REFERENCES
1. Steiner, D.F. 1967. Evidence for a precursor in the biosynthesis of insulin. Trans. N. Y. Acad. Sci. 30:60-68.
2. Adams, M.J., Blundell, T.L., Dodson, E.J., Dodson, G.G., Vijayan, M., Baker, E.N., Hardine, M.M., Hodgkin, D.C., Rimer, B., and Sheet, S. 1969. Structure of rhombohedral 2 zinc insulin crystals. Nature 224:491-495.
3. Blundell, T.L., Cutfield, J.F., Cutfield, S.M., Dodson, E.J., Dodson, G.G., Hodgkin, D.C., Mercola, D.A., and Vijayan, M. 1971. Atomic positions in rhombohedral 2-zinc insulin crystals. Nature 231:506-511.
4. Brange, J., Ribel, U., Hansen, J.F., Dodson, G., Hansen, M.T., Havelund, S., Melberg, S.G., Norris, F., Norris, K., and Snel, L. 1988. Monomeric insulins obtained by protein engineering and their medical implications. Nature 333:679-682.
5. Brange, J., and Vølund, A. 1999. Insulin analogs with improved pharmacokinetic profiles. Adv. Drug Deliv. Rev. 35:307-335.
6. Hirsch, I.B. 2005. Insulin analogues. N. Engl. J. Med. 352:174-183.
7. Bell, G.I., Pictet, R.L., Rutter, W.J., Cordell, B., Tischer, E., and Goodman, H.M. 1980. Sequence of the human insulin gene. Nature 284:26-32.
8. Steiner, D.F., Tager, H.S., Chan, S.J., Nanjo, K., Sanke, T., and Rubenstein, A.H. 1990. Lessons learned from molecular biology of insulin-gene mutations. Diabetes Care 13:600-609.
9. Stoy, J., Edghill, E.L., Flanagan, S.E., Ye, H., Paz, V.P., Pluzhnikov, A., Below, J.E., Hayes, M.G., Cox, N.J., Lipkind, G.M., et al. 2007. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc. Natl. Acad. Sci. U. S. A. 104:15040-15044.
10. Weiss, M.A. 2013. Diabetes mellitus due to the toxic misfolding of proinsulin variants. FEBS Lett. 587:1942-1950.
11. Greeley, S.A., Tucker, S.E., Naylor, R.N., Bell, G.I., and Philipson, L.H. 2010. Neonatal diabetes mellitus: a model for personalized medicine. Trends Endocrinol. Metab. 21:464-472.
12. Liu, M., Hodish, I., Haataja, L., Lara-Lemus, R., Rajpal, G., Wright, J., and Arvan, P. 2010. Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. Trends Endocrinol. Metab. 21:652-659.
13. De Meyts, P., and Whittaker, J. 2002. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat. Rev. Drug Discov. 1:769-783.
14. Greeley, S.A., Naylor, R.N., Philipson, L.H., and Bell, G.I. 2011. Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment. Curr. Diab. Rep. 11:519-532.
15. Scott, E.L. 1912. On the influence of intravenous injections of an extract of the pancreas on experimental pancreatic diabetes. Am. J. Physiol. 29:306-310.
16. Duvillie, B., Cordonnier, N., Deltour, L., Dandoy-Dron, F., Itier, J.M., Monthioux, E., Jami, J., Joshi, R.L., and Bucchini, D. 1997. Phenotypic alterations in insulin-deficient mutant mice. Proc. Natl. Acad. Sci. U. S. A. 94:5137-5140.
17. Jonsson, J., Carlsson, L., Edlund, T., and Edlund, H. 1994. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606-609.
18. Schӓfer, E.A. 1916. The Endocrine Organs: An introduction to the study of internal secretion . London: Longmans, Green, and Co. 27 pp.
19. Bliss, M., editor. 1982. The discovery of insulin . Chicago, Illinois: University of Chicago Press. 93-99 pp.
20. Nandi, A., Kitamura, T., Kahn, C.R., and Accili, D. 2004. Mouse models of insulin resistance. Physiol. Rev. 84:623-647.
21. Leslie, R.D.G., and Robbins, D.C. 1995. Diabetes: Clinical Science in Practice : Cambridge University Press. 492 pp.
22. Von Mering, J., and Minkowski, O. 1890. Diabetes mellitus nach pankreas exterpation. Arch. Exp. Path. Pharmacol. 26:371.
23. Barron, M. 1920. The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis. In Surgery, gynecology, and obstetrics . Chicago: The Surgical Publishing Company of Chicago. 437-448.
24. Langerhans, P. 1869. Beitrage zur Mikroskopischen Anatomie der Bauchspeicheldruse. In Institute of Pathology . Berlin: University of Berlin. 32.
25. Banting, F.G., and Best, C.H. 1922. The internal secretion of the pancreas. J. Lab. Clin. Med. 7.
26. Ullrich, K.J. 1979. Sugar, amino acid, and Na + cotransport in the proximal tubule. Annu. Rev. Physiol. 41:181-195.
27. Kahn, C.R., Neville, D.M., and Roth, J. 1973. Insulin receptor interaction in the obese hyperglycemic mouse. A model of insulin resistance. J. Biol. Chem. 248:244-250.
28. Petruzzelli, L., Herrera, R., and Rosen, O.M. 1984. Insulin receptor is an insulin-dependent tyrosine protein kinase: copurification of insulin-binding activity and protein kinase activity to homogeneity from human placenta. Proc. Natl. Acad. Sci. U. S. A. 81:3327-3331.
29. Ullrich, A., Bell, J.R., Chen, E.Y., Herrera, R., Petruzelli, L.M., Dull, T.J., Gray, A., Coussens, L., Liao, Y.C., Tsubokawa, M., et al. 1985. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756-761.
30. Ward, C.W., and Lawrence, M.C. 2011. Landmarks in insulin research. Front. Endocrin. 2:1-11.
31. De Meyts, P. 2008. The insulin receptor: a prototype for dimeric, allosteric membrance receptors? Trends Biochem. Sci. 33:376-384.
32. Hopfer, U. 1987. Membrane transport mechanisms for hexoses and and amino acids in the small intestine. In Physiology of the Gastrointestinal Tract . L.R. Johnson, editor. New York: Raven Press. 1499-1526.
33. Haase, W., and Koepsell, H. 1989. Electron microscopic immunohistochemical localization of components of Na+-cotransporters along the rat nephron. Eur. J. Cell Biol. 48:360-374.
34. Rosholt, M.N., and King, P.A. 1995. Diabetes: Clinical science in practice. In Diabetes: Clinical science in practice . R.D.G. Leslie, and D.C. Robbins, editors. Cambridge, MA: Cambridge University Press. 77-95.
35. Fukumoto, H., Kayano, T., Buse, J.B., Edwards, Y., Pilch, P.F., Bell, G.I., and Seino, S. 1989. Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues. J. Biol. Chem. 264:7776-7779.
36. James, D.E., Strube, M., and Mueckler, M. 1989. Molecular cloning and characterization of an insulin-regulatable glucose transporter Nature (Lond) 338:83-87
37. Charron, M.J., and Kahn, B.B. 1990. Divergent molecular mechanisms for insulin-resistant glucose transport in muscle and adipose cells in vivo . J. Biol. Chem. 265:7994-8000.
38. Cushman, S.W., and Wardzala, L.J. 1980. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane. J. Biol. Chem. 255:4758-4762.
39. Kono, T., Suzuki, K., Dansey, L.E., Robinson, F.W., and Blevins, T.L. 1981. Energy-dependent and protein synthesis-independent recycling of the insulin-sensitive glucose transport mechanism in fat cells. J. Biol. Chem. 256:6400-6407.
40. Rosholt, M.N., King, P.A., and Horton, E.S. 1994. High-fat diet reduces glucose transporter responses to both insulin and exercise. Am. J. Physiol. 266:R95-101.
41. King, P.A., Betts, J.J., Horton, E.D., and Horton, E.S. 1993. Exercise, unlike insulin, promotes glucose transporter translocation in obese Zucker rat muscle. Am. J. Physiol. 265:R447-452.
42. Wheeler, T.J. 1988. Translocation of glucose transporters in response to anoxia in heart. J. Biol. Chem. 263:19447-19454.
43. Karnieli, E., Chernow, B., Hissin, P.J., Simpson, I.A., and Foley, J.E. 1986. Insulin stimulates glucose transport in isolated human adipose cells through a translocation of intracellular glucose transporters to the plasma membrane: a preliminary report. Horm. Metab. Res. 18:867-868.
44. Clark, A.E., Holman, G.D., and Kozka, I.J. 1991. Determination of the rates of appearance and loss of glucose transporters at the cell surface of rat adipose cells. Biochem. J. 278 ( Pt 1):235-241.
45. Baron, A.D., Brechtel, G., Wallace, P., and Edelman, S.V. 1988. Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am. J. Physiol. 255:E769-774.
46. Barnard, R.J., Lawani, L.O., Martin, D.A., Youngren, J.F., Singh, R., and Scheck, S.H. 1992. Effects of maturation and aging on the skeletal muscle glucose transport system. Am. J. Physiol. 262:E619-626.
47. Bourey, R.E., Koranyi, L., James, D.E., Mueckler, M., and Permutt, M.A. 1990. Effects of altered glucose homeostasis on glucose transporter expression in skeletal muscle of the rat. J. Clin. Invest. 86:542-547.
48. Klip, A., Ramlal, T., Bilan, P.J., Cartee, G.D., Gulve, E.A., and Holloszy, J.O. 1990. Recruitment of GLUT-4 glucose transporters by insulin in diabetic rat skeletal muscle. Biochem. Biophys. Res. Commun. 172:728-736.
49. Unger, R.H. 1991. Diabetic hyperglycemia: link to impaired glucose transport in pancreatic β cells. Science 251:1200-1205.
50. Thorens, B., Wu, Y.J., Leahy, J.L., and Weir, G.C. 1992. The loss of GLUT2 expression by glucose-unresponsive β cells of db/db mice is reversible and is induced by the diabetic environment. J. Clin. Invest. 90:77-85.
51. Kulkarni, R.N., Bruning, J.C., Winnay, J.N., Postic, C., Magnuson, M.A., and Kahn, C.R. 1999. Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329-339.
52. Kitamura, T., Kahn, C.R., and Accili, D. 2003. Insulin receptor knockout mice. Annu. Rev. Physiol. 65:313-332.
53. Braun, M., Ramracheya, R., and Rorsman, P. 2012. Autocrine regulation of insulin secretion. Diabetes Obes. Metab. 14 Suppl 3:143-151.
54. Baker, E.N., Blundell, T.L., Cutfield, J.F., Cutfield, S.M., Dodson, E.J., Dodson, G.G., Hodgkin, D.M., Hubbard, R.E., Isaacs, N.W., and Reynolds, C.D. 1988. The structure of 2Zn pig insulin crystals at 1.5 Å resolution. Philos. Trans. R. Soc. Lond. B Biol. Sci. 319:369-456.
55. Steiner, D.F. 1977. The Banting Memorial Lecture 1976. Insulin today. Diabetes 26:322-340.
56. Steiner, D.F. 1978. On the role of the proinsulin C-peptide. Diabetes 27 Suppl 1:145-148.
57. Dodson, G., and Steiner, D. 1998. The role of assembly in insulin's biosynthesis. Curr. Opin. Struct. Biol. 8:189-194.
58. Steiner, D.F. 2000. New aspects of proinsulin physiology and pathophysiology. J. Pediatr. Endocrinol. Metab. 13:229-239.
59. Seidah, N.G., and Prat, A. 2007. The proprotein convertases are potential targets in the treatment of dyslipidemia. J. Mol. Med. 85:685-696.
60. Yang, Y., Hua, Q.X., Liu, J., Shimizu, E.H., Choquette, M.H., Mackin, R.B., and Weiss, M.A. 2010. Solution structure of proinsulin: connecting domain flexibility and prohormone processing. J. Biol. Chem. 285:7847-7851.
61. Smith, B.J., Huang, K., Kong, G., Chan, S.J., Nakagawa, S., Menting, J.G., Hu, S.-Q., Whittaker, J., Steiner, D.F., Katsoyannis, P.G., et al. 2010. Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists. Proc. Natl. Acad. Sci. U. S. A. 107:6771-6776.
62. Menting, J.G., Whittaker, J., Margetts, M.B., Whittaker, L.J., Kong, G.K., Smith, B.J., Watson, C.J., Zakova, L., Kletvikova, E., Jiracek, J., et al. 2013. How insulin engages its primary binding site on the insulin receptor. Nature 493:241-245.
63. Abel, J.J. 1926. Crystalline Insulin. Proc. Natl. Acad. Sci. U. S. A. 12:132-136.
64. Murnaghan, J.H., and Talalay, P. 1967. John Jacob Abel and the crystallization of insulin. Perspect. Biol. Med. 10:334-380.
65. Jensen, H., and Evans, J., E. A. . 1935. Studies on crystalline insulin: xviii. the nature of the free amino groups in insulin and the isolation of phenylalanine and proline from crystalline insulin J. Biol. Chem. 108 1-9.
66. Ryle, A.P., Sanger, F., Smith, L.F., and Kitai, R. 1955. The disulphide bonds of insulin. Biochem. J. 60:541-556.
67. Sanger, F. 1959. Chemistry of insulin; determination of the structure of insulin opens the way to greater understanding of life processes. Science 129:1340-1344.
68. Chance, R.E., Ellis, R.M., and Bromer, W.W. 1968. Porcine proinsulin: characterization and amino acid sequence. Science 161:165-167.
69. Harfenist, E.J., and Craig, L.C. 1952. The molecular weight of insulin. J. Am. Chem. Soc. 74 J. Am. Chem. Soc.,.
70. Steiner, D.F., and Oyer, P.E. 1967. The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma. Proc. Natl. Acad. Sci. U. S. A. 57:473-480.
71. Steiner, D.F., Cunningham, D., Spigelman, L., and Aten, B. 1967. Insulin biosynthesis: evidence for a precursor. Science 157:697-700.
72. Steiner, D.F., Clark, J.L., Nolan, C., Rubenstein, A.H., Margoliash, E., Aten, B., and Oyer, P.E. 1969. Proinsulin and the biosynthesis of insulin. Recent Prog. Horm. Res. 25:207-282.
73. Clark, J.L., Cho, S., Rubenstein, A.H., and Steiner, D.F. 1969. Isolation of a proinsulin connecting peptide fragment (C-peptide) from bovine and human pancreas. Biochem. Biophys. Res. Commun. 35:456-461.
74. Brown, H., Sangar, F., and Kitai, R. 1955. The structure of pig and sheep insulins. Biochem. J. 60:555-565.
75. Chan, S.J., Keim, P., and Steiner, D.F. 1976. Cell-free synthesis of rat preproinsulins: characterization and partial amino acid sequence determination. Proc. Natl. Acad. Sci. U. S. A. 73:1964-1968.
76. Lomedico, P.T., Chan, S.J., Steiner, D.F., and Saunders, G.F. 1977. Immunological and chemical characterization of bovine preproinsulin. J. Biol. Chem. 252:7971-7978.
77. Steiner, D.F., Chan, S.J., Welsh, J.M., Nielsen, D., Michael, J., Tager, H.S., and Rubenstein, A.H. 1986. Models of peptide biosynthesis: the molecular and cellular basis of insulin production. Clin. Invest. Med. 9:328-336.
78. Sanders, S.L., and Schekman, R. 1992. Polypeptide translocation across the endoplasmic reticulum membrane. J. Biol. Chem. 267:13791-13794.
79. Kreil, G. 1981. Transfer of proteins across membranes. Annu. Rev. Biochem. 50:317-348.
80. Steiner, D.F., editor. 2001. The prohormone convertases and precursor processing in protein biosynthesis : Academic Press, New York. 163-198 pp.
81. Liu, M., Lara-Lemus, R., Shan, S.O., Wright, J., Haataja, L., Barbetti, F., Guo, H., Larkin, D., and Arvan, P. 2012. Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes. Diabetes 61:828-837.
82. Walter, P., Gilmore, R., and Blobel, G. 1984. Protein translocation across the endoplasmic reticulum. Cell 38:5-8.
83. Patzelt, C., Chan, S.J., Duguid, J., Hortin, G., Keim, P., Heinrikson, R.L., and Steiner, D.F. 1978. In Regulatory proteolytic enzymes and their inhibitors . S. Magnusson, M. Ottensen, B. Foltmann, K. Dano, and H. Neurath, editors. New York: Pergamon. p 69 Pergaman, New Yor.
84. Steiner, D.F., Clark, J.L., Nolan, C., Rubenstein, A.H., Margoliash, E., Melani, F., and Oyer, P.E., editors. 1970. The biosynthesis of insulin and some speculation regarding the pathogenesis of human diabetes . New York: John Wiley & Sons. 57 pp.
85. Steiner, D.F., Kemmler, W., Clark, J.L., Oyer, P.E., and Rubenstein, A.H., editors. 1972. The biosynthesis of insulin . Baltimore: Williams & Wilkins. 175-198 pp.
86. Frank, B.H., and Veros, A.J. 1968. Physical studies on proinsulin-association behavior and conformation in solution. Biochem. Biophys. Res. Commun. 32:155-160.
87. Rubenstein, A.H., Melani, F., Pilkis, S., and Steiner, D.F. 1969. Proinsulin. Secretion, metabolism, immunological and biological properties. Postgrad. Med. J. 45:Suppl:476-481.
88. Fullerton, W.W., Potter, R., and Low, B.W. 1970. Proinsulin: Crystallization and preliminary x-ray diffraction studies. Proc. Natl. Acad. Sci. U. S. A. 66:1213-1219.
89. Freychet, P., Brandenburg, D., and Wollmer, A. 1974. Receptor-binding assay of chemically modified insulins. Comparison with in vitro and in vivo bioassays. Diabetologia 10:1-5.
90. Orci, L., Ravazzola, M., Amherdt, M., Madsen, O., Vassalli, J.D., and Perrelet, A. 1985. Direct identification of prohormone conversion site in insulin-secreting cells. Cell 42:671-681.
91. Orci, L., Glick, B.S., and Rothman, J.E. 1986. A new type of coated vesicular carrier that appears not to contain clathrin: its possible role in protein transport within the Golgi stack. Cell 46:171-184.
92. Wattenberg, B.W., and Rothman, J.E. 1986. Multiple cytosolic components promote intra-Golgi protein transport. Resolution of a protein acting at a late stage, prior to membrane fusion. J. Biol. Chem. 261:2208-2213.
93. Nagamatsu, S., Bolaffi, J.L., and Grodsky, G.M. 1987. Direct effects of glucose on proinsulin synthesis and processing during desensitization. Endocrinology 120:1225-1231.
94. Kemmler, W., Peterson, J.D., and Steiner, D.F. 1971. Studies on the conversion of proinsulin to insulin. I. Conversion in vitro with trypsin and carboxypeptidase B. J. Biol. Chem. 246:6786-6791.
95. Nolan, C., Margoliash, E., Peterson, J.D., and Steiner, D.F. 1971. The structure of bovine proinsulin. J. Biol. Chem. 246:2780-2795.
96. Oyer, P.E., Cho, S., Peterson, J.D., and Steiner, D.F. 1971. Studies on human proinsulin. Isolation and amino acid sequence of the human pancreatic C-peptide. J. Biol. Chem. 246:1375-1386.
97. Busse, W.D., and Gattner, H.G. 1973. Selective cleavage of one disulfide bond in insulin: preparation and properties of insulin A7-B7-di-S-sulfonate. Hoppe Seylers Z Physiol. Chem. 354:147-155.
98. Tager, H.S., Emdin, S.O., Clark, J.L., and Steiner, D.F. 1973. Studies on the conversion of proinsulin to insulin. II. Evidence for a chymotrypsin-like cleavage in the connecting peptide region of insulin precursors in the rat. J. Biol. Chem. 248:3476-3482.
99. Davidson, H.W., Rhodes, C.J., and Hutton, J.C. 1988. Intraorganellar calcium and pH control proinsulin cleavage in the pancreatic β cell via two distinct site-specific endopeptidases. Nature 333:93-96.
100. Rhodes, C.J., Lincoln, B., and Shoelson, S.E. 1992. Preferential cleavage of des-31,32-proinsulin over intact proinsulin by the insulin secretory granule type II endopeptidase. Implication of a favored route for prohormone processing. J. Biol. Chem. 267:22719-22727.
101. Julius, D., Brake, A., Blair, L., Kunisawa, R., and Thorner, J. 1984. Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-α-factor. Cell 37:1075-1089.
102. Fuller, R.S., Sterne, R.E., and Thorner, J. 1988. Enzymes required for yeast prohormone processing. Annu. Rev. Physiol. 50:345-362.
103. Mizuno, K., Nakamura, T., Ohshima, T., Tanaka, S., and Matsuo, H. 1988. Yeast KEX2 genes encodes an endopeptidase homologous to subtilisin-like serine proteases. Biochem. Biophys. Res. Commun. 156:246-254.
104. Smeekens, S.P., and Steiner, D.F. 1990. Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J. Biol. Chem. 265:2997-3000.
105. Smeekens, S.P., Avruch, A.S., LaMendola, J., Chan, S.J., and Steiner, D.F. 1991. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proc. Natl. Acad. Sci. U. S. A. 88:340-344.
106. Seidah, N.G., Marcinkiewicz, M., Benjannet, S., Gaspar, L., Beaubien, G., Mattei, M.G., Lazure, C., Mbikay, M., and Chretien, M. 1991. Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Mol. Endocrinol. 5:111-122.
107. Shennan, K.I., Smeekens, S.P., Steiner, D.F., and Docherty, K. 1991. Characterization of PC2, a mammalian Kex2 homologue, following expression of the cDNA in microinjected Xenopus oocytes. FEBS Lett. 284:277-280.
108. Bailyes, E.M., Shennan, K.I., Seal, A.J., Smeekens, S.P., Steiner, D.F., Hutton, J.C., and Docherty, K. 1992. A member of the eukaryotic subtilisin family (PC3) has the enzymic properties of the type 1 proinsulin-converting endopeptidase. Biochem. J. 285 (Pt 2):391-394.
109. Zhou, A., Webb, G., Zhu, X., and Steiner, D.F. 1999. Proteolytic processing in the secretory pathway. J. Biol. Chem. 274:20745-20748.
110. Seidah, N.G., and Prat, A. 2012. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov 11:367-383.
111. Smeekens, S.P., Montag, A.G., Thomas, G., Albiges-Rizo, C., Carroll, R., Benig, M., Phillips, L.A., Martin, S., Ohagi, S., Gardner, P., et al. 1992. Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3. Proc. Natl. Acad. Sci. U. S. A. 89:8822-8826.
112. Tanaka, S., Kurabuchi, S., Mochida, H., Kato, T., Takahashi, S., Watanabe, T., and Nakayama, K. 1996. Immunocytochemical localization of prohormone convertases PC1/PC3 and PC2 in rat pancreatic islets. Arch. Histol. Cytol. 59:261-271.
113. Skidgel, R.A. 1988. Basic carboxypeptidases: regulators of peptide hormone activity. Trends Pharmacol. Sci. 9:299-304.
114. Fricker, L.D., Evans, C.J., Esch, F.S., and Herbert, E. 1986. Cloning and sequence analysis of cDNA for bovine carboxypeptidase E. Nature 323:461-464.
115. Furuta, M., Carroll, R., Martin, S., Swift, H.H., Ravazzola, M., Orci, L., and Steiner, D.F. 1998. Incomplete processing of proinsulin to insulin accompanied by elevation of Des-31,32 proinsulin intermediates in islets of mice lacking active PC2. J. Biol. Chem. 273:3431-3437.
116. Steiner, D.F. 2011. Adventures with insulin in the islets of Langerhans. J Biol Chem 286:17399-17421.
117. Zhu, X., Zhou, A., Dey, A., Norrbom, C., Carroll, R., Zhang, C., Laurent, V., Lindberg, I., Ugleholdt, R., Holst, J.J., et al. 2002. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl. Acad. Sci. U. S. A. 99:10293-10298.
118. Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J.J., Carroll, R.J., Ravazzola, M., Orci, L., Furuta, H., and Steiner, D.F. 1997. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Natl. Acad. Sci. U. S. A. 94:6646-6651.
119. Muller, L., Zhu, X., and Lindberg, I. 1997. Mechanism of the facilitation of PC2 maturation by 7B2: involvement in ProPC2 transport and activation but not folding. J Cell Biol 139:625-638.
120. Westphal, C.H., Muller, L., Zhou, A., Zhu, X., Bonner-Weir, S., Schambelan, M., Steiner, D.F., Lindberg, I., and Leder, P. 1999. The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease. Cell 96:689-700.
121. Greider, M.H., Howell, S.L., and Lacy, P.E. 1969. Isolation and properties of secretory granules from rat islets of Langerhans. II. Ultrastructure of the β granule. J. Cell Biol. 41:162-166.
122. Lange, R.H. 1974. Crystalline islet B-granules in the grass snake (Natrix natrix (L.)): tilting experiments in the electron microscope. J. Ultrastruct. Res. 46:301-307.
123. Michael, J., Carroll, R., Swift, H.H., and Steiner, D.F. 1987. Studies on the molecular organization of rat insulin secretory granules. J. Biol. Chem. 262:16531-16535.
124. Lemaire, K., Ravier, M.A., Schraenen, A., Creemers, J.W., Van de Plas, R., Granvik, M., Van Lommel, L., Waelkens, E., Chimienti, F., Rutter, G.A., et al. 2009. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc. Natl. Acad. Sci. U. S. A. 106:14872-14877.
125. Steiner, D.F. 1973. Cocrystallization of proinsulin and insulin. Nature 243:528-530.
126. Frank, B.H., and Veros, A.J. 1970. Interaction of zinc with proinsulin. Biochem. Biophys. Res. Commun. 38:284-289.
127. Grant, P.T., Coombs, T.L., and Frank, B.H. 1972. Differences in the nature of the interaction of insulin and proinsulin with zinc. Biochem. J. 126:433-440.
128. Howell, S.L., Tyhurst, M., Duvefelt, H., Andersson, A., and Hellerstrom, C. 1978. Role of zinc and calcium in the formation and storage of insulin in the pancreatic β-cell. Cell Tissue Res. 188:107-118.
129. Kemmler, W., Steiner, D.F., and Borg, J. 1973. Studies on the conversion of proinsulin to insulin. 3. Studies in vitro with a crude secretion granule fraction isolated from rat islets of Langerhans. J. Biol. Chem. 248:4544-4551.
130. Steiner, D.F., and Rubenstein, A. 1973. In Proceedings of the 8th Midwest Conference on Endocrinology and Metabolism . F.M. Matschinsky, R. Fertel, J. Kotler-Brajtburg, S. Stillings, J. Ellerman, F. Raybaud, J.H. Thurston, R.P. Breitenbach, and X.J. Mussachia, editors: University of Missouri. 43-59.
131. Prentki, M., and Matschinsky, F.M. 1987. Ca 2+ , cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev 67:1185-1248.
132. Hughes, S.J., and Ashcroft, S.H.J. 1992. In Nutrient regulation of insulin secretion . P.R. Flatt, editor. Colchester, England: Portland Press. 271-289
133. Nielsen, D.A., Welsh, M., Casadaban, M.J., and Steiner, D.F. 1985. Control of insulin gene expression in pancreatic β-cells and in an insulin-producing cell line, RIN-5F cells. I. Effects of glucose and cyclic AMP on the transcription of insulin mRNA. J. Biol. Chem. 260:13585-13589.
134. Welsh, M., Nielsen, D.A., MacKrell, A.J., and Steiner, D.F. 1985. Control of insulin gene expression in pancreatic β-cells and in an insulin-producing cell line, RIN-5F cells. II. Regulation of insulin mRNA stability. J. Biol. Chem. 260:13590-13594.
135. Rabinovitch, A., Blondel, B., Murray, T., and Mintz, D.H. 1980. Cyclic adenosine-3',5'-monophosphate stimulates islet B cell replication in neonatal rat pancreatic monolayer cultures. J. Clin. Invest. 66:1065-1071.
136. Swenne, I. 1982. Effects of cyclic AMP on DNA replication and protein biosynthesis in fetal rat islets of Langerhans maintained in tissue culture. Biosci. Rep. 2:867-876.
137. Tanese, T., Lazarus, N.R., Devrim, S., and Recant, L. 1970. Synthesis and release of proinsulin and insulin by isolated rat islets of Langerhans. J. Clin. Invest. 49:1394-1404.
138. Rhodes, C.J., and Halban, P.A. 1987. Newly synthesized proinsulin/insulin and stored insulin are released from pancreatic B cells predominantly via a regulated, rather than a constitutive, pathway. J. Cell Biol. 105:145-153.
139. Kelly, R.B. 1985. Pathways of protein secretion in eukaryotes. Science 230:25-32.
140. Valverde, I., Garcia-Morales, P., Ghiglione, M., and Malaisse, W.J. 1983. The stimulus-secretion coupling of glucose-induced insulin release. LIII. Calcium-dependency of the cyclic AMP response to nutrient secretagogues. Horm. Metab. Res. 15:62-68.
141. Holst, J.J., Orskov, C., Nielsen, O.V., and Schwartz, T.W. 1987. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 211:169-174.
142. Rajan, S., Torres, J., Thompson, M.S., and Philipson, L.H. 2012. SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion. Am. J. Physiol. Endocrinol. Metab. 302:E714-723.
143. Howell, S.L., Jones, P.M., and Persaud, S.J. 1994. Regulation of insulin secretion: the role of second messengers. Diabetologia 37 Suppl 2:S30-35.
144. Berggren, P.O., Rorsman, P., and Efendic, S. 1992. In Nutrient regulation of insulin secretion . P.R. Flatt, editor. Colchester, England: Portland Press. 289-318
145. Persaud, S.J., Jones, P.M., and Howell, S.L. 1989. Effects of Bordetella pertussis toxin on catecholamine inhibition of insulin release from intact and electrically permeabilized rat islets. Biochem. J. 258:669-675.
146. Rorsman, P., and Braun, M. 2013. Regulation of insulin secretion in human pancreatic islets. Annu. Rev. Physiol. 75:155-179.
147. Fridlyand, L.E., and Philipson, L.H. 2011. Coupling of metabolic, second messenger pathways and insulin granule dynamics in pancreatic b -cells: a computational analysis. Prog. Biophys. Mol. Biol. 107:293-303.
148. Fridlyand, L.E., Jacobson, D.A., and Philipson, L.H. 2013. Ion channels and regulation of insulin secretion in human b -cells: a computational systems analysis. Islets 5:1-15.
149. Tabei, S.M., Burov, S., Kim, H.Y., Kuznetsov, A., Huynh, T., Jureller, J., Philipson, L.H., Dinner, A.R., and Scherer, N.F. 2013. Intracellular transport of insulin granules is a subordinated random walk. Proc. Natl. Acad. Sci. U. S. A. 110:4911-4916.
150. Polonsky, K.S. 1995. Lilly Lecture 1994. The β-cell in diabetes: from molecular genetics to clinical research. Diabetes 44:705-717.
151. Taylor, S.I., Accili, D., and Imai, Y. 1994. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes 43:735-740.
152. Turner, R.C., Hattersley, A.T., Shaw, J.T., and Levy, J.C. 1995. Type II diabetes: clinical aspects of molecular biological studies. Diabetes 44:1-10.
153. Dean, P.M., and Matthews, E.K. 1968. Electrical activity in pancreatic islet cells. Nature 219:389-390.
154. Dean, P.M., and Matthews, E.K. 1970. Glucose-induced electrical activity in pancreatic islet cells. J. Physiol. 210:255-264.
155. Ashcroft, F.M., Harrison, D.E., and Ashcroft, S.J. 1984. Glucose induces closure of single potassium channels in isolated rat pancreatic β-cells. Nature 312:446-448.
156. Cook, D.L., and Hales, C.N. 1984. Intracellular ATP directly blocks K + channels in pancreatic B-cells. Nature 311:271-273.
157. Cook, D.L., Ikeuchi, M., and Fujimoto, W.Y. 1984. Lowering of pHi inhibits Ca2+-activated K+ channels in pancreatic B-cells. Nature 311:269-271.
158. McTaggart, J.S., Clark, R.H., and Ashcroft, F.M. 2010. The role of the KATP channel in glucose homeostasis in health and disease: more than meets the islet. J. Physiol. 588:3201-3209.
159. Doyle, D.A., Morais Cabral, J., Pfuetzner, R.A., Kuo, A., Gulbis, J.M., Cohen, S.L., Chait, B.T., and MacKinnon, R. 1998. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69-77.
160. Nishida, M., and MacKinnon, R. 2002. Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution. Cell 111:957-965.
161. Ashcroft, F.M., and Rorsman, P. 1990. ATP-sensitive K + channels: a link between B-cell metabolism and insulin secretion. Biochem. Soc. Trans. 18:109-111.
162. Seino, S., Iwanaga, T., Nagashima, K., and Miki, T. 2000. Diverse roles of K ATP channels learned from K ir 6.2 genetically engineered mice. Diabetes 49:311-318.
163. Huopio, H., Shyng, S.L., Otonkoski, T., and Nichols, C.G. 2002. K ATP channels and insulin secretion disorders. Am. J. Physiol. Endocrinol. Metab. 283:E207-216.
164. Stoffel, M., Espinosa, R., 3rd, Powell, K.L., Philipson, L.H., Le Beau, M.M., and Bell, G.I. 1994. Human G-protein-coupled inwardly rectifying potassium channel (GIRK1) gene (KCNJ3): localization to chromosome 2 and identification of a simple tandem repeat polymorphism. Genomics 21:254-256.
165. Reuveny, E., Slesinger, P.A., Inglese, J., Morales, J.M., Iniguez-Lluhi, J.A., Lefkowitz, R.J., Bourne, H.R., Jan, Y.N., and Jan, L.Y. 1994. Activation of the cloned muscarinic potassium channel by G protein β γ subunits. Nature 370:143-146.
166. Philipson, L.H., Kuznetsov, A., Toth, P.T., Murphy, J.F., Szabo, G., Ma, G.H., and Miller, R.J. 1995. Functional expression of an epitope-tagged G protein-coupled K + channel (GIRK1). J. Biol. Chem. 270:14604-14610.
167. Aguilar-Bryan, L., and Bryan, J. 1999. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr. Rev. 20:101-135.
168. Katz, B., and Miledi, R. 1965. The effect of calcium on acetylcholine release from motor nerve terminals. Proc. R. Soc. Lond. B Biol. Sci. 161:496-503.
169. Douglas, W.W. 1968. Stimulus-secretion coupling: the concept and clues from chromaffin and other cells. Br. J. Pharmacol. 34:451-474.
170. Wollheim, C.B., and Sharp, G.W. 1981. Regulation of insulin release by calcium. Physiol. Rev. 61:914-973.
171. Rorsman, P., Braun, M., and Zhang, Q. 2012. Regulation of calcium in pancreatic a - and b -cells in health and disease. Cell Calcium 51:300-308.
172. Tsien, R.W., Ellinor, P.T., and Horne, W.A. 1991. Molecular diversity of voltage-dependent Ca 2+ channels. Trends Pharmacol. Sci. 12:349-354.
173. Namkung, Y., Skrypnyk, N., Jeong, M.J., Lee, T., Lee, M.S., Kim, H.L., Chin, H., Suh, P.G., Kim, S.S., and Shin, H.S. 2001. Requirement for the L-type Ca 2+ channel α 1D subunit in postnatal pancreatic β cell generation. J. Clin. Invest. 108:1015-1022.
174. Braun, M., Ramracheya, R., Bengtsson, M., Zhang, Q., Karanauskaite, J., Partridge, C., Johnson, P.R., and Rorsman, P. 2008. Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion. Diabetes 57:1618-1628.
175. Straub, S.G., and Sharp, G.W. 2012. Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins. Am. J. Physiol. Cell Physiol. 302:C1687-1698.
176. Sutton, R.B., Fasshauer, D., Jahn, R., and Brunger, A.T. 1998. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution. Nature 395:347-353.
177. Regazzi, R., Ravazzola, M., Iezzi, M., Lang, J., Zahraoui, A., Andereggen, E., Morel, P., Takai, Y., and Wollheim, C.B. 1996. Expression, localization and functional role of small GTPases of the Rab3 family in insulin-secreting cells. J. Cell Sci. 109 ( Pt 9):2265-2273.
178. Mizuta, M., Kurose, T., Miki, T., Shoji-Kasai, Y., Takahashi, M., Seino, S., and Matsukura, S. 1997. Localization and functional role of synaptotagmin III in insulin secretory vesicles in pancreatic β-cells. Diabetes 46:2002-2006.
179. Peking, I.R.G. 1971. Insulin's crystal structure at 2.5A resolution. Peking Rev. 40:11-16.
180. Blundell, T.L., Dodson, G.G., Hodgkin, D.C., and Mercola, D.A. 1972. Insulin: the structure in the crystal and its reflection in chemistry and biology. Adv. Protein Chem. 26:279-402.
181. Bentley, G., Dodson, E., Dodson, G., Hodgkin, D., and Mercola, D. 1976. Structure of insulin in 4-zinc insulin. Nature 261:166-168.
182. Derewenda, U., Derewenda, Z., Dodson, E.J., Dodson, G.G., Reynolds, C.D., Smith, G.D., Sparks, C., and Swenson, D. 1989. Phenol stabilizes more helix in a new symmetrical zinc insulin hexamer. Nature 338:594-596.
183. Smith, G.D., Pangborn, W.A., and Blessing, R.H. 2003. The structure of T6 human insulin at 1.0 A resolution. Acta Crystallogr. D Biol. Crystallogr. 59:474-482.
184. Hua, Q.X., Shoelson, S.E., Kochoyan, M., and Weiss, M.A. 1991. Receptor binding redefined by a structural switch in a mutant human insulin. Nature 354:238-241.
185. Knegtel, R.M., Boelens, R., Ganadu, M.L., and Kaptein, R. 1991. The solution structure of a monomeric insulin. A two-dimensional 1 H-NMR study of des -(B26-B30)-insulin in combination with distance geometry and restrained molecular dynamics. Eur. J. Biochem. 202:447-458.
186. Jørgensen, A.M., Kristensen, S.M., Led, J.J., and Balschmidt, P. 1992. Three-dimensional solution structure of an insulin dimer. A study of the B9(Asp) mutant of human insulin using nuclear magnetic resonance, distance geometry and restrained molecular dynamics. J. Mol. Biol. 227:1146-1163.
187. Olsen, H.B., Ludvigsen, S., and Kaarsholm, N.C. 1996. Solution structure of an engineered insulin monomer at neutral pH. Biochemistry 35:8836-8845.
188. Hua, Q.X., Hu, S.Q., Frank, B.H., Jia, W., Chu, Y.C., Wang, S.H., Burke, G.T., Katsoyannis, P.G., and Weiss, M.A. 1996. Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue. J. Mol. Biol. 264:390-403.
189. Sorensen, M.D., Bjorn, S., Norris, K., Olsen, O., Petersen, L., James, T.L., and Led, J.J. 1997. Solution structure and backbone dynamics of the human α3-chain type VI collagen C-terminal Kunitz domain. Biochemistry 36:10439-10450.
190. Ludvigsen, S., Olsen, H.B., and Kaarsholm, N.C. 1998. A structural switch in a mutant insulin exposes key residues for receptor binding. J. Mol. Biol. 279:1-7.
191. Xu, B., Hua, Q.X., Nakagawa, S.H., Jia, W., Chu, Y.C., Katsoyannis, P.G., and Weiss, M.A. 2002. Chiral mutagensis of insulin's hidden receptor-binding surface: structure of an allo -isoleucine A2 analogue. J. Mol. Biol. 316:435-441.
192. Hua, Q.X., Xu, B., Huang, K., Hu, S.Q., Nakagawa, S., Jia, W., Wang, S., Whittaker, J., Katsoyannis, P.G., and Weiss, M.A. 2009. Enhancing the activity of insulin by stereospecific unfolding. Conformational life cycle of insulin and its evolutionary origins. J. Biol. Chem. 284:14586-14596.
193. Žáková, L., Kletvíková, E., Veverka, V., Lepsík, M., Watson, C.J., Turkenburg, J.P., Jirácek, J., and Brzozowski, A.M. 2013. Structural integrity of the B24 site in human insulin is important for hormone functionality. J. Biol. Chem. 288:10230-10240.
194. Liang, D.C., Chang, W.R., and Wan, Z.L. 1994. A proposed interaction model of the insulin molecule with its receptor. Biophys. Chem. 50:63-71.
195. Scott, D.A. 1934. Crystalline insulin. Biochem. J. 28:1592-1602 1591.
196. Scott, D.A., and Fisher, A.M. 1935. Crystalline insulin. Biochem. J. 29:1048-1054.
197. Brader, M.L., and Dunn, M.F. 1991. Insulin hexamers: new conformations and applications. Trends Biochem. Sci. 16:341-345.
198. Badger, J., Harris, M.R., Reynolds, C.D., Evans, A.C., Dodson, E.J., Dodson, G.G., and North, A.C. 1991. Structure of the pig insulin dimer in the cubic crystal. Acta Crystallogr. B Struct. Sci. 47:127-136.
199. Badger, J. 1992. Flexibility in crystalline insulins. Biophys. J. 61:816-819.
200. Bi, R.C., Dauter, Z., Dodson, E., Dodson, G., Giordano, F., and Reynolds, C. 1984. Insulin structure as a modified and monomeric molecule. Biopolymers 23:391-395.
201. Liang, D.C., Stuart, D., B., D.J., Todd, R., You, J.M., and Luo, M.Z. 1985. X-ray studies of des-pentapeptide (B26-B30) insulin at 2.4 Å resolution: The DPI molecule and its structural relationship with insulin. Sci. Sin. 28:472-484.
202. Bao, S.J., Xie, D.L., Zhang, J.P., Chang, W.R., and Liang, D.C. 1997. Crystal structure of des heptapeptide(B24-B30)insulin at 1.6 Å resolution: implications for receptor binding. Proc. Natl. Acad. Sci. U. S. A. 94:2975-2980.
203. Wan, Z., Huang, K., Whittaker, J., and Weiss, M.A. 2008. The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition. J. Biol. Chem. 283:21198-21210.
204. Derewenda, U., Derewenda, Z.S., Dodson, G.G., and Hubbard, R.E. 1990. Insulin structure. In Insulin—the handbook of experimental pharmacology . P. Cuatrecasas, and S. Jacobs, editors. Berlin: Springer-Verlag. 23-39.
205. Jacoby, E., Hua, Q.X., Stern, A.S., Frank, B.H., and Weiss, M.A. 1996. Structure and dynamics of a protein assembly. 1 H-NMR studies of the 36 kDa R6 insulin hexamer. J. Mol. Biol. 258:136-157.
206. Chang, X., Jorgensen, A.M., Bardrum, P., and Led, J.J. 1997. Solution structures of the R6 human insulin hexamer. Biochemistry 36:9409-9422.
207. Jørgensen, L.N., Dideriksen, L.H., and Drejer, K. 1992. Carcinogenic effect of the human insulin analog B-10 Asp in female rats. Diabetologia 35 Suppl 1:A3.
208. Hua, Q.X., and Weiss, M.A. 1990. Toward the solution structure of human insulin: sequential 2D 1 H NMR assignment of a des -pentapeptide analogue and comparison with crystal structure. Biochemistry 29:10545-10555.
209. Derewenda, U., Derewenda, Z., Dodson, E.J., Dodson, G.G., Bing, X., and Markussen, J. 1991. X-ray analysis of the single chain B29-A1 peptide-linked insulin molecule. A completely inactive analogue. J. Mol. Biol. 220:425-433.
210. Smith, G.D., and Dodson, G.G. 1992. Structure of a rhombohedral R6 insulin/phenol complex. Proteins 14:401-408.
211. Dodson, E.J., Dodson, G.G., Lewitova, A., and Sabesan, M. 1978. Zinc-free cubic pig insulin: crystallization and structure determination. J. Mol. Biol. 125:387-396.
212. Cutfield, J.F., Cutfield, S.M., Dodson, E.J., Dodson, G.G., Emdin, S.F., and Reynolds, C.D. 1979. Structure and biological activity of hagfish insulin. J. Mol. Biol. 132:85-100.
213. Nakagawa, S.H., Zhao, M., Hua, Q.X., Hu, S.Q., Wan, Z.L., Jia, W., and Weiss, M.A. 2005. Chiral mutagenesis of insulin. Foldability and function are inversely regulated by a stereospecific switch in the B chain. Biochemistry 44:4984-4999.
214. Hua, Q.X., Nakagawa, S.H., Hu, S.Q., Jia, W., Wang, S., and Weiss, M.A. 2006. Toward the active conformation of insulin. Stereospecific modulation of a structural switch in the B chain. J. Biol. Chem. 281:24900-24909.
215. Nakagawa, S.H., Hua, Q.X., Hu, S.Q., Jia, W., Wang, S., Katsoyannis, P.G., and Weiss, M.A. 2006. Chiral mutagenesis of insulin. Contribution of the B20-B23 β-turn to activity and stability. J. Biol. Chem. 281:22386-22396.
216. Weiss, M.A. 2009. Proinsulin and the genetics of diabetes mellitus. J. Biol. Chem. 284:19159-19163.
217. Frank, B.H., Pekar, A.H., and Veros, A.J. 1972. Insulin and proinsulin conformation in solution. Diabetes 21:486-491.
218. Goldman, J., and Carpenter, F.H. 1974. Zinc binding, circular dichroism, and equilibrium sedimentation studies on insulin (bovine) and several of its derivatives. Biochemistry 13:4566-4574.
219. Milthorpe, B.K., Nichol, L.W., and Jeffrey, P.D. 1977. The polymerization pattern of zinc(II)-insulin at pH 7.0. Biochim. Biophys. Acta 495:195-202.
220. McKern, N.M., Lawrence, M.C., Streltsov, V.A., Lou, M.Z., Adams, T.E., Lovrecz, G.O., Elleman, T.C., Richards, K.M., Bentley, J.D., Pilling, P.A., et al. 2006. Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature 443:218-221.
221. Kruger, P., Strassburger, W., Wollmer, A., van Gunsteren, W.F., and Dodson, G.G. 1987. The simulated dynamics of the insulin monomer and their relationship to the molecule's structure. Eur. Biophys. J. 14:449-459.
222. Wodak, S.J., Alard, P., Delhaise, P., and Renneboog-Squilbin, C. 1985. Simulation of conformational changes in 2 Zn insulin. J. Mol. Biol. 181:317-322.
223. Weiss, M.A., Hua, Q.X., Lynch, C.S., Frank, B.H., and Shoelson, S.E. 1991. Heteronuclear 2D NMR studies of an engineered insulin monomer: assignment and characterization of the receptor-binding surface by selective 2 H and 13 C labeling with application to protein design. Biochemistry 30:7373-7389.
224. Tidor, B., and Karplus, M. 1994. The contribution of vibrational entropy to molecular association. The dimerization of insulin. J. Mol. Biol. 238:405-414.
225. Rupley, J.A. 1967. The binding and cleavage by lysozyme of N-acetylglucosamine oligosaccharides. Proc. R. Soc. Lond. B Biol. Sci. 167:416-428.
226. Jeffrey, P.D., Milthorpe, B.K., and Nichol, L.W. 1976. Polymerization pattern of insulin at pH 7.0. Biochemistry 15:4660-4665.
227. Pocker, Y., and Biswas, S.B. 1981. Self-association of insulin and the role of hydrophobic bonding: a thermodynamic model of insulin dimerization. Biochemistry 20:4354-4361.
228. Cutfield, J.F., Cutfield, S.M., Dodson, E.J., dodson, G.G., Reynolds, C.D., and Vallely, D. 1981. In Structural studies on molecules of biological interest . G.G. Dodson, J. Glusker, and D. Sayre, editors. Oxford: Oxford University Press. 527-546.
229. Chothia, C., Lesk, A.M., Dodson, G.G., and Hodgkin, D.C. 1983. Transmission of conformational change in insulin. Nature 302:500-505.
230. Ciszak, E., and Smith, G.D. 1994. Crystallographic evidence for dual coordination around zinc in the T 3 R 3 human insulin hexamer. Biochemistry 33:1512-1517.
231. Schlichtkrull, J. 1958. Insulin Crystals: chemical and biological studies on insulin crystals and insulin zinc suspensions. Copenhagen, Munksgaard: Kobenhavns universitet. 139.
