Cargo Molecules in Secretory Granule: Comparison
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Melkam Alamerew Kebede.

The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. The luminal components of the insulin SG can be functionally segregated into four groups. These are cargo molecules, luminal enzymes and chaperones, ions (and their transporters and channels), and sorting receptors.

  • insulin
  • islet amyloid polypeptide (IAPP)
  • granin
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References

  1. Orci, L.; Halban, P.; Amherdt, M.; Ravazzola, M.; Vassalli, J.D.; Perrelet, A. Nonconverted, Amino Acid Analog-Modified Proinsulin Stays in a Golgi-Derived Clathrin-Coated Membrane Compartment. J. Cell Biol. 1984, 99, 2187–2192.
  2. Rhodes, C.J.; Halban, P.A. 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. 1987, 105, 145–153.
  3. Michael, J.; Carroll, R.; Swift, H.H.; Steiner, D.F. Studies on the Molecular Organization of Rat Insulin Secretory Granules. J. Biol. Chem. 1987, 262, 16531–16535.
  4. Davidson, H.W.; Rhodes, C.J.; Hutton, J.C. Intraorganellar Calcium and pH Control Proinsulin Cleavage in the Pancreatic Beta Cell via Two Distinct Site-Specific Endopeptidases. Nature 1988, 333, 93–96.
  5. Smeekens, S.P.; Montag, A.G.; Thomas, G.; Albiges-Rizo, C.; Carroll, R.; Benig, M.; Phillips, L.A.; Martin, S.; Ohagi, S.; Gardner, P. Proinsulin Processing by the Subtilisin-Related Proprotein Convertases Furin, PC2, and PC3. Proc. Natl. Acad. Sci. USA 1992, 89, 8822–8826.
  6. Orci, L.; Ravazzola, M.; Storch, M.J.; Anderson, R.G.; Vassalli, J.D.; Perrelet, A. Proteolytic Maturation of Insulin Is a Post-Golgi Event Which Occurs in Acidifying Clathrin-Coated Secretory Vesicles. Cell 1987, 49, 865–868.
  7. Kuliawat, R.; Klumperman, J.; Ludwig, T.; Arvan, P. Differential Sorting of Lysosomal Enzymes out of the Regulated Secretory Pathway in Pancreatic Beta-Cells. J. Cell Biol. 1997, 137, 595–608.
  8. Baker, E.N.; Blundell, T.L.; Cutfield, J.F.; Dodson, E.J.; Dodson, G.G.; Hodgkin, D.M.C.; Hubbard, R.E.; Isaacs, N.W.; Reynolds, C.D.; Sakabe, K.; et al. The Structure of 2Zn Pig Insulin Crystals at 1.5 Å Resolution. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1988, 319, 369–456.
  9. Halban, P.A. Inhibition of Proinsulin to Insulin Conversion in Rat Islets Using Arginine and Lysine Analogs. Lack of Effect on Rate of Release of Modified Products. J. Biol. Chem. 1982, 257, 13177–13180.
  10. Seaquist, E.R.; Kahn, S.E.; Clark, P.M.; Hales, C.N.; Porte, D., Jr.; Robertson, R.P. Hyperproinsulinemia Is Associated with Increased Beta Cell Demand after Hemipancreatectomy in Humans. J. Clin. Investig. 1996, 97, 455–460.
  11. Mezza, T.; Ferraro, P.M.; Sun, V.A.; Moffa, S.; Cefalo, C.M.A.; Quero, G.; Cinti, F.; Sorice, G.P.; Pontecorvi, A.; Folli, F.; et al. Increased β-Cell Workload Modulates Proinsulin-to-Insulin Ratio in Humans. Diabetes 2018, 67, 2389–2396.
  12. Alarcon, C.; Boland, B.B.; Uchizono, Y.; Moore, P.C.; Peterson, B.; Rajan, S.; Rhodes, O.S.; Noske, A.B.; Haataja, L.; Arvan, P.; et al. Pancreatic β-Cell Adaptive Plasticity in Obesity Increases Insulin Production but Adversely Affects Secretory Function. Diabetes 2016, 65, 438–450.
  13. Ward, W.K.; LaCava, E.C.; Paquette, T.L.; Beard, J.C.; Wallum, B.J.; Porte, D., Jr. Disproportionate Elevation of Immunoreactive Proinsulin in Type 2 (non-Insulin-Dependent) Diabetes Mellitus and in Experimental Insulin Resistance. Diabetologia 1987, 30, 698–702.
  14. Yoshino, H.; Kawakami, K.; Yoshino, G.; Hirose, T. Age-Related Changes of Proinsulin Processing in Diabetic and Non-Diabetic Japanese Individuals. Geriatr. Gerontol. Int. 2018, 18, 1046–1050.
  15. Pfützner, A.; Standl, E.; Hohberg, C.; Konrad, T.; Strotmann, H.-J.; Lübben, G.; Langenfeld, M.R.; Schulze, J.; Forst, T. IRIS II Study: Intact Proinsulin Is Confirmed as a Highly Specific Indicator for Insulin Resistance in a Large Cross-Sectional Study Design. Diabetes Technol. Ther. 2005, 7, 478–486.
  16. Pradhan, A.D.; Manson, J.E.; Meigs, J.B.; Rifai, N.; Buring, J.E.; Liu, S.; Ridker, P.M. Insulin, Proinsulin, Proinsulin:insulin Ratio, and the Risk of Developing Type 2 Diabetes Mellitus in Women. Am. J. Med. 2003, 114, 438–444.
  17. Nijpels, G.; Popp-Snijders, C.; Kostense, P.J.; Bouter, L.M.; Heine, R.J. Fasting Proinsulin and 2-H Post-Load Glucose Levels Predict the Conversion to NIDDM in Subjects with Impaired Glucose Tolerance: The Hoorn Study. Diabetologia 1996, 39, 113–118.
  18. Vangipurapu, J.; Stančáková, A.; Kuulasmaa, T.; Kuusisto, J.; Laakso, M. Both Fasting and Glucose-Stimulated Proinsulin Levels Predict Hyperglycemia and Incident Type 2 Diabetes: A Population-Based Study of 9,396 Finnish Men. PLoS ONE 2015, 10, e0124028.
  19. Yang, Y.; Wang, M.; Tong, J.; Dong, Z.; Deng, M.; Ren, X.; Li, H.; Yang, J.; Meng, Z.; Sun, J.; et al. Impaired Glucose-Stimulated Proinsulin Secretion Is an Early Marker of β-Cell Impairment Before Prediabetes Stage. J. Clin. Endocrinol. Metab. 2019, 104, 4341–4346.
  20. Porte, D., Jr.; Kahn, S.E. Hyperproinsulinemia and Amyloid in NIDDM. Clues to Etiology of Islet Beta-Cell Dysfunction? Diabetes 1989, 38, 1333–1336.
  21. Rhodes, C.J.; Alarcón, C. What Beta-Cell Defect Could Lead to Hyperproinsulinemia in NIDDM? Some Clues from Recent Advances Made in Understanding the Proinsulin-Processing Mechanism. Diabetes 1994, 43, 511–517.
  22. Ohsawa, H.; Kