RE (1983) Two routes for producing human insulin utilizing recombinant DNA technology. Munch Med Wochenschr Suppl 1:S14–S20Google Scholar
  40. Freychet P, Brandenburg D, Wollmer A (1974) Receptor-binding assay of chemically modified insulins. Comparison with in vitro and in vivo bioassays. Diabetologia 10(1):1–5PubMedGoogle Scholar
  41. Fry A (2012) Insulin delivery device technology 2012: where are we after 90 years? J Diabetes Sci Technol 6(4):947–953. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr Diabetes Rev 9(1):25–53PubMedPubMedCentralGoogle Scholar
  43. Galloway JA, Hooper SA, Spradlin CT, Howey DC, Frank BH, Bowsher RR, Anderson JH (1992) Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience. Diabetes Care 15(5):666–692. CrossRefPubMedGoogle Scholar
  44. Geho WB (2014) The importance of the liver in insulin replacement therapy in insulin-deficient diabetes. Diabetes 63(5):1445–1447. CrossRefPubMedGoogle Scholar
  45. Glidden MD, Aldabbagh K, Phillips NB, Carr K, Chen YS, Whittaker J, Phillips M, Wickramasinghe NP, Rege N, Swain M, Peng Y, Yang Y, Lawrence MC, Yee VC, Ismail-Beigi F, Weiss MA (2018a) An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein. J Biol Chem 293(1):47–68. CrossRefPubMedGoogle Scholar
  46. Glidden MD, Yang Y, Smith NA, Phillips NB, Carr K, Wickramasinghe NP, Ismail-Beigi F, Lawrence MC, Smith BJ, Weiss MA (2018b) Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding. J Biol Chem 293(1):69–88. CrossRefPubMedGoogle Scholar
  47. Goeddel DV, Kleid DG, Bolivar F, Heyneker HL, Yansura DG, Crea R, Hirose T, Kraszewski A, Itakura K, Riggs AD (1979) Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc Natl Acad Sci U S A 76(1):106–110. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Grodsky GM (1965) Production of autoantibodies to insulin in man and rabbits. Diabetes 14:396–403PubMedGoogle Scholar
  49. Grodsky GM, Forsham PH (1966) Insulin and the pancreas. Annu Rev Physiol 28:347–380. CrossRefPubMedGoogle Scholar
  50. Gross DJ, Villa-Komaroff L, Kahn CR, Weir GC, Halban PA (1989) Deletion of a highly conserved tetrapeptide sequence of the proinsulin connecting peptide (C-peptide) inhibits proinsulin to insulin conversion by transfected pituitary corticotroph (AtT20) cells. J Biol Chem 264(36):21486–21490PubMedGoogle Scholar
  51. Guo H, Xiong Y, Witkowski P, Cui J, Wang LJ, Sun J, Lara-Lemus R, Haataja L, Hutchison K, Shan SO, Arvan P, Liu M (2014) Inefficient translocation of preproinsulin contributes to pancreatic beta cell failure and late-onset diabetes. J Biol Chem 289(23):16290–16302. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Hao C, Whittaker L, Whittaker J (2006) Characterization of a second ligand binding site of the insulin receptor. Biochem Biophys Res Commun 347(1):334–339. CrossRefPubMedGoogle Scholar
  53. Heath WF, Belagaje RM, Brooke GS, Chance RE, Hoffmann JA, Long HB, Reams SG, Roundtree C, Shaw WN, Slieker LJ, Sundell KL, DiMarchi RD (1992) (A-C-B) human proinsulin, a novel insulin agonist and intermediate in the synthesis of biosynthetic human insulin. J Biol Chem 267(1):419–425PubMedGoogle Scholar
  54. Hua Q (2010) Insulin: a small protein with a long journey. Protein & Cell 1(6):537–551. CrossRefGoogle Scholar
  55. Hua QX, Hu SQ, Jia W, Chu YC, Burke GT, Wang SH, Wang RY, Katsoyannis PG, Weiss MA (1998) Mini-proinsulin and mini-IGF-I: homologous protein sequences encoding non-homologous structures. J Mol Biol 277(1):103–118. CrossRefPubMedGoogle Scholar
  56. Hua QX, Nakagawa SH, Jia W, Huang K, Phillips NB, Hu SQ, Weiss MA (2008) Design of an active ultrastable single-chain insulin analog: synthesis, structure, and therapeutic implications. J Biol Chem 283(21):14703–14716. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Huang XF, Arvan P (1995) Intracellular transport of proinsulin in pancreatic beta-cells. Structural maturation probed by disulfide accessibility. J Biol Chem 270(35):20417–20423. CrossRefPubMedGoogle Scholar
  58. Huang Y, Liang Z, Feng Y (2001) The relationship between the connecting peptide of recombined single chain insulin and its biological function. Sci China, Ser C: Life Sci 44(6):593–600. CrossRefGoogle Scholar
  59. Humbel RE (1990) Insulin-like growth factors I and II. Eur J Biochem 190(3):445–462. CrossRefPubMedGoogle Scholar
  60. International Diabetes Federation (2017) IDF diabetes atlas-8th edition. International Diabetes Federation. Accessed 5 Jan 2019
  61. Ivanova MI, Sievers SA, Sawaya MR, Wall JS, Eisenberg D (2009) Molecular basis for insulin fibril assembly. Proc Natl Acad Sci U S A 106(45):18990–18995. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Jensen H, Wintersteiner O, du Vigneaud V (1928) Studies on crystalline insulin IV. the isolation of arginine, histidine, and leucine. J Pharmacol Exp Ther 32(5):387–396Google Scholar
  63. Jiracek J, Zakova L (2017) Structural perspectives of insulin receptor isoform-selective insulin analogs. Front Endocrinol (Lausanne) 8:167. CrossRefGoogle Scholar
  64. Johnson IS (1983) Human insulin from recombinant DNA technology. Science 219(4585):632–637PubMedGoogle Scholar
  65. Katsoyannis PG, Tometsko AM, Suzuki K, Tilak M (1964) Insulin peptides. Ix. The synthesis of the a-chain of insulin and its combination with natural b-chain to generate insulin activity. J Am Chem Soc 86:930–932Google Scholar
  66. Kaur ZP, Ochman AR, Mayer JP, Gelfanov VM, DiMarchi RD (2013) Discovery of high potency, single-chain insulin analogs with a shortened B-chain and nonpeptide linker. ACS Chem Biol 8(8):1822–1829. CrossRefPubMedGoogle Scholar
  67. Keen H, Glynne A, Pickup JC, Viberti GC, Bilous RW, Jarrett RJ, Marsden R (1980) Human insulin produced by recombinant DNA technology: safety and hypoglycaemic potency in healthy men. Lancet 2(8191):398–401PubMedGoogle Scholar
  68. Keller KJ (2003) Insulin storage and stability update. S D J Med 56(8):303–304PubMedGoogle Scholar
  69. Khafagy el S, Morishita M, Onuki Y, Takayama K (2007) Current challenges in non-invasive insulin delivery systems: a comparative review. Adv Drug Delivery Rev 59(15):1521–1546. CrossRefGoogle Scholar
  70. Kjeldsen T (2000) Yeast secretory expression of insulin precursors. Appl Microbiol Biotechnol 54(3):277–286PubMedGoogle Scholar
  71. Kobayashi M, Sasaoka T, Sugibayashi M, Iwanishi M, Shigeta Y (1989) Receptor binding and biologic activity of biosynthetic human insulin and mini-proinsulin produced by recombinant gene technology. Diabetes Res Clin Pract 7(1):25–28PubMedGoogle Scholar
  72. Kristensen C, Andersen AS, Hach M, Wiberg FC, Schaffer L, Kjeldsen T (1995) A single-chain insulin-like growth factor I/insulin hybrid binds with high affinity to the insulin receptor. Biochem J 305(Pt 3):981–986. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Kubiak T, Cowburn D (1986) Trypsin-catalysed formation of pig des-(23-63)-proinsulin from desoctapeptide-(B23-30)-insulin. Biochem J 234(3):665–670. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Laranjeira FO, de Andrade KRC, Figueiredo A, Silva EN, Pereira MG (2018) Long-acting insulin analogues for type 1 diabetes: an overview of systematic reviews and meta-analysis of randomized controlled trials. PloS One 13(4):e0194801. CrossRefPubMedPubMedCentralGoogle Scholar
  75. Lee HC, Kim SJ, Kim KS, Shin HC, Yoon JW (2000) Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 408(6811):483–488. CrossRefPubMedGoogle Scholar
  76. Lee HC, Kim KS, Shin HC (2009) Retraction. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 458(7238):660. CrossRefPubMedGoogle Scholar
  77. Libianto R, Ekinci EI (2019) New agents for the treatment of type 2 diabetes. Crit Care Clin 35(2):315–328. CrossRefPubMedGoogle Scholar
  78. Liu M, Ramos-Castaneda J, Arvan P (2003) Role of the connecting peptide in insulin biosynthesis. J Biol Chem 278(17):14798–14805. CrossRefPubMedGoogle Scholar
  79. Liu M, Li Y, Cavener D, Arvan P (2005) Proinsulin disulfide maturation and misfolding in the endoplasmic reticulum. J Biol Chem 280(14):13209–13212. CrossRefPubMedPubMedCentralGoogle Scholar
  80. Madison JH (1989) Manufacturing pharmaceuticals: Eli Lilly and Company, 1876-1948. Bus Econ Hist 18:72–78Google Scholar
  81. Mao R, Wu D, Wang Y (2016) Surface display on lactic acid bacteria without genetic modification: strategies and applications. Appl Microbiol Biotechnol 100(22):9407–9421. CrossRefPubMedGoogle Scholar
  82. Mao R, Wu D, Hu S, Zhou K, Wang M, Wang Y (2017) Secretory expression and surface display of a new and biologically active single-chain insulin (SCI-59) analog by lactic acid bacteria. Appl Microbiol Biotechnol 101(8):3259–3271. CrossRefPubMedGoogle Scholar
  83. Mao R, Chen Y, Wu Q, Zhang T, Diao E, Wu D, Wang M, Liu Y, Lu L, Chang X, Zheng Y, Wang Y (2019) Oral delivery of single-chain insulin (SCI-59) analog by bacterium-like particles (BLPs) induces oral tolerance and prevents autoimmune diabetes in NOD mice. Immunol Lett 214:37–44. CrossRefPubMedGoogle Scholar
  84. Markussen J (1985) Comparative reduction/oxidation studies with single chain des-(B30) insulin and porcine proinsulin. Int J Pept Protein Res 25(4):431–434PubMedGoogle Scholar
  85. Markussen J, Jorgensen KH, Sorensen AR, Thim L (1985) Single chain des-(B30) insulin. Intramolecular crosslinking of insulin by trypsin catalyzed transpeptidation. Int J Pept Protein Res 26(1):70–77PubMedGoogle Scholar
  86. Mayer JP, Zhang F, DiMarchi RD (2007) Insulin structure and function. Biopolymers 88(5):687–713. CrossRefPubMedGoogle Scholar
  87. McAuley A, Jacob J, Kolvenbach C, Westland K, Jin Lee H, Brych S, Rehder D, Kleemann G, Brems DN, Matsumura M (2008) Contributions of a disulfide bond to the structure, stability, and dimerization of human IgG1 antibody CH3 domain. Protein Sci 17:95–106. CrossRefPubMedPubMedCentralGoogle Scholar
  88. McKern NM, Lawrence MC, Streltsov VA, Lou MZ, Adams TE, Lovrecz GO, Elleman TC, Richards KM, Bentley JD, Pilling PA, Hoyne PA, Cartledge KA, Pham TM, Lewis JL, Sankovich SE, Stoichevska V, Da Silva E, Robinson CP, Frenkel MJ, Sparrow LG, Fernley RT, Epa VC, Ward CW (2006) Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature 443(7108):218–221. CrossRefPubMedGoogle Scholar
  89. Meetoo D, McGovern P, Safadi R (2007) An epidemiological overview of diabetes across the world. Br J Nurs 16(16):1002–1007. CrossRefPubMedGoogle Scholar
  90. Meienhofer J, Schnabel E, Bremer H, Brinkhoff O, Zabel R, Sroka W, Klostermayer H, Brandenburg D, Okuda T, Zahn H (1963) Synthesis of insulin chains and their combination to insulin-active preparations. Z Naturforsch, B 18:1120–1121Google Scholar
  91. Melo KFS, Bahia LR, Pasinato B, Porfirio GJM, Martimbianco AL, Riera R, Calliari LEP, Minicucci WJ, Turatti LAA, Pedrosa HC, Schaan BD (2019) Short-acting insulin analogues versus regular human insulin on postprandial glucose and hypoglycemia in type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetol Metab Syndr 11:2–13. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GKW, Smith BJ, Watson CJ, Žáková L, Kletvíková E, Jiráček J, Chan SJ, Steiner DF, Dodson GG, Brzozowski AM, Weiss MA, Ward CW, Lawrence MC (2013) How insulin engages its primary binding site on the insulin receptor. Nature 493:241–245. CrossRefPubMedPubMedCentralGoogle Scholar
  93. Min CY, Qiao ZS, Feng YM (2004) Unfolding of human proinsulin. Intermediates and possible role of its C-peptide in folding/unfolding. Eur J Biochem 271(9):1737–1747. CrossRefPubMedGoogle Scholar
  94. Moroder L, Musiol HJ (2017) Insulin-from its discovery to the industrial synthesis of modern insulin analogues. Angew Chem, Int Ed Engl 56(36):10656–10669. CrossRefGoogle Scholar
  95. Nakagawa SH, Tager HS (1989) Perturbation of insulin-receptor interactions by intramolecular hormone cross-linking. Analysis of relative movement among residues A1, B1, and B29. J Biol Chem 264(1):272–279PubMedGoogle Scholar
  96. Ng DT, Sarkar CA (2011) Nisin-inducible secretion of a biologically active single-chain insulin analog by Lactococcus lactis NZ9000. Biotechnol Bioeng 108(8):1987–1996. CrossRefPubMedGoogle Scholar
  97. Nicol DS, Smith LF (1960) Amino-acid sequence of human insulin. Nature 187:483–485PubMedGoogle Scholar
  98. Okun MM, Shields D (1992) Translocation of preproinsulin across the endoplasmic reticulum membrane. The relationship between nascent polypeptide size and extent of signal recognition particle-mediated inhibition of protein synthesis. J Biol Chem 267(16):11476–11482PubMedGoogle Scholar
  99. Owens DR, Matfin G, Monnier L (2014) Basal insulin analogues in the management of diabetes mellitus: what progress have we made? Diabetes Metab Res Rev 30(2):104–119. CrossRefPubMedGoogle Scholar
  100. Pandyarajan V, Weiss MA (2012) Design of non-standard insulin analogs for the treatment of diabetes mellitus. Curr Diab Rep 12(6):697–704. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Patzelt C, Labrecque AD, Duguid JR, Carroll RJ, Keim PS, Heinrikson RL, Steiner DF (1978) Detection and kinetic behavior of preproinsulin in pancreatic islets. Proc Natl Acad Sci U S A 75(3):1260–1264. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez JC (2014) Metformin pharmacogenomics: current status and future directions. Diabetes 63(8):2590–2599. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 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 IM-9 lymphocytes and in vivo and in vitro in rats. J Biol Chem 260(26):13989–13994PubMedGoogle Scholar
  104. Phillips NB, Whittaker J, Ismail-Beigi F, Weiss MA (2012) Insulin fibrillation and protein design: topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir. J Diabetes Sci Technol 6(2):277–288. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Pingel M, Volund A (1972) Stability of insulin preparations. Diabetes 21(7):805–813PubMedGoogle Scholar
  106. Plavec TV, Berlec A (2019) Engineering of lactic acid bacteria for delivery of therapeutic proteins and peptides. Appl Microbiol Biotechnol 103(5):2053–2066. CrossRefPubMedGoogle Scholar
  107. Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS (2006) Regulation of the insulin gene by glucose and fatty acids. J Nutr 136(4):873–876. CrossRefPubMedPubMedCentralGoogle Scholar
  108. Powell SK, Orci L, Craik CS, Moore HP (1988) Efficient targeting to storage granules of human proinsulins with altered propeptide domain. J Cell Biol 106(6):1843–1851. CrossRefPubMedGoogle Scholar
  109. Qiao ZS, Guo ZY, Feng YM (2006) In vitro folding/unfolding of insulin/single-chain insulin. Protein Pept Lett 13(5):423–429PubMedGoogle Scholar
  110. Rajpal G, Liu M, Zhang Y, Arvan P (2009) Single-chain insulins as receptor agonists. Mol Endocrinol 23(5):679–688. CrossRefPubMedPubMedCentralGoogle Scholar
  111. Rolla AR, Rakel RE (2005) Practical approaches to insulin therapy for type 2 diabetes mellitus with premixed insulin analogues. Clin Ther 27(8):1113–1125. CrossRefPubMedGoogle Scholar
  112. Rosenfeld L (2002) Insulin: discovery and controversy. Clin Chem 48(12):2270–2288PubMedGoogle Scholar
  113. Ryle AP, Sanger F, Smith LF, Kitai R (1955) The disulphide bonds of insulin. Biochem J 60(4):541–556. CrossRefPubMedPubMedCentralGoogle Scholar
  114. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414(6865):799–806. CrossRefPubMedGoogle Scholar
  115. Sato A, Nishimura S, Ohkubo T, Kyogoku Y, Koyama S, Kobayashi M, Yasuda T, Kobayashi Y (1993) Three-dimensional structure of human insulin-like growth factor-I (IGF-I) determined by 1H-NMR and distance geometry. Int J Pept Protein Res 41(5):433–440PubMedGoogle Scholar
  116. Scapin G, Dandey VP, Zhang Z, Prosise W, Hruza A, Kelly T, Mayhood T, Strickland C, Potter CS, Carragher B (2018) Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis. Nature 556(7699):122–125. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Seino S, Seino M, Nishi S, Bell GI (1989) Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci U S A 86(1):114–118. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Sharma AK, Taneja G, Kumar A, Sahu M, Sharma G, Kumar A, Sardana S, Deep A (2019) Insulin analogs: Glimpse on contemporary facts and future prospective. Life Sci 219:90–99. CrossRefPubMedGoogle Scholar