232. Roy, M., Brader, M.L., Lee, R.W., Kaarsholm, N.C., Hansen, J.F., and Dunn, M.F. 1989. Spectroscopic signatures of the T to R conformational transition in the insulin hexamer. J. Biol. Chem. 264:19081-19085.
233. Wollmer, A., Rannefeld, B., Johansen, B.R., Hejnaes, K.R., Balschmidt, P., and Hansen, F.B. 1987. Phenol-promoted structural transformation of insulin in solution. Biol. Chem. Hoppe Seyler 368:903-911.
234. Coffman, F.D., and Dunn, M.F. 1988. Insulin-metal ion interactions: the binding of divalent cations to insulin hexamers and tetramers and the assembly of insulin hexamers. Biochemistry 27:6179-6187.
235. Wood, S.P., Blundell, T.L., Wollmer, A., Lazarus, N.R., and Neville, R.W. 1975. The relation of conformation and association of insulin to receptor binding; a-ray and circular-dichroism studies on bovine and hystricomorph insulins. Eur. J. Biochem. 55:531-542.
236. Renscheidt, H., Strassburger, W., Glatter, U., Wollmer, A., Dodson, G.G., and Mercola, D.A. 1984. A solution equivalent of the 2Zn→4Zn transformation of insulin in the crystal. Eur. J. Biochem. 142:7-14.
237. Williamson, K.L., and Williams, R.J. 1979. Conformational analysis by nuclear magnetic resonance: insulin. Biochemistry 18:5966-5972.
238. Ramesh, V., and Bradbury, J.H. 1986. 1 H-NMR studies of insulin. Reversible transformation of 2Zn→4Zn insulin hexamer. Int. J. Pept. Protein Res. 28:146-153.
239. Brange, J., editor. 1987. Galenics of Insulin: The Physico-chemical and Pharmaceutical Aspects of Insulin and Insulin Preparations . Berlin: Springer Berlin Heidelberg. 1-103 pp.
240. Brange, J., and Langkjoer, L. 1993. Insulin structure and stability. Pharm. Biotechnol. 5:315-350.
241. Weiss, M.A. 2013. Design of ultra-stable insulin analogues for the developing world. Journal of Health Specialties 1:59-70.
242. Ciszak, E., Beals, J.M., Frank, B.H., Baker, J.C., Carter, N.D., and Smith, G.D. 1995. Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric Lys B28 Pro B29 -human insulin. Structure (Lond.) 3:615-622.
243. Howell, S.L., Young, D.A., and Lacy, P.E. 1969. Isolation and properties of secretory granules from rat islets of Langerhans. 3. Studies of the stability of the isolated b granules. J. Cell Biol. 41:167-176.
244. Howell, S.L., Kostianovsky, M., and Lacy, P.E. 1969. b granule formation in isolated islets of Langerhans: a study by electron microscopic radioautography. J. Cell Biol. 42:695-705.
245. Katsoyannis, P.G. 1966. Synthesis of insulin. Science 154:1509-1514.
246. De Meyts, P., van Obberghen, E., and Roth, J. 1978. Mapping of the residues responsible for the negative cooperativity of the receptor-binding region of insulin. Nature 273:504-509.
247. Kristensen, C., Kjeldsen, T., Wiberg, F.C., Schaffer, L., Hach, M., Havelund, S., Bass, J., Steiner, D.F., and Andersen, A.S. 1997. Alanine scanning mutagenesis of insulin. J. Biol. Chem. 272:12978-12983.
248. Liang, D.C., Chang, W.R., Zhang, J.P., and Wan, Z.L. 1992. The possible mechanism of binding interaction of insulin molecule with its receptor. Sci. China B 35:547-557.
249. Shoelson, S.E., Lee, J., Lynch, C.S., Backer, J.M., and Pilch, P.F. 1993. Bpa B25 insulins. Photoactivatable analogues that quantitatively cross-link, radiolabel, and activate the insulin receptor. J. Biol. Chem. 268:4085-4091.
250. Kurose, T., Pashmforoush, M., Yoshimasa, Y., Carroll, R., Schwartz, G.P., Burke, G.T., Katsoyannis, P.G., and Steiner, D.F. 1994. Cross-linking of a B25 azidophenylalanine insulin derivative to the carboxyl-terminal region of the α-subunit of the insulin receptor. Identification of a new insulin-binding domain in the insulin receptor. J. Biol. Chem. 269:29190-29197.
251. Xu, B., Hu, S.Q., Chu, Y.C., Wang, S., Wang, R.Y., Nakagawa, S.H., Katsoyannis, P.G., and Weiss, M.A. 2004. Diabetes-associated mutations in insulin identify invariant receptor contacts. Diabetes 53:1599-1602.
252. Xu, B., Huang, K., Chu, Y.C., Hu, S.Q., Nakagawa, S., Wang, S., Wang, R.Y., Whittaker, J., Katsoyannis, P.G., and Weiss, M.A. 2009. Decoding the cryptic active conformation of a protein by synthetic photoscanning: Insulin inserts a detachable arm between receptor domains. J. Biol. Chem. 284:14597-14608.
253. Tager, H.S. 1995. Diabetes: Clinical Science in Practice . Cambridge: Cambridge University Press. 492 pp.
254. Pullen, R.A., Lindsay, D.G., Wood, S.P., Tickle, I.J., Blundell, T.L., Wollmer, A., Krail, G., Brandenburg, D., Zahn, H., Gliemann, J., et al. 1976. Receptor-binding region of insulin. Nature 259:369-373.
255. Kwok, S.C., Steiner, D.F., Rubenstein, A.H., and Tager, H.S. 1983. Identification of a point mutation in the human insulin gene giving rise to a structurally abnormal insulin (insulin Chicago). Diabetes 32:872-875.
256. Shoelson, S., Haneda, M., Blix, P., Nanjo, A., Sanke, T., Inouye, K., Steiner, D., Rubenstein, A., and Tager, H. 1983. Three mutant insulins in man. Nature 302:540-543.
257. Shoelson, S., Fickova, M., Haneda, M., Nahum, A., Musso, G., Kaiser, E.T., Rubenstein, A., and Tager, H. 1983. Indentification of a mutant human insulin predicetd to contain a serine-for -phenylalanine substitition. Proc. Natl. Acad. Sci. U. S. A. 80:7390-7394.
258. Kobayashi, M., Ohgaku, S., Iwasaki, M., Maegawa, H., Shigeta, Y., and Inouye, K. 1982. Characterization of [Leu B24 ]- and [Leu B25 ]-insulin analogues. Receptor binding and biological activity. Biochem. J. 206:597-603.
259. Kobayashi, M., Ohgaku, S., Iwasaki, M., Maegawa, H., Shigeta, Y., and Inouye, K. 1982. Supernormal insulin: [D-Phe B24 ]-insulin with increased affinity for insulin receptors. Biochem. Biophys. Res. Commun. 107:329-336.
260. Nanjo, K., Sanke, T., Miyano, M., Okai, K., Sowa, R., Kondo, M., Nishimura, S., Iwo, K., Miyamura, K., Given, B.D., et al. 1986. Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [Leu A3 ] insulin. J. Clin. Invest. 77:514-519.
261. Hua, Q.X., Shoelson, S.E., Inouye, K., and Weiss, M.A. 1993. Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus. Proc. Natl. Acad. Sci. U. S. A. 90:582-586.
262. Liu, M., Haataja, L., Wright, J., Wickramasinghe, D.N., Hua, Q.X., Phillips, N.B., Barbetti, F., Weiss, M.A., and Arvan, P. 2010. Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on nonmutant proinsulin transport. PLos-One 5:e13333.
263. Huang, K., Xu, B., Hu, S.Q., Chu, Y.C., Hua, Q.X., Qu, Y., Li, B., Wang, S., Wang, R.Y., Nakagawa, S.H., et al. 2004. How insulin binds: the B-chain α-helix contacts the L1 β-helix of the insulin receptor. J. Mol. Biol. 341:529-550.
264. Schäffer, L. 1994. A model for insulin binding to the insulin receptor. Eur. J. Biochem. 221:1127-1132.
265. De Meyts, P. 1994. The structural basis of insulin and insulin-like growth factor-I receptor binding and negative co-operativity, and its relevance to mitogenic versus metabolic signaling. Diabetologia 37:S135-S148.
266. De Meyts, P., Palsgaard, J., Sajid, W., Theede, A.M., and Aladdin, H. 2004. Structural biology of insulin and IGF-1 receptors. Novartis Found. Symp. 262:160-171.
267. De Meyts, P., and Shymko, R.M. 2000. Timing-dependent modulation of insulin mitogenic versus metabolic signalling. Novartis Found. Symp. 227:46-57.
268. Hansen, B.F., Kurtzhals, P., Jensen, A.B., Dejgaard, A., and Russell-Jones, D. 2011. Insulin X10 revisited: a super-mitogenic insulin analogue. Diabetologia 54:2226-2231.
269. Hemkens, L.G., Bender, R., Grouven, U., and Sawicki, P.T. 2009. Insulin glargine and cancer. Lancet 374:1743-1744.
270. Weinstein, D., Simon, M., Yehezkel, E., Laron, Z., and Werner, H. 2009. Insulin analogues display IGF-I mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab. Res. Rev. 25:41-49.
271. Sciacca, L., Cassarino, M.F., Genua, M., Pandini, G., LeMoli, R., Squatrito, S., and Vigneri, R. 2010. Insulin analogues differently activate insulin receptor isoforms and post-receptor signaling. Diabetologia 53:1743-1753.
272. Sciacca, L., Le Moli, R., and Vigneri, R. 2012. Insulin analogs and cancer. Front. Endocrinol. (Lausanne) 3:21.
273. Cosmatos, A., Cheng, K., Okada, Y., and Katsoyannis, P.G. 1978. The chemical synthesis and biological evaluation of [1-L-alanine-A]-and [1-D-alanine-A]insulins. J. Biol. Chem. 253:6586-6590.
