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Insulin Degradation and Insulin‐Degrading Enzyme

William C. Duckworth, Frederick G. Hamel

10.1002/cphy.cp070207

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Historical Perspective
2 Current Model of Insulin Degradation
2.1 Insulin Clearance
2.2 Liver
2.3 Kidney
2.4 Orfier Tissues
2.5 General Cellular Processes
2.6 Enzymatic Mechanisms for Cellular Metabolism of Insulin
3 Insulin‐Degrading Enzyme
3.1 General Characteristics
3.2 Molecular Characteristics
3.3 Cellular Characteristics
4 Intracellular Insulin and Insulin Action
5 Conclusions and Future Prospects
Figure 1. Figure 1.

High‐performance liquid chromatographic (HPLC) profile of intracellular and endosomal insulin‐sized products. Extracted material was chromatographed on Sephadex G50 and the insulin peak run on reversed‐phase HPLC 87.
Figure 2. Figure 2.

Proposed scheme for cellular processing of insulin. After receptor binding (1), some insulin is degraded (1A) and some is released intact (2). Membrane translocation (3), invagination (4), and internalization (5) can then occur. Partial (6A) or complete (6B) endosomal degradation can occur, and products or intact insulin can be released from the cell (9A) or delivered to other subcellular compartments (7A–7C). Intracellular insulin and fragments may be delivered to lysosomes (7B, 8A) for further degradation. Endosomal insulin receptors can recycle to the plasma membrane (9B). From Duckworth 49 with permission.
Figure 3. Figure 3.

Three‐dimensional structure of insulin with cleavage sites of insulin‐degrading enzyme shown by arrows 60.
Figure 4. Figure 4.

Three‐dimensional structure of transforming growth factor (TGFα) with insulin‐degrading enzyme cleavage sites identified by arrows 85.
Figure 5. Figure 5.

Proposed mechanism of insulin‐degrading enzyme‐mediated intracellular action of insulin.


Figure 1.

High‐performance liquid chromatographic (HPLC) profile of intracellular and endosomal insulin‐sized products. Extracted material was chromatographed on Sephadex G50 and the insulin peak run on reversed‐phase HPLC 87.



Figure 2.

Proposed scheme for cellular processing of insulin. After receptor binding (1), some insulin is degraded (1A) and some is released intact (2). Membrane translocation (3), invagination (4), and internalization (5) can then occur. Partial (6A) or complete (6B) endosomal degradation can occur, and products or intact insulin can be released from the cell (9A) or delivered to other subcellular compartments (7A–7C). Intracellular insulin and fragments may be delivered to lysosomes (7B, 8A) for further degradation. Endosomal insulin receptors can recycle to the plasma membrane (9B). From Duckworth 49 with permission.



Figure 3.

Three‐dimensional structure of insulin with cleavage sites of insulin‐degrading enzyme shown by arrows 60.



Figure 4.

Three‐dimensional structure of transforming growth factor (TGFα) with insulin‐degrading enzyme cleavage sites identified by arrows 85.



Figure 5.

Proposed mechanism of insulin‐degrading enzyme‐mediated intracellular action of insulin.

References
 1. Adames, N., K., Blandell, M. N. Ashby, and C. Boone. Role of yeast insulin‐degrading enzyme homologs in propheromone processing and bud site selection. Science 270: 464–467, 1995.
 2. Adrogue, H. J., J., Pena, and J. P. Comstock. Glyburide increases the secretion, tissue uptake, and action of insulin in conscious normal dogs. Metabolism 45: 579–586, 1996.
 3. Affholter, J. A., M. A., Casciere, M. L. Bayne, J. Brange, M. Casaretto, and R. A. Roth. Identification of residues in the insulin molecule important for binding to insulin‐degrading enzyme. Biochemistry 29: 7727–7733, 1990.
 4. Affholter, J. A., V. A., Fried, and R. A. Roth. Human insulin‐degrading enzyme shares structural and functional homologies with E. coli protease III. Science 242: 1415–1418, 1988.
 5. Affholter, J. A., C. L., Hsieh, U. Francke, and R. A. Roth. Insulin‐degrading enzyme: stable expression of the human complementary DNA, characterization of its protein product, and chromosomal mapping of the human and mouse genes. Mol. Endocrinol. 4: 1125–1135, 1990.
 6. Akiyama, H., K., Yokono, K. Shii, W. Ogawa, H. Taniguchi, S. Baba, and M. Kasuga. Natural regulatory mechanisms of insulin degradation by insulin degrading enzyme. Biochem. Biophys. Res. Commun. 170: 1325–1330, 1990.
 7. Ansorge, S., P. L., Bohley, J. Kirschke, J. Langner, and B. Wiederanders. The insulin and glucagon degrading proteinase of rat liver: a metal dependent enzyme. Biomed. Biochim. Acta 43: 39–46, 1984.
 8. Antoniello, S., S. La Rocca, E. Cavalcanti, M. Auletta, F. Salvatore, and L. Cacciatore. Insulin and glucagon degradation in liver are not affected by hepatic cirrhosis. Clin. Chim. Acta 183: 343–350, 1989.
 9. Ardevol, A., C., Adan, X. Canas, I. Rafecas, M. Mesteve, X. Remesar, J. A. Fernandez‐Lopez, and M. Alemany. Adipose tissue extraction of circulating insulin in anaesthetized Zucker obese rats. Int. J. Obes. 20: 837–841, 1996.
 10. Assoian, R. K., and H. S. Tager. [125I] Iodotyrosyl insulin: semisynthesis receptor binding and cell mediated degradation of a B chain labeled insulin. J. Biol. Chem. 256: 4042, 1981.
 11. Assoian, R. K., and H. S. Tager. Peptide intermediates in the cellular metabolism of insulin. J. Biol. Chem. 257: 9078, 1982.
 12. Auletta, M., S., Antoniello, and N. Abrescia. Insulin‐degrading activity in experimental liver cirrhosis of the rat. Enzyme Protein 95: 197–201, 1994.
 13. Authier, F., J. J., Bergeron, W. J. Ou, R. A. Rachubinski, B. I. Posner, and P. A. Walton. Degradation of the cleaved leader peptide of thiolase by a peroxisomal proteinase. Proc. Natl. Acad. Sci. U.S.A. 92: 3859–3863, 1995.
 14. Authier, F., P. H., Cameron, and V. Taupin. Association of insulin‐degrading enzyme with a 70 kDa cytosolic protein in hepatoma cells. Biochem. J. 319: 149–158, 1996.
 15. Authier, F., R. A., Rachubinski, B. I. Posner, and J. J. M. Bergeron. Endosomal proteolysis of insulin by an acidic thiol metalloprotease unrelated to insulin degrading enzyme. J. Biol. Chem. 269: 3010–3016, 1994.
 16. Backer, J. M., C. R., Kahn, and M. F. White. The dissociation and degradation of internalized insulin occur in the endosomes of rat hepatoma cells. J. Biol. Chem. 265: 14828–14835, 1990.
 17. Baldwin, D., Jr., M. Prince, P. Tsai, C. Johnson, R. Lotan, A. H. Rubenstein, and J. M. Olefsky. Insulin binding, internalization, and receptor regulation in cultured human fibroblasts. Am. J. Physiol. 241 (Endocrinol. Metab. 4) : E251–E260, 1981.
 18. Baskin, F. K., and A. E. Kitabchi. Substrate studies for insulin specific protease. Eur. J. Biochem. 37: 489–496, 1973.
 19. Baumeister, H., D., Muller, M. Rehbein, and D. Richter. The rat insulin degrading enzyme: molecular cloning and characterization of tissue‐specific transcripts. FEBS Lett. 317: 250–254, 1993.
 20. Becker, A. B., and R. A. Roth. An unusual active site identified in a family of zinc metalloendopeptidases. Proc. Nat. Acad. Sci. U. S.A. 89: 3835–3839, 1992.
 21. Becker, A. B., and R. A. Roth. Identification of glutamate‐169 as the third zinc‐binding residue in proteinase III, a member of the family of insulin‐degrading enzymes. Biochem. J. 292: 137–142, 1993.
 22. Bennett, R. G., F. G., Hamel, and W. C. Duckworth. Identification and isolation of a cytosolic proteolytic complex containing insulin degrading enzyme and the multicatalytic proteinase. Biochem. Biophys. Res. Commun. 202: 1047–1053, 1994.
 23. Bennett, R. G., F. G., Hamel, and W. C. Duckworth. Characterization of the insulin inhibition of the peptidolytic activities of the insulin‐degrading enzyme‐proteasome complex. Diabetes 46: 197–203, 1997.
 24. Benzi, L., P., Cecchetti, A. Ciccarone, A. Pilo, G. Di Cianni, and R. Navalesi. Insulin degradation in vitro and in vivo: a comparative study in men. Diabetes 43: 297–304, 1994.
 25. Bergeron, J. J. M., N., Searle, M. N. Khan, and B. I. Posner. Differential and analytical subfractionation of rat liver components internalizing insulin and prolactin. Biochemistry 25: 1756–1764, 1986.
 26. Blache, P., A., Kervran, D. Le‐Nguyen, M. Dufour, A. Cohen‐Sodal, W. Duckworth, and D. Bataille. Endopeptidase from rat liver membranes, which generates miniglucagon from glucagon. J. Biol. Chem. 268: 21748–21753, 1993.
 27. Bondy, C. A., J., Zhou, E. Chin, R. R. Reinhardt, and R. A. Roth. Cellular distribution of insulin‐degrading enzyme gene expression: comparison with insulin and insulin‐like growth factor receptors. J. Clin. Invest. 93: 966–973, 1994.
 28. Bonora, E., I., Zavaroni, C. Coscelli, and U. Butturini. Decreased hepatic insulin extraction in subjects with mild glucose interolerance. Metabolism 32: 438–446, 1983.
 29. Bonora, E., I. Zavaroni, V. Manicardi, C. Coscelli, and U. Butturini. Further evidence that insulin metabolism is a major determinant of peripheral insulin response to oral glucose in subjects with mild glucose intolerance. J. Endocrinol. Invest. 9: 371–374, 1986.
 30. Brush, J. S.. Purification and characterization of a protease with specificity for insulin from rat muscle. Diabetes 20: 140–145, 1971.
 31. Buffington, C. K., T. el‐Shiekh, A. E. Kitabchi, and R. Matteri. Phytohemagglutinin (PHA) activated human T lymphocytes: concomitant appearance of insulin binding, degradation, and insulin mediated activation of pyruvate dehydrogenase. Biochem. Biophys. Res. Commun. 134: 412–419, 1986.
 32. Burghen, G. A., W. C., Duckworth, A. E. Kitabchi, S. S. Solomon, and P. L. Poffenbarger. Inhibition of insulin degradation by non‐suppressible insulin‐like activity. J. Clin. Invest. 57: 1089–1093, 1976.
 33. Burghen, G. A., A. E., Kitabchi, and J. S. Brush. Characterization of a rat liver protease with specificity for insulin. Endocrinology 91: 633–642, 1972.
 34. Canas, X., J. A., Fernandez‐Lopez, A. Ardevol, C. Adan, M. Esteve, I. Rafecas, X. Remesar, and M. Alemany. Rat insulin turnover in vivo. Endocrinology 136: 3871–3876, 1995.
 35. Caro, J. F., and J. M. Amatruda. Functional relationships between insulin binding, action, and degradation. A reassessment. J. Biol. Chem. 255: 10052–10055, 1980.
 36. Caro, J. F., and J. M. Amatruda. Evidence for modulation of insulin action and degradation independently of insulin binding. Am. J. Physiol. 240 (Endocrinol. Metab. 3): E325–E332, 1981.
 37. Castillo, M. J., A. J., Scheen, M. R. Letiexhe, and P. J. Lefebvre. How to measure insulin clearance. Diabetes Metab. Rev. 10: 119–150, 1994.
 38. Chen, H., F. G., Hamel, G. L. Silford, and W. C. Duckworth. Alteration of rat hepatic insulin metabolism by glyburide and glipizide. J. Pharmacol. Exp. Ther. 264: 1293–1298, 1993.
 39. Cheng, Y. E., and D. Zipser. Purification and characterization of protease III from Escherichia coli. J. Biol. Chem. 254: 4698–4706, 1979.
 40. Dahl, D. C., T., Tsao, W. C. Duckworth, B. H. Frank, and R. Rabkin. Effect of bacitracin on the retroendocytosis and degradation of insulin in cultured kidney epithelial cell line. Diabetes 39: 1339–1346, 1990.
 41. Davies, J. G., A. V., Muir, and R. E. Offord. Identification of some cleavage sites of insulin by insulin proteinase. Biochem. J. 240: 609–612, 1986.
 42. Davies, J. G., A. V., Muir, K. Rose, and R. E. Offord. Identification of radioactive insulin fragments liberated during the degradation of semisynthetic [3H]GlyA1 insulin and [3H]PheB1 insulin. Biochem. J. 249: 209–214, 1988.
 43. Delovitch, T., W., Semple, P. Naquet, N. Bernard, J. Ellis, P. Champagne, and M. Phillips. Pathways of processing of insulin by antigen‐presenting cells. Immunol. Rev. 106: 195–222, 1988.
 44. de Vries, C. P., T. W. Van Haeften, B. R. Rao, and E. A. Van Der Veen. Effect of the insulin degradation inhibitors bacitracin and chloroquine on insulin binding data to H35 rat hepatoma cells. Diabetes Metab. 16: 70–76, 1990.
 45. Ding, L., A. B., Becker, A. Suzuki, and R. A. Roth. Comparison of the enzymatic and biochemical properties of human insulin‐degrading enzyme and Escherichia coli protease III. J. Biol. Chem. 267: 2414–2420, 1992.
 46. Draznin, B., and M. Trowbridge. Inhibition of intracellular proteolysis by insulin in isolated rat hepatocytes: possible role of internalized hormone. J. Biol. Chem. 257: 11988–11993, 1982.
 47. Duckworth, W. C.. Insulin and glucagon binding and degradation by the kidney cell membrane. Endocrinology 102: 1766–1774, 1979.
 48. Duckworth, W. C.. Insulin degradation by liver cell membranes. Endocrinology 104: 1758–1764, 1979.
 49. Duckworth, W. C.. Insulin degradation: mechanisms, products, and significance. Endocr. Rev. 9: 319–345, 1988.
 50. Duckworth, W. C.. Insulin degrading enzyme. In: The Handbook of Experimental Pharmacology, edited by P. Cuatrecasas and S. Jacobs. Berlin: Springer‐Verlag, 1990, vol. 92, p. 143–165.
 51. Duckworth, W. C.. Increasing understanding of calmodulin‐insulin interactions. J. Lab. Clin. Med. 124: 311–312, 1994.
 52. Duckworth, W. C., R. G., Bennett, and F. G. Hamel. A direct inhibitory effect of insulin on a cytosolic proteolytic complex containing insulin‐degrading enzyme and multicatalytic proteinase. J. Biol. Chem. 269: 24575–24580, 1994.
 53. Duckworth, W. C., R. G., Bennett, and F. G. Hamel. The significance of intracellular insulin to insulin action. J. Invest. Med. 45: 20–27, 1997.
 54. Duckworth, W. C., R. G., Bennett, and F. G. Hamel. Insulin acts intracellularly on proteasomes through insulin‐degrading enzyme. Biochem. Biophys. Res. Commun. 244: 390–398, 1998.
 55. Duckworth, W. C., R. G., Bennett, and F. G. Hamel. Insulin degradation: progress and potential. Endocr. Rev. 19: 608–624 (1998) 1998.
 56. Duckworth, W. C., J. V., Garcia, J. J. Liepnieks, F. G. Hamel, M. A. Hermodson, and M. R. Rosner. Drosophila insulin degrading enzyme and rat skeletal muscle insulin protease cleave insulin at similar sites. Biochemistry 28: 2471–2477, 1989.
 57. Duckworth, W. C., D., Gifford, A. E. Kitabchi, K. Runyan, and S. S. Solomon. Insulin binding and degradation by muscles from streptozotocin‐diabetic rats. Diabetes 28: 414–417, 1979.
 58. Duckworth, W. C., F. G., Hamel, R. G. Bennett, M. P. Ryan, and R. A. Roth. Human red blood cell insulin‐degrading enzyme and rat skeletal muscle insulin protease share antigenic sites and generate identical products from insulin. J. Biol. Chem. 265: 2984–2987, 1990.
 59. Duckworth, W. C., F. G., Hamel, J. J. Liepnieks, D. E. Peavy, M. P. Ryan, M. A. Hermodson, and B. H. Frank. Identification of A chain cleavage sites in intact insulin produced by insulin protease and isolated hepatocytes. Biochem. Biophys. Res. Commun. 147: 615–621, 1987.
 60. Duckworth, W. C., F. G., Hamel, D. E. Peavy, J. J. Liepnieks, M. P. Ryan, M. A. Hermodson, and B. H. Frank. Degradation products of insulin generated by hepatocytes and by insulin protease. J. Biol. Chem. 263: 1826–1833, 1988.
 61. Duckworth, W., M., Heinemann, and A. Kitabchi. Purification of insulin specific protease by affinity chromatography. Proc. Natl. Acad. Set U.S.A. 69: 3698–3702, 1972.
 62. Duckworth, W. C., and A. E. Kitabchi. Insulin and glucagon degradation by the same enzyme. Diabetes 23: 536–543, 1974.
 63. Duckworth, W. C., and A. E. Kitabchi. The effect of age on plasma proinsulin in response to oral glucose. J. Lab. Clin. Med. 88: 359–367, 1976.
 64. Duckworth, W. C., and A. E. Kitabchi. Insulin metabolism and degradation. Endocr. Rev. 2: 210–233, 1981.
 65. Dykstra, C. C., and S. R. Kushner. Physical characterization of the cloned protease III gene from Escherichia coli K‐12. J. Bacteriol. 163: 1055–1059, 1985.
 66. Ebrahim, A., F. G., Hamel, R. G. Bennett, and W. C. Duckworth. Identification of the metal associated with the insulin degrading enzyme. Biochem. Biophys. Res. Commun. 181: 1398–1406, 1991.
 67. Evans, D. J., R. G., Hoffman, R. K. Kalkhoff, and A. H. Kissebah. Relationship of body fat topography to insulin sensitivity and metabolic profiles of premenopausal women. Metabolism 33: 68–75, 1984.
 68. Evans, D. J., R., Murray, and A. H. Kissebah. Relationship between skeletal muscle insulin resistance, insulin‐mediated glucose disposal, and insulin binding: effects of obesity and body fat topography. J. Clin. Invest. 74: 1575, 1984.
 69. Fagan, J. M., and L. Waxman. Purification of a protease in red blood cells that degrades oxidatively damaged haemoglobin. Biochem. J. 277: 779–786, 1991.
 70. Fawcett, J., and R. Rabkin. Degradation of insulin by isolated rat renal cortical endosomes. Endocrinology 133: 1539–1547, 1993.
 71. Fawcett, J., and R. Rabkin. Sequential processing of insulin by cultured kidney cells. Endocrinology 136: 39–45, 1995.
 72. Freedman, R. B.. Protein disulfide isomerase: multiple roles in the modification of nascent secretory proteins. Cell 57: 1069–1072, 1989.
 73. Fricke, B., R., Betz, and S. Friebe. A periplasmic insulin‐cleaving proteinase (ICP) from Acinetobacter calcoaceticus sharing properties with protease III from Escherichia coli and IDE from eucaryotes. J. Basic. Microbiol. 35: 21–31, 1995.
 74. Fujita, A., C., Oka, Y. Arikawa, T. Katagal, A. Tonouchi, S. Kuhara, and Y. Misumi. A yeast gene necessary for bud‐site selection encodes a protein similar to insulin‐degrading enzymes. Nature 372: 567–570, 1994.
 75. Garcia, J. V., B. W., Fenton, and M. R. Rosner. Isolation and characterization of an insulin‐degrading enzyme from Drosophila melanogaster. Biochemistry 27: 4237–4244, 1988.
 76. Garcia, J. V., M. P., Stopelli, S. J. Decker, and M. R. Rosner. An insulin epidermal growth factor‐binding protein from Drosophila has insulin‐degrading activity. J. Cell. Biol. 108: 177–182, 1989.
 77. Gehm, B. D., W. L., Kuo, R. K. Perlman, and M. R. Rosner. Mutations in a zinc‐binding domain of human insulin‐degrading enzyme eliminate catalytic activity but not insulin binding. J. Biol. Chem. 268: 7943–7948, 1993.
 78. Gehm, B. D., and M. R. Rosner. Regulation of insulin, epidermal growth factor, and transforming growth factor‐α levels by growth factor degrading enzymes. Endocrinology 128: 1603–1609, 1991.
 79. Gliemann, J., and O. Sonne. Uptake and degradation of insulin and macroglobulin‐trypsin complex in rat adipocyte. Evidence for different pathways. Biochim. Biophys. Acta 845: 124.
 80. Goldfine, I. D., A. L., Jones, G. T. Hradek, and K. Y. Wong. Electron microscope autoradiographic analysis of 125I iodoinsulin entry into adult rat hepatocytes in vivo: evidence for multiple sites of hormone localization. Endocrinology 108: 1821–1828, 1981.
 81. Goldfine, I. D., J. A., Williams, A. C. Bailey, K. Y. Wong, Y. Iwamoto, K. Yokono, S. Baba, and R. A. Rother. Degradation of insulin by isolated mouse pancreatic acini: Evidence for cell surface protease activity. Diabetes 33: 64–72, 1984.
 82. Groop, L., L., Luzi, A. Melander, P. H. Groop, K. Ratheiser, D. C. Simonson, and R. A. DeFronzo. Different effects of glyburide and glipizide on insulin secretion and hepatic glucose production in normal and NIDDM subjects. Diabetes 36: 1320–1328, 1987.
 83. Hachiya, H. L., T., Treves, C. T. Kahn, J. C. Sodoyez, and F. Socoyez‐Gofaux. Altered insulin distribution and metabolism in type I diabetics assessed by 123I insulin scanning. J. Clin. Endocrinol Metab. 64: 801, 1987.
 84. Hamel, F. G., R. G., Bennett, K. S. Harmon, and W. C. Duckworth. Insulin inhibition of proteasomes in intact cells. Biochem. Biophys. Res. Commun. 234: 671–674, 1997.
 85. Hamel, F. G., B. D., Gehm, R. G. Rosner, and W. C. Duckworth. Identification of the cleavage sites of transforming growth factor‐alpha by insulin degrading enzymes. Biochim. Biophys. Acta 1338: 207–214, 1997.
 86. Hamel, F. G., M. J., Mahoney, and W. C. Duckworth. Degradation of intraendosomal insulin by insulin degrading enzyme without acidification. Diabetes 40: 436–443, 1991.
 87. Hamel, F. G., D. E., Peavy, M. P. Ryan, and W. C. Duckworth. High performance liquid chromatographic analysis of insulin degradation by rat skeletal muscle insulin protease. Endocrinology 118: 328–333, 1986.
 88. Hamel, F. G., D. E., Peavy, M. P. Ryan, and W. C. Duckworth. High performance liquid chromatographic analysis of insulin degradation products from isolated hepatocytes: effects of inhibitors suggest intracellular and extracellular pathways. Diabetes 36: 702–708, 1987.
 89. Hamel, F. G., B. I., Posner, J. J. M. Bergeron, B. H. Frank, and W. C. Duckworth. Isolation of insulin degradation products from endosomes derived from intact rat liver. J. Biol. Chem. 263: 6703–6708, 1988.
 90. Harada, S., R. M., Smith, J. A. Smith, and L. Jarett. Inhibition of insulin‐degrading enzyme increases translocation of insulin to the nucleus in H35 rat hepatoma cells: evidence of a cytosolic pathway. Endocrinology 132: 2293–2298, 1993.
 91. Hari, J., K., Shii, and R. A. Roth. In vivo association of 125I insulin with a cytosolic insulin‐degrading enzyme: detection by covalent cross‐linking and immuno‐precipitation with a monoclonal antibody. Endocrinology 120: 829–831, 1987.
 92. Heckmeyer, C., S. S., Solomon, J. Barker, and W. C. Duckworth. Selective antilipolytic effect of bacitracin in the isolated fat cell. Biochem. Biophys. Res. Commun. 108: 336–343, 1982.
 93. Hennes, M. M., A., Dua, and A. H. Kissebah. Effects of free fatty acids and glucose on splanchnic insulin dynamics. Diabetes 46: 57–62, 1997.
 94. Hofmann, C. A., R. M., Lotan, W. W. Ku, and T. N. Oeltmann. Insulin‐ricin B hybrid molecules mediate an insulin‐associated effect on cells which do not bind insulin. J. Biol. Chem. 258: 11774–11779, 1983.
 95. Hovorka, R., J. K., Powrie, G. D. Smith, P. H. Sonksen, E. R. Carson, and R. H. Jones. Five‐compartment model of insulin kinetics and its use to investigate action of chloroquine in NIDDM. Am. J. Physiol. 265 (Endocrinol. Metab. 28): E162–E175, 1993.
 96. Huber, C. T., S. S., Solomon, and W. C. Duckworth. The time course of insulin degradation in the perfused isolated fat cell. J. Clin. Invest. 65: 461–468, 1980.
 97. Ishida, T., Z., Chap, J. Chou, R. Lewis, C. Hartley, M. Entman, and J. B. Field. Differential effects of oral, peripheral intravenous, and intraportal glucose on hepatic glucose uptake and insulin and glucagon extraction in conscious dogs. J. Clin. Invest. 72: 590–601, 1983.
 98. Ishida, T., J., Chou, R. M. Lewis, C. J. Hartley, M. Entman, and J. B. Field. The effect of ingestion of meat on hepatic extraction of insulin and glucagon and hepatic glucose output in conscious dogs. J. Clin. Endocrinol. Metab. 32: 558–567, 1983.
 99. Ishida, T., M. C. Y., Chou, R. M. Lewis, C. J. Hartley, M. Entman, and J. B. Field. The effect of tolbutamide on hepatic extraction of insulin and glucagon and hepatic glucose output in anesthetized dogs. Endocrinology 109: 443–450, 1981.
 100. Ishida, T., R. M., Lewis, C. J. Hartley, M. Entman, and J. B. Field. Comparison of hepatic extraction of insulin and glucagon in conscious and anesthetized dogs. Endocrinology 112: 1098–1109, 1983.
 101. Ishida, T., S., Rojdmark, G. Bloom, M. C. Y. Chou, and J. B. Field. The effect of somatostatin on the hepatic extraction of insulin and glucagon in the anesthetized dog. Endocrinology 106: 220–230, 1980.
 102. Jochen, A., J., Hays, and M. Lee. Kinetics of insulin internalization and processing in adipocytes: Effects of insulin concentration. J. Cell. Physiol. 141: 527–534, 1989.
 103. Jochen, A. L., and P. Berhanu. Insulin‐stimulated glucose transport and insulin internalization share a common postbinding step in adipocytes. Diabetes 36: 542–545, 1987.
 104. Jones, C. N., D., Pei, P. Starts, K. S. Polonsky, Y. D. Chen, and G. M. Reaven. Alterations in the glucose‐stimulated insulin secretory dose‐response curve and in insulin clearance in nondiabetic insulin‐resistant individuals. J. Clin. Endocrinol. Metab. 82: 1834–1838, 1997.
 105. Kaderbhai, M. A., and B. M. Austen. Studies on the formation of interchain disulfide bonds in newly synthesized bovine prolactin. Eur. J. Biochem. 153: 167–178, 1985.
 106. Katzen, H., and F. Tietze. Studies on the specificity and mechanism of action of hepatic glutathione‐insulin transhydrogenase. J. Biol. Chem. 241: 3561, 1972.
 107. Kayalar, C., and W. Wong. Metalloendoprotease inhibitors which block the differentiation of L6 myoblasts inhibit insulin degradation by the endogenous insulin‐degrading enzyme. J. Biol. Chem. 264: 8928–8934, 1989.
 108. Kayalar, C., W. T., Wong, and L. Hendrickson. Differentiation of BC3H1 and primary skeletal muscle cells and the activity of their endogenous insulin‐degrading enzyme are inhibited by the same metalloendoprotease inhibitors. J. Cell. Biochem. 44: 137–151, 1990.
 109. Kitabchi, A. E., W. C., Duckworth, J. S. Brush, and M. Heinemann. 1971. Direct measurement of proinsulin in human plasma by the use of an insulin degrading enzyme. J. Clin. Invest. 50: 1792–1799, 1971.
 110. Kolb, H., and E. Standi. Purification to homogeneity of an insulin‐degrading enzyme from human erythrocytes. Hoppe Seyler Z. Physiol. Chem. 361: 1029–1039, 1980.
 111. Kole, H. K., G., Muthukumar, and J. Lenard. Purification and properties of a membrane‐bound insulin binding protein, a putative receptor, from Neurospora crassa. Biochemistry 30: 682–688, 1991.
 112. Kole, H. K., D. R., Smith, and J. Lenard. Characterization and partial purification of an insulinase from Neurospora crassa. Arch. Biochem. Biophys. 297: 199–204, 1992.
 113. Krakover, G. R., D. A., Meier, and A. H. Kissebah. Female sex hormones, perinatal, and peripubertal androgenization on hepatocyte insulin dynamics in rats. Am. J. Physiol. 264 (Endocrinol. Metab. 27): E342–E347, 1993.
 114. Kruse, V., I., Jensen, L. Permin, and A. Heding. Fate of insulin analogs in intact and nephrectomized rats determined by their receptor binding constants. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E1089–E1098, 1997.
 115. Kuo, W. L., B. D., Gehm, and M. R. Rosner. Regulation of insulin degradation: expression of an evolutionarily conserved insulin‐degrading enzyme increases degradation via an intracellular pathway. Mol. Endocrinol. 5: 1467–1476, 1991.
 116. Kuo, W. L., B. D., Gehm, M. R. Rosner, W. Li, and G. Keller. Inducible expression and cellular localization of insulin‐degrading enzyme in a stably transfected cell line. J. Biol. Chem. 269: 22599–22606, 1994.
 117. Kuo, W. L., A. G., Montag, and M. R. Rosner. Insulin‐degrading enzyme is differentially expressed and developmentally regulated in various rat tissues. Endocrinology 132: 604–611, 1993.
 118. Kupfer, S. R., E. M., Wilson, and F. S. French. Androgen and glucocorticoid receptors interact with insulin degrading enzyme. J. Biol. Chem. 269: 20622–20628, 1994.
 119. Kurochkin, I. V., and S. Goto. Alzheimer's β‐amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 345: 33–37, 1994.
 120. Lau, P. P., M. Van Handel, M. Larvin, M. J. McMahon, and M. C. Geokas. Proteolytic degradation of human recombinant proinsulin/insulin by sera from acute pancreatitis patients and complete inhibition by Eglin‐C. Pancreas 5: 17–26, 1990.
 121. Letiexhe, M. R., A. J., Scheen, P. L. Gerard, B. H. Basterns, J. Pirotte, J. Belaiche, and P. J. Lefebvre. Insulin secretion, clearance, and action on glucose metabolism in cirrhotic patients. J. Clin. Endocrinol. Metab. 77: 1263–1268, 1993.
 122. Levy, J., and J. Olefsky. Retroendocytosis of insulin in rat adipocytes. Endocrinology 119: 572–579, 1986.
 123. Levy, J., and J. M. Olefsky. The effect of insulin concentration on retroendocytosis in isolated rat adipocytes. Endocrinology 120: 450–456, 1987.
 124. Marshall, S.. Degradative processing of internalized insulin in isolated adipocytes. J. Biol. Chem. 260: 13517, 1985.
 125. Marshall, S., W. T., Garvey, and R. Monzon. Shunting of insulin from a retroendocytotic pathway to a degradative pathway by sodium vanadate. J. Biol. Chem. 262: 12005, 1987.
 126. McDermott, J. R., and A. M. Gibson. Degradation of Alzheimer's β‐amyloid protein by human and rat brain peptidases: involvement of insulin‐degrading enzyme. Neurochem. Res. 22: 49–56, 1997.
 127. McKenzie, R. A., and G. A. Burghen. Partial purification and characterization of insulin protease and its intracellular inhibitor from rat liver. Arch. Biochem. Biophys. 229: 604–611, 1984.
 128. Medina, V., L., Kesner, and A. Stracher. Purification of nonantibiotic insulinase inhibitors from bacitracin. Biochem. Med. Metab. Biol. 49: 255–264, 1993.
 129. Miller, D. S.. Stimulation of RNA and protein synthesis by intracellular insulin. Science 240: 506–509, 1988.
 130. Miller, D. S.. Stimulation of protein synthesis in stage IV Xenopus oocytes by microinjected insulin. J. Biol. Chem. 264: 10438–10446, 1989.
 131. Miller, D. S., and D. B. Sykes. Stimulation of protein synthesis by internalized insulin. J. Cell. Physiol. 147: 487–194, 1991.
 132. Mirsky, I. A.. Some considerations of the etiology of diabetes mellitus in man. Proc. Am. Diabetes Assoc. 5: 119–138, 1945.
 133. Mirsky, I. A.. Insulinase, insulinase inhibitors, and diabetes mellitus. Recent Prog. Horm. Res. 13: 429–471, 1957.
 134. Misbin, R. I., and E. C. Almira. Degradation of insulin and insulin‐like growth factors by enzyme purified from human erythrocytes. Comparison of degradatic products observed with a B26–[125I]monoiodoinsulin. Diabetes 38: 152–157, 1989.
 135. Misbin, R. I., E. C., Almira, and M. W. Cleman. Insulin degradation in serum of a patient with apparent insulin resistance. J. Clin. Endocrinol. Metab. 52: 177–180, 1981.
 136. Misbin, R. I., E. C., Almira, W. C. Duckworth, and T. D. Mehl. 1983. Inhibition of insulin degradation by insulin‐like growth factors. Endocrinology 113: 1525–1527, 1983.
 137. Mondon, C. E., G. M., Reaven, S. Azhar, C. M. Lee, and R. Rabkin. Abnormal insulin metabolism by specific organs from rats with spontaneous hypertension. Am. J. Physiol. 257 (Endocrinol. Metab. 20): E491–E498, 1989.
 138. Morishima, T., S., Pye, C. Bradshaw, and J. Radziuk. Posthepatic rate of appearance of insulin: measurement and validation in the nonsteady state. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E772–E779, 1992.
 139. Muir, A., R. E., Offord, and J. G. Davies. The identification of a major product of the degradation of insulin by “insulin proteinase.” Biochem. J. 237: 631–637, 1986.
 140. Muller, D., H., Baumeister, F. Buck, and D. Richter. Atrial natriuretic peptide (ANP) is a high‐affinity substrate for rat insulin‐degrading enzyme. Eur. J. Biochem. 202: 285–292, 1991.
 141. Muller, D., C., Schulze, H. Baumeister, F. Buck, and D. Richter. Rat insulin‐degrading enzyme: cleavage pattern of the natriuretic peptide hormones ANP, BNP and CNP revealed by HPLC and mass spectrometry. Biochemistry 31: 11138–11143, 1992.
 142. Naquet, P., J., Ellis, B. Singh, R. S. Hodges, and T. L. Delovitch. Processing and presentation of insulin I. Analysis of immunogenic peptides and processing requirements for insulin A loop‐specific T cells. J. Immunol. 139: 3955–3963, 1987.
 143. Neal, G. W., S. S., Solomon, and W. C. Duckworth. Internalization and degradation of glucagon by human mononuclear cells. Horm. Metab. Res. 18: 540–545, 1986.
 144. Noiva, R., and W. Lennarz. Protein disulfide isomerase. J. Biol. Chem. 267: 3553–3556, 1992.
 145. Ogawa, W., K., Shii, K. Yonezawa, S. Baba, and K. Yokono. Affinity purification of insulin‐degrading enzyme and its endogenous inhibitor from rat liver. J. Biol. Chem. 267: 1310–1316, 1992.
 146. Okuda, Y., J., Pena, J. Chou, and J. B. Field. Effect of growth hormone on hepatic glucose and insulin metabolism after oral glucose in conscious dogs. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E454–E460, 1994.
 147. Olefsky, J. M., and M. Saekow. Mechanisms of insulin degradation by isolated rat adipocytes. Mol. Cell. Biochem. 47: 23, 1982.
 148. Paulsen, E. P., J. W., Courtney, and W. C. Duckworth. Insulin resistance due to massive destruction of subcutaneous insulin. Diabetes 28: 640–645, 1979.
 149. Pease, R. J., G. D., Smith, and T. J. Peters. Degradation of endocytosed insulin in rat liver is mediated by low density vesicles. Biochem. J. 228: 137–146, 1985.
 150. Peavy, D. E., J. W., Edmondson, and W. C. Duckworth. Selective effects of inhibitors of hormone processing on insulin action in isolated hepatocytes. Endocrinology 114: 753–760, 1984.
 151. Peiris, A. N., R. A., Mueller, M. F. Struve, G. A. Smith, and A. H. Kissebah. Splanchnic insulin metabolism in obesity—influence of body fat distribution. J. Clin. Invest. 78: 1648–1657, 1986.
 152. Peiris, A. N., R. A., Mueller, M. F. Struve, G. A. Smith, and A. H. Kissebah. Relationship of andogenic activity to splanchnic insulin metabolism and peripheral glucose utilization in premenopausal women. J. Clin. Endocrinol. Metab. 64: 162–169, 1987.
 153. Pell, M. E., W. C., Duckworth, and D. E. Peavy. Localization of insulin degradation products to an intracellular site in isolated rat hepatocytes. Biochem. Biophys. Res. Commun. 137: 1034–1040, 1986.
 154. Perlman, R. K., B. D., Gehm, W. L. Kuo, and M. R. Rosner. Functional analysis of conserved residues in the active site of insulin‐degrading enzyme. J. Biol. Chem. 268: 21538–21544, 1993.
 155. Perlman, R. K., and M. R. Rosner. Identification of zinc ligands of the insulin‐degrading enzyme. J. Biol. Chem. 269: 33140–33145, 1994.
 156. Petersen, J., J., Kitaji, W. C. Duckworth, and R. Rabkin. Fate of 125I‐insulin removed from the peritubular circulation of the isolated perfused rat kidney. Am. J. Physiol. 243: (Renal Fluid Electrolyte Physiol. 12): F126–F132, 1982.
 157. Petruzzelli, L., R., Herrera, R. Garcia‐Arenas, and O. M. Rosen. Acquisition of insulin‐dependent protein tyrosine kinase activity during Drosophila embryogenesis. J. Biol. Chem. 260: 16072–16075, 1985.
 158. Philippe, J., P. A., Halban, A. Gjinovci, W. C. Duckworth, J. Estreicher, and A. E. Renold. Increased clearance and degradation of 3H insulin in streptozotocin diabetic rats: role of the insulin‐receptor compartment. J. Clin. Invest. 67: 673–680, 1981.
 159. Pierotti, A. R., A., Prat, V. Chesneau, F. Gaudoux, A. M. Leseney, T. Foulon, and P. Cohen. N‐Arginine dibasic convertase, a metalloendopeptidase as a prototype of a class of processing enzymes. Proc. Natl. Acad. Sci. U.S.A. 91: 6078–6082, 1994.
 160. Powers, A. C., S. S., Solomon, and W. C. Duckworth. Insulin degradation by mononuclear cells. Diabetes 29: 27—32, 1980.
 161. Rabkin, R., and J. Kitaji. Renal metabolism of peptide hormones. Miner. Electrolyte. Metab. 9: 212–226, 1983.
 162. Rabkin, R., M. P., Ryan, and W. C. Duckworth. Renal metabolism of insulin. Diabetologia 27: 351–357, 1984.
 163. Rabkin, R., S. A., Unterhalter, and W. C. Duckworth. Effect of prolonged uremia on insulin metabolism by isolated liver and muscle. Kidney. Int. 16: 433–439, 1979.
 164. Rawlings, N. D., and A. J. Barrett. Homologues of insulinase, a new superfamily of metalloendopeptidases. Biochem. J. 275: 389–391, 1991.
 165. Rawlings, N. D., and A. J. Barrett. Evolutionary families of peptidases. Biochem. J. 290: 205–218, 1993.
 166. Rojdmark, S., G., Bloom, C. Y. Chou, and J. B. Field. Hepatic extraction of exogenous insulin and glucagon in the dog. Endocrinology 102: 806–813, 1978.
 167. Rojdmark, S., G., Bloom, M. C. Y. Chou, J. B. Jaspan, and J. B. Field. Hepatic insulin and glucagon extraction after their augmented secretion in dogs. Am. J. Physiol. 235 (Edocrinol. Metab. Gastrointest. Physiol. 4): E88–E96, 1978.
 168. Roth, R., M., Mesirow, D. Cassell, K. Yokono, and S. Baba. Characterization of an insulin degrading enzyme from cultured human lymphocytes. Diabetes. Res. Clin. Pract. 1: 31–39, 1985.
 169. Roth, R. A., and M. E. Koshland. Role of disulfide interchange enzyme in immunoglobulin synthesis. Biochemistry 20: 6594–6599, 1981.
 170. Roth, R. A., and B. Maddux. Insulin‐cholera toxin binding unit conjugate: a hybrid molecule with insulin biological activity and cholera toxin binding specificity. J. Cell. Physiol. 115: 151, 1983.
 171. Roth, R. A., M. L., Mesirow, K. Yokono, and S. Baba. Degradation of insulin‐like growth factors I and II by a human insulin degrading enzyme. Endocr. Res. 10: 101–112, 1984.
 172. Roth, R. A., B., Zhang, J. E. Chin, and K. Kovacina. Substrates and signalling complexes: the tortured path to insulin action. J. Cell. Biochem. 48: 12–18, 1992.
 173. Ryan, M. P., and W. C. Duckworth. Partial characterization of an endogenous inhibitor of a calcium‐dependent form of insulin protease. Biochem. Biophys. Res. Commun. 116: 195–203, 1983.
 174. Ryan, M. P., J. D., Gifford, S. S. Solomon, and W. C. Duckworth. The calcium dependence of insulin degradation by rat skeletal muscle. Endocrinology 117: 1693–1698, 1985.
 175. Safavi, A., B. C., Miller, L. Cottam, and L. B. Hersh. Identification of γ endorphin‐generating enzyme as insulin‐degrading enzyme. Biochemistry 35: 14318–14325, 1996.
 176. Sato, H., T., Terasaki, H. Mizuguchi, K. Okumura, and A. Tsuji. Receptor‐recycling model of clearance and distribution of insulin in the perfused mouse liver. Diabetologia 34: 613–621, 1991.
 177. Sato, H., K., Yoshioka, T. Terasaki, and A. Tsuji. Receptor‐mediated endocytosis of A14‐125I‐insulin by the nonfiltering perfused rat kidney. Biochim. Biophys. Acta 1073: 442–450, 1991.
 178. Savoy, L. A., R. M., Jones, S. Pochon, J. G. Davies, A. V. Muir, R. E. Offord, and K. Rose. Identification by fast atom bombardment mass spectrometry of insulin fragments produced by insulin proteinase. Biochem. J. 249: 215–222, 1988.
 179. Schade, D. S., D. A., Drumm, W. C. Duckworth, and R. P. Eaton. 1985. The etiology of incapacitating brittle diabetes. Diabetes Care 8: 18–20, 1985.
 180. Schade, D. S., and W. C. Duckworth. In search of the subcutaneous insulin degradation syndrome. N. Engl J. Med. 315: 147–153, 1986.
 181. Schade, D. S., R. P., Eaton, D. A. Drumm, and W. C. Duckworth. 1985. A clinical algorithm to determine the etiology of brittle diabetes. Diabetes Care 8: 5–11, 1985.
 182. Seabright, P. J., and G. D. Smith. The characterization of endosomal insulin degradation intermediates and their sequence of production. Biochem. J. 320: 947–956, 1996.
 183. Semple, J., J., Ellis, and T. Delovitch. Processing and presentation of insulin II. Evidence for intracellular, plasma membrane‐associated and extracellular degradation of human insulin by antigen presenting B cells. J. Immunol. 142: 4184–4193, 1989.
 184. Semple, J. W., Y., Lang, E. R. Speck, and T. L. Delovitch. Processing and presentation of insulin. III. Insulin degrading enzyme: a neutral metalloendoproteinase that is non‐homologous to classical endoproteinases mediates the processing of insulin epitopes for helper T cells. Int. Immunol. 4: 1161–1167, 1992.
 185. Seta, K. A., and R. A. Roth. Overexpression of insulin degrading enzyme: Cellular localization and effects on insulin signaling. Biochem. Biophys. Res. Commun. 231: 167–171, 1997.
 186. Shearer, J. D., C. F., Coulter, W. C. Engeland, R. A. Roth, and M. D. Caldwell. Insulin is degraded extracellularly in wounds by insulin‐degrading enzyme (EC 3.4.24.56). Amer. J. Physiol. 273: E657–E664, 1997.
 187. Shii, K., S., Baba, K. Yokono, and R. A. Roth. Covalent linkage of 125I insulin to a cytosolic insulin degrading enzyme. J. Biol. Chem. 260: 6503–6506, 1985.
 188. Shii, K., and R. A. Roth. Inhibition of insulin degradation by hepatoma cells after microinjections of monoclonal antibodies to a specific cytosolic protease. Proc. Natl. Acad. Sci. U.S.A. 83: 4147–4151, 1986.
 189. Shii, K., K., Yokono, S. Baba, and R. Roth. Purification and characterization of insulin‐degrading enzyme from human erythrocytes. Diabetes 35: 675–683, 1986.
 190. Smith, R. M., S., Harada, and L. Jarett. Insulin internalization and other signaling pathways in the pleiotropic effects of insulin. Int. Rev. Cytol. 173: 243–280, 1997.
 191. Smith, R. M., and L. Jarett. Ultrastructural evidence for the accumulation of insulin in nuclei of intact 3T3–L1 adipocytes by an insulin‐receptor mediated process. Proc. Natl. Acad. Sci. U.S.A. 84: 459–463, 1987.
 192. Smith, R. M., and L. Jarett. Differences in adenosine triphosphate dependency of receptor‐mediated endocytosis of α2‐macroglobulin and insulin correlate with separate routes of ligand‐receptor complex internalization. Endocrinology 126: 1551–1560, 1990.
 193. Smith, R. M., and L. Jarett. Partial characterization of mechanism of insulin accumulation in H35 hepatoma cell nuclei. Diabetes 39: 683–689, 1990.
 194. Soler, A. P., K. A., Thompson, R. M. Smith, and L. Jarett. Immunological demonstration of the accumulation of insulin, but not insulin receptors, in nuclei of insulin‐treated cells. Proc. Natl. Acad. Sci. U.S.A. 86: 6640–6644, 1989.
 195. Sonne, O.. The reversible receptor binding of insulin in isolated rat adipocytes measured at 37 degrees: the binding is not rate limiting for cellular uptake. Biochim. Biophys. Acta 886: 302–309, 1986.
 196. Sonne, O., and J. Gliemann. The mechanisms of receptor mediated degradation of insulin in isolated rat adipocytes: indirect evidence for a nonlysosomal pathway. Mol. Cell. Endocrinol. 31: 315, 1983.
 197. Steiner, D. F.. Insulin today. Diabetes 26: 322–331, 1977.
 198. Stentz, F. B., H. L., Harris, and A. E. Kitabchi. Characterization of insulin‐degrading activity of intact and subcellular components of human fibroblasts. Endocrinology 116: 926–934, 1985.
 199. Stentz, F. B., A., Kitabchi, J. W. Schilling, L. R. Schronk, and J. M. Seyer. Identification of insulin intermediates and sites of cleavage of native insulin by insulin protease from human fibroblasts. J. Biol. Chem. 264: 20275–20282, 1989.
 200. Stoppelli, M. P., J. V., Garcia, S. J. Decker, and M. R. Rosner. Developmental regulation of an insulin degrading enzyme from Drosophila melanogaster. Proc. Natl. Acad. Sci. U.S.A. 85: 3469–3473, 1988.
 201. Surmacz, C. A., J. J., Wert, W. F. Ward, and G. E. Mortimore. Uptake and intracellular fate of [14C] sucrose‐insulin in perfused rat livers. Am. J. Physiol. 255 (Cell Physiol. 24): C70–C75, 1988.
 202. Svedberg, J., P., Bjorntorp, U. Smith, and P. Lonnroth. Free‐fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 39: 570–574, 1990.
 203. Terris, S., and D. F. Steiner. Binding and degradation of 125I‐insulin by rat hepatocytes. J. Biol. Chem. 250: 8389–8398, 1975.
 204. Thies, R. S., A., Ullrich, and D. A. McClain. Augmented mitogenesis and impaired metabolic signaling mediated by a truncated insulin receptor. J. Biol. Chem. 264: 12820–12825, 1989.
 205. Thompson, K. A., A. P., Soler, R. M. Smith, and L. Jarett. Intranuclear localization of insulin in rat hepatoma cells: insulin/matrix association. Eur. J. Cell. Biol. 50: 442–446, 1989.
 206. Tsao, T. C., J. D., Shi, G. E. Mortimore, E. J. Cragoe, Jr., and R., Rabkin. Modulation of kidney cell protein degradation by insulin. J. Lab. Clin. Med. 116: 369–376, 1990.
 207. Varandani, P. T., L. A., Shroyer, and M. A. Nafz. Sequential degradation of insulin by rat liver homogenates. Proc. Natl. Acad. Sci. U.S.A. 69: 1681–1684, 1972.
 208. Wahlqvist, M. L., L., Kaijser, B. W. Lassers, H. Low, and L. A. Carlson. Release of immunoreactive insulin from the human heart. Eur. J. Clin. Invest. 2: 407–411, 1972.
 209. Ward, W. F., and A. L. Moss. Effects of lysosomal inhibitors on 125I insulin and 125I asioalofetuin degradation by the isolated, perfused rat liver and isolated rat hepatocytes. Diabetes 34: 446–451, 1985.
 210. Wilden, P. A., J. M., Backer, C. R. Kahn, D. A. Cahill, G. J. Schroeder, and M. F. White. The insulin receptor with phenylalanine replacing tyrosine‐1146 provides evidence for separate signals regulating cellular metabolism and growth. Proc. Natl. Acad. Sci. U.S.A. 87: 3358–3362, 1990.
 211. Williams, F. G., D. E., Johnson, and G. E. Bauer. [125I]‐Insulin Metabolism by the rat liver in vivo: Evidence that a neutral thiol‐protease mediates rapid intracellular insulin degradation. Metabolism 39: 231–241, 1990.
 212. Yokono, K., Y., Imamura, H. Sakai, and S. Baba. Insulin‐degrading activity of plasma membranes from rat skeletal muscle: its isolation, characterization, and biologic significance. Diabetes 28: 810–817, 1979.
 213. Yokono, K., Y., Imamura, K. Shii, H. Sakai, and S. Baba. Purification and characterization of insulin‐degrading enzyme from pig skeletal muscle. Endocrinology 108: 1527–1532, 1981.
 214. Yokono, K., R. A., Roth, and S. Baba. Identification of insulin‐degrading enzyme on the surface of cultured human lymphocytes, rat hepatoma cells, and primary cultures of rat hepatocytes. Endocrinology 111: 1102–1108, 1982.
 215. Yonezawa, K., K., Yokono, K. Shii, J. Hari, S. Yaso, K. Amano, T. Sakamoto, Y. Kawase, H. Akiyama, M. Nagata, and S. Baba. Insulin‐degrading enzyme is capable of degrading receptor‐bound insulin. Biochem. Biophys. Res. Commun. 150: 605–614, 1988.
 216. Yonezawa, K., K., Yokono, S. Yaso, J. Hari, K. Amano, Y. Kawase, T. Sakamoto, K. Shii, S. Baba and Y. Imamura. Degradation of insulin by insulin degrading enzyme and biological characterization of its fragments. Endocrinology 118: 1989, 1986.

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Article Title: Insulin Degradation and Insulin‐Degrading Enzyme
 

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William C. Duckworth, Frederick G. Hamel. Insulin Degradation and Insulin‐Degrading Enzyme. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 177-194. First published in print 2001. doi: 10.1002/cphy.cp070207