  119. Sousa F, Castro P, Fonte P, Sarmento B (2015) How to overcome the limitations of current insulin administration with new non-invasive delivery systems. Ther Deliv 6(1):83–94. CrossRefPubMedGoogle Scholar
  120. Steiner DF (1967) Evidence for a precursor in the biosynthesis of insulin. Trans N Y Acad Sci 30(1):60–68PubMedGoogle Scholar
  121. Steiner DF (1978) On the role of the proinsulin C-peptide. Diabetes 27(Suppl 1):145–148. CrossRefPubMedGoogle Scholar
  122. Steiner DF (1998) The proprotein convertases. Curr Opin Chem Biol 2(1):31–39PubMedGoogle Scholar
  123. Steiner DF, Cunningham D, Spigelman L, Aten B (1967) Insulin biosynthesis: evidence for a precursor. Science 157(3789):697–700Google Scholar
  124. Steiner DF, Chan SJ, Welsh JM, Kwok SC (1985) Structure and evolution of the insulin gene. Annu Rev Genet 19:463–484. CrossRefPubMedGoogle Scholar
  125. Storvick WO, Henry HJ (1968) Effect of storage temperature on stability of commercial insulin preparations. Diabetes 17(8):499–502PubMedGoogle Scholar
  126. Takiishi T, Korf H, Van Belle TL, Robert S, Grieco FA, Caluwaerts S, Galleri L, Spagnuolo I, Steidler L, Van Huynegem K, Demetter P, Wasserfall C, Atkinson MA, Dotta F, Rottiers P, Gysemans C, Mathieu C (2012) Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J Clin Invest 122(5):1717–1725. CrossRefPubMedPubMedCentralGoogle Scholar
  127. 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. Proc Natl Acad Sci U S A 83(18):6766–6770. CrossRefPubMedPubMedCentralGoogle Scholar
  128. Vajo Z, Fawcett J, Duckworth WC (2001) Recombinant DNA technology in the treatment of diabetes: insulin analogs. Endocr Rev 22(5):706–717. CrossRefPubMedGoogle Scholar
  129. Van Belle TL, Coppieters KT, von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91(1):79–118. CrossRefPubMedGoogle Scholar
  130. Vienberg SG, Bouman SD, Sorensen H, Stidsen CE, Kjeldsen T, Glendorf T, Sorensen AR, Olsen GS, Andersen B, Nishimura E (2011) Receptor-isoform-selective insulin analogues give tissue-preferential effects. Biochem J 440(3):301–308. CrossRefPubMedGoogle Scholar
  131. Vinther TN, Norrman M, Ribel U, Huus K, Schlein M, Steensgaard D, Pedersen T, Pettersson I, Ludvigsen S, Kjeldsen T, Jensen K, Hubalek F (2013) Insulin analog with additional disulfide bond has increased stability and preserved activity. Protein Sci 22:296–305. CrossRefPubMedGoogle Scholar
  132. Ward CW, Lawrence MC (2009) Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor. BioEssays 31(4):422–434. CrossRefPubMedGoogle Scholar
  133. Ward CW, Menting JG, Lawrence MC (2013) The insulin receptor changes conformation in unforeseen ways on ligand binding: sharpening the picture of insulin receptor activation. BioEssays 35(11):945–954PubMedGoogle Scholar
  134. Whittaker L, Hao C, Fu W, Whittaker J (2008) High-affinity insulin binding: insulin interacts with two receptor ligand binding sites. Biochemistry 47:12900–12909. CrossRefPubMedPubMedCentralGoogle Scholar
  135. Wolin SL, Walter P (1993) Discrete nascent chain lengths are required for the insertion of presecretory proteins into microsomal membranes. J Cell Biol 121(6):1211–1219. CrossRefPubMedGoogle Scholar
  136. Xin GLL, Khee YP, Ying TY, Chellian J, Gupta G, Kunnath AP, Nammi S, Collet T, Hansbro PM, Dua K, Chellappan DK (2019) Current status on immunological therapies for type 1 diabetes mellitus. Curr Diabetes Rep 19(5):22–10. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life ScienceHuaiyin Normal UniversityHuai’anChina
  2. 2.Huai’an First People’s HospitalNanjing Medical UniversityHuai’anChina
  3. 3.State Key Laboratory of Virology, College of Life SciencesWuhan UniversityWuhanChina

Personalised recommendations