274. Geiger, R., Geisen, K., Summ, H.D., and Langer, D. 1975. (A1-D-alanine) insulin. Hoppe Seylers Z Physiol. Chem. 356:1635-1649.
275. Geiger, R., Geisen, K., Regitz, G., Summ, H.D., and Langner, D. 1980. Insulin analogues with substitution of A1-glycine by D-amino acids and omega-amino acids (author's transl). Hoppe Seylers Z Physiol. Chem. 361:563-570.
276. Geiger, R., Geisen, K., and Summ, H.D. 1982. Astausch von A1-Glycin in Rinderinsulin gegen L-und D-Tryptophan. Hoppe Seylers Z Physiol. Chem. 363:S1231-1239.
277. Nakagawa, S.H., and Tager, H.S. 1989. Perturbation of insulin-receptor interactions by intramolecular hormone cross-linking. Analysis of relative movement among residues A1, B1, and B29. J. Biol. Chem. 264:272-279.
278. Kitagawa, K., Ogawa, H., Burke, G.T., Chanley, J.D., and Katsoyannis, P.G. 1984. Critical role of the A2 amino acid residue in the biological activity of insulin: [2-glycine-A]- and [2-alanine-A]insulins. Biochemistry 23:1405-1413.
279. Nakagawa, S.H., and Tager, H.S. 1992. Importance of aliphatic side-chain structure at positions 2 and 3 of the insulin A chain in insulin-receptor interactions. Biochemistry 31:3204-3214.
280. Kitagawa, K., Ogawa, H., Burke, G.T., Chanley, J.D., and Katsoyannis, P.G. 1984. Interaction between the A2 and A19 amino acid residues is of critical importance for high biological activity in insulin: [19-leucine-A]insulin. Biochemistry 23:4444-4448.
281. Wieneke, H.J., Danho, W., Bullesbach, E.E., Gattner, H.G., and Zahn, H. 1983. The synthesis of [A 19-3-iodotyrosine] and [A 19-3,5-diiodotyrosine]insulin (porcine). Hoppe Seylers Z Physiol. Chem. 364:537-550.
282. Ohta, N., Burke, G.T., and Katsoyannis, P.G. 1988. Synthesis of an insulin analogue embodying a strongly fluorescent moiety, [19-tryptophan-A]insulin. J. Protein Chem. 7:55-65.
283. Du, X., and Tang, J.G. 1998. Hydroxyl group of insulin A19Tyr is essential for receptor binding: studies on (A19Phe)insulin. Biochem. Mol. Biol. Int. 45:255-260.
284. Sonne, O., Linde, S., Larsen, T.R., and Gliemann, J. 1983. Monoiodoinsulin labelled in tyrosine residue 16 or 26 of the B-chain or 19 of the A-chain. II. Characterization of the kinetic binding constants and determination of the biological potency. Hoppe Seylers Z Physiol. Chem. 364:101-110.
285. Hamlin, J.L., and Arquilla, E.R. 1974. Monoiodoinsulin. Preparation, purification, and characterization of a biologically active derivative substituted predominantly on tyrosine A14. J. Biol. Chem. 249:21-32.
286. Linde, S., Welinder, B.S., Hansen, B., and Sonne, O. 1986. Preparative reversed-phase high-performance liquid chromatography of iodinated insulin retaining full biological activity. J. Chromatogr. 369:327-339.
287. Chu, Y.C., Zong, L., Burke, G.T., and Katsoyannis, P.G. 1992. The A14 position of insulin tolerates considerable structural alterations with modest effects on the biological behavior of the hormone. J. Protein Chem. 11:571-577.
288. Slobin, L.I., and Carpenter, F.H. 1963. Action of carboxypeptidase- A on bovine insulin: preparation of desalanine-desasparagine-insulin. Biochemistry 2:16-22.
289. Chu, Y.C., Wang, R.Y., Burke, G.T., Chanley, J.D., and Katsoyannis, P.G. 1987. Possible involvement of the A20-A21 peptide bond in the biological activity of insulin. 1. [21-Desasparagine,20-cysteinamide-A]insulin and [21-desasparagine,20-cysteine isopropylamide-A]insulin. Biochemistry 26:6966-6971.
290. Chu, Y.C., Wang, R.Y., Burke, G.T., Chanley, J.D., and Katsoyannis, P.G. 1987. Possible involvement of the A20-A21 peptide bond in the expression of the biological activity of insulin. 3. [21- Des asparagine,20-cysteine ethylamide-A]insulin and [21- des asparagine,20-cysteine 2,2,2-trifluoroethylamide-A]insulin. Biochemistry 26:6975-6979.
291. Chu, Y.C., Burke, G.T., Chanley, J.D., and Katsoyannis, P.G. 1987. Possible involvement of the A20-A21 peptide bond in the expression of the biological activity of insulin. 2. [21-Asparagine diethylamide-A]insulin. Biochemistry 26:6972-6975.
292. Thomas, B., and Wollmer, A. 1989. Cobalt probing of structural alternatives for insulin in solution. Biol. Chem. Hoppe Seyler 370:1235-1244.
293. Kaarsholm, N.C., Ko, H.C., and Dunn, M.F. 1989. Comparison of solution structural flexibility and zinc binding domains for insulin, proinsulin, and miniproinsulin. Biochemistry 28:4427-4435.
294. Wollmer, A., Rannefeld, B., Stahl, J., and Melberg, S.G. 1989. Structural transition in the metal-free hexamer of protein-engineered [B13 Gln]insulin. Biol. Chem. Hoppe Seyler 370:1045-1053.
295. Kruger, P., Gilge, G., Cabuk, Y., and Wollmer, A. 1990. Cooperativity and intermediate states in the T----R-structural transformation of insulin. Biol. Chem. Hoppe Seyler 371:669-673.
296. Roy, M., Lee, R.W., Brange, J., and Dunn, M.F. 1990. 1 H NMR spectrum of the native human insulin monomer. Evidence for conformational differences between the monomer and aggregated forms. J. Biol. Chem. 265:5448-5452.
297. Mirmira, R.G., and Tager, H.S. 1989. Role of the phenylalanine B24 side chain in directing insulin interaction with its receptor: Importance of main chain conformation. J. Biol. Chem. 264:6349-6354.
298. Mirmira, R.G., Nakagawa, S.H., and Tager, H.S. 1991. Importance of the character and configuration of residues B24, B25, and B26 in insulin-receptor interactions. J. Biol. Chem. 266:1428-1436.
299. Mirmira, R.G., and Tager, H.S. 1991. Disposition of the phenylalanine B25 side chain during insulin-receptor and insulin-insulin interactions. Biochemistry 30:8222-8229.
300. Cao, Q.P., Geiger, R., Langner, D., and Geisen, K. 1986. Biological activity in vivo of insulin analogues modified in the N-terminal region of the B-chain. Biol. Chem. Hoppe Seyler 367:135-140.
301. Schwartz, G., and Katsoyannis, P.G. 1978. Synthesis of des(tetrapeptide B(1-4)) and des(pentapeptide B(1-5) human insulins. Two biologically active analogues. Biochemistry 17:4550-4556.
302. Geiger, R. 1977. In Molecular Endocrinology . I. MacIntyre, and M. Szelke, editors. Amsterdam: Holland Biomedical Press. 27-41.
303. Nakagawa, S.H., and Tager, H.S. 1991. Implications of invariant residue LeuB6 in insulin-receptor interactions. J. Biol. Chem. 266:11502-11509.
304. Hua, Q.X., Liu, M., Hu, S.Q., Jia, W., Arvan, P., and Weiss, M.A. 2006. A conserved histidine in insulin is required for the foldability of human proinsulin. Structure and function of an Ala B5 analog. J. Biol. Chem. 281:24889-24899.
305. Cosmatos, A., Ferderigos, N., and Katsoyannis, P.G. 1979. Chemical synthesis of [ des (tetrapeptide B27-30), Tyr(NH2)26-B] and [ des (pentapeptide B26-30), Phe(NH2)25-B] bovine insulins. Int. J. Protein Res. 14:457-471.
306. Fischer, W.H., Saunders, D., Brandenburg, D., Wollmer, A., and Zahn, H. 1985. A shortened insulin with full in vitro potency. Biol. Chem. Hoppe Seyler 366:521-525.
307. Zakova, L., Brynda, J., Au-Alvarez, O., Dodson, E.J., Dodson, G.G., Whittingham, J.L., and Brzozowski, A.M. 2004. Toward the insulin-IGF-I intermediate structures: functional and structural properties of the [TyrB25NMePheB26] insulin mutant. Biochemistry 43:16293-16300.
308. Žáková, L., Kazdová, L., Hančlová, I., Protivínská, E., Šanda, M., Buděšínský, M., and Jiráček, J. 2008. Insulin analogues with modifications at position B26. Divergence of binding affinity and biological activity. Biochemistry 47:5858-5868.
309. Dai, J.B., Lou, M.Z., You, J.M., and Liang, D.C. 1987. Refinement of the structure of despentapetide (B26-B30) insulin at 1.5 Å resolution. Sci. Sin. 30:55-65.
310. Casaretto, M., Spoden, M., Diaconescu, C., Gattner, H.G., Zahn, H., Brandenburg, D., and Wollmer, A. 1987. Shortened insulin with enhanced in vitro potency. Biol. Chem. Hoppe Seyler 368:709-716.
311. Nakagawa, S.H., and Tager, H.S. 1993. Importance of main-chain flexibility and the insulin fold in insulin-receptor interactions. Biochemistry 32:7237-7243.
312. Boelens, R., Ganadu, M.L., Verheyden, P., and Kaptein, R. 1990. Two-dimensional NMR studies on des-pentapeptide-insulin. Proton resonance assignments and secondary structure analysis. Eur. J. Biochem. 191:147-153.
313. Nakagawa, S.H., and Tager, H.S. 1986. Role of the phenylalanine B25 side chain in directing insulin interaction with its receptor. Steric and conformational effects. J. Biol. Chem. 261:7332-7341.
314. Xu, B., Hu, S.Q., Chu, Y.C., Huang, K., Nakagawa, S.H., Whittaker, J., Katsoyannis, P.G., and Weiss, M.A. 2004. Diabetes-associated mutations in insulin: consecutive residues in the B chain contact distinct domains of the insulin receptor. Biochemistry 43:8356-8372.
315. Shoelson, S.E., Lu, Z.X., Parlautan, L., Lynch, C.S., and Weiss, M.A. 1992. Mutations at the dimer, hexamer, and receptor-binding, surfaces of insulin independently affect insulin-insulin and insulin-receptor interactions. Biochemistry 31:1757-1767.
316. Pittman, I., Nakagawa, S.H., Tager, H.S., and Steiner, D.F. 1997. Maintenance of the B-chain β-turn in [Gly B24 ] insulin mutants: a steady-state fluorescence anisotropy study. Biochemistry 36:3430-3437.
317. De Meyts, P. 2004. Insulin and its receptor: structure, function and evolution. Bioessays 26:1351-1362.
318. Kiselyov, V.V., Versteyhe, S., Gaugin, L., and De Meyts, P. 2009. Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation. Mol. Syst. Biol. 5:243.
319. Whittaker, J., Whittaker, L.J., Roberts, C.T., Jr., Phillips, N.B., Ismail-Beigi, F., Lawrence, M.C., and Weiss, M.A. 2012. α-Helical element at the hormone-binding surface of the insulin receptor functions as a signaling element to activate its tyrosine kinase. Proc. Natl. Acad. Sci. U. S. A. 109:11166-11171.
320. Ward, C.W., and Lawrence, M.C. 2009. Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor. Bioessays 31:422-434.
321. Henzen, C. 2012. Monogenic diabetes mellitus due to defects in insulin secretion. Swiss Med. Wkly. 142:w13690.
322. Chan, S.J., Seino, S., Gruppuso, P.A., Schwartz, R., and Steiner, D.F. 1987. A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. Proc. Natl. Acad. Sci. U. S. A. 84:2194-2197.
323. Gruppuso, P.A., Gorden, P., Kahn, C.R., Cornblath, M., Zeller, W.P., and Schwartz, R. 1984. Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin. N. Engl. J. Med. 311:629-634.
324. Schwartz, G.P., Burke, G.T., and Katsoyannis, P.G. 1987. A superactive insulin: [B10-aspartic acid]insulin(human). Proc. Natl. Acad. Sci. U. S. A. 84:6408-6411.
325. Burgess, T.L., and Kelly, R.B. 1987. Constitutive and regulated secretion of proteins. Annu. Rev. Cell Biol. 3:243-293.
326. Carroll, R.J., Hammer, R.E., Chan, S.J., Swift, H.H., Rubenstein, A.H., and Steiner, D.F. 1988. A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway. Proc. Natl. Acad. Sci. U. S. A. 85:8943-8947.
327. Robbins, D.C., Shoelson, S., Rubenstein, A., and Tager, H. 1984. Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion. J. Clin. Invest. 73:714-719.
328. Gabbay, K.H., DeLuca, K., Fisher, J.N., Jr., Mako, M.E., and Rubenstein, A.H. 1976. Familial hyperproinsulinemia. An autosomal dominant defect. N. Engl. J. Med. 294:911-915.
329. Edghill, E.L., Flanagan, S.E., Patch, A.M., Boustred, C., Parrish, A., Shields, B., Shepherd, M.H., Hussain, K., Kapoor, R.R., Malecki, M., et al. 2008. Insulin mutation screening in 1044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 57:1034-1042.
330. Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., et al. 2008. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J. Clin. Invest. 118:2148-2156.
331. Molven, A., Ringdal, M., Nordbo, A.M., Raeder, H., Stoy, J., Lipkind, G.M., Steiner, D.F., Philipson, L.H., Bergmann, I., Aarskog, D., et al. 2008. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 57:1131-1135.
332. Slingerland, A.S., and Hattersley, A.T. 2005. Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment. Ann. Med. 37:186-195.
333. Babenko, A.P., Polak, M., Cave, H., Busiah, K., Czernichow, P., Scharfmann, R., Bryan, J., Aguilar-Bryan, L., Vaxillaire, M., and Froguel, P. 2006. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N. Engl. J. Med. 355:456-466.
334. Park, S.Y., Ye, H., Steiner, D.F., and Bell, G.I. 2010. Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not efficiently secreted. Biochem. Biophys. Res. Commun. 391:1449-1454.
335. Meur, G., Simon, A., Harun, N., Virally, M., Dechaume, A., Bonnefond, A., Fetita, S., Tarasov, A.I., Guillausseau, P.J., Boesgaard, T.W., et al. 2010. Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes 59:653-661.
336. Yoshioka, M., Kayo, T., Ikeda, T., and Koizumi, A. 1997. A novel locus, Mody4 , distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes 46:887-894.
337. Wang, J., Takeuchi, T., Tanaka, S., Kubo, S.K., Kayo, T., Lu, D., Takata, K., Koizumi, A., and Izumi, T. 1999. A mutation in the insulin 2 gene induces diabetes with severe pancreatic b -cell dysfunction in the Mody mouse. J. Clin. Invest. 103:27-37.
338. Oyadomari, S., Koizumi, A., Takeda, K., Gotoh, T., Akira, S., Araki, E., and Mori, M. 2002. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J. Clin. Invest. 109:525-532.
339. Izumi, T., Yokota-Hashimoto, H., Zhao, S., Wang, J., Halban, P.A., and Takeuchi, T. 2003. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Diabetes 52:409-416.
340. Zuber, C., Fan, J.Y., Guhl, B., and Roth, J. 2004. Misfolded proinsulin accumulates in expanded pre-Golgi intermediates and endoplasmic reticulum subdomains in pancreatic β cells of Akita mice. FASEB J. 18:917-919.
341. Liu, M., Hodish, I., Rhodes, C.J., and Arvan, P. 2007. Proinsulin maturation, misfolding, and proteotoxicity. Proc. Natl. Acad. Sci. U. S. A. 104:15841-15846.
342. Yoshinaga, T., Nakatome, K., Nozaki, J., Naitoh, M., Hoseki, J., Kubota, H., Nagata, K., and Koizumi, A. 2005. Proinsulin lacking the A7-B7 disulfide bond, Ins2Akita, tends to aggregate due to the exposed hydrophobic surface. Biol. Chem. 386:1077-1085.
343. Hua, Q.X., Nakagawa, S.H., Jia, W., Hu, S.Q., Chu, Y.C., Katsoyannis, P.G., and Weiss, M.A. 2001. Hierarchical protein folding: asymmetric unfolding of an insulin analogue lacking the A7-B7 interchain disulfide bridge. Biochemistry 40:12299-12311.
344. Jia, X.Y., Guo, Z.Y., Wang, Y., Xu, Y., Duan, S.S., and Feng, Y.M. 2003. Peptide models of four possible insulin folding intermediates with two disulfides. Protein Sci. 12:2412-2419.
345. Herbach, N., Rahtkolb, B., Kemter, E., Pichl, L., Klaften, M., De Angelis, M.H., Halban, P., Wolf, E., Aigner, B., and Wanker, R. 2007. Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severe β-cell loss in Munich Ins2C95S mutant mice. Diabetes 56:1268-1276.
346. Hodish, I., Liu, M., Rajpal, G., Larkin, D., Holz, R.W., Adams, A., Liu, L., and Arvan, P. 2010. Misfolded proinsulin affects bystander proinsulin in neonatal diabetes. J. Biol. Chem. 285:685-694.
347. Hodish, I., Absood, A., Liu, L., Liu, M., Haataja, L., Larkin, D., Al-Khafaji, A., Zaki, A., and Arvan, P. 2011. In vivo misfolding of proinsulin below the threshold of frank diabetes. Diabetes 60:2092-2101.
348. Haataja, L., Snapp, E., Wright, J., Liu, M., Hardy, A.B., Wheeler, M.B., Markwardt, M.L., Rizzo, M., and Arvan, P. 2013. Proinsulin intermolecular interactions during secretory trafficking in pancreatic β cells. J. Biol. Chem. 288:1896-1906.
349. Absood, A., Gandomani, B., Zaki, A., Nasta, V., Michail, A., Habib, P.M., and Hodish, I. 2013. Insulin therapy for pre-hyperglycemic β-cell endoplasmic reticulum crowding. PLoS One 8:e54351.
350. Shoelson, S.E., Polonsky, K.S., Zeidler, A., Rubenstein, A.H., and Tager, H.S. 1984. Human insullin B24 (Phe ® Ser), secretion and metabolic clearance of the abnormal insulin in man and in a dog model. J. Clin. Invest. 73:1351-1358.
351. Fonseca, S.G., Gromada, J., and Urano, F. 2011. Endoplasmic reticulum stress and pancreatic β-cell death. Trends Endocrinol. Metab. 22:266-274.
352. Thomas, S.E., Dalton, L., Malzer, E., and Marciniak, S.J. 2011. Unravelling the story of protein misfolding in diabetes mellitus. World J. Diabetes 2:114-118.
353. Ron, D. 2002. Proteotoxicity in the endoplasmic reticulum: lessons from the Akita diabetic mouse. J. Clin. Invest. 109:443-445.
354. Yuan, Q., Tang, W., Zhang, X., Hinson, J.A., Liu, C., Osei, K., and Wang, J. 2012. Proinsulin atypical maturation and disposal induces extensive defects in mouse Ins2 +/Akita β-cells. PLoS One 7:e35098.
355. Despa, F. 2010. Endoplasmic reticulum overcrowding as a mechanism of β-cell dysfunction in diabetes. Biophys. J. 98:1641-1648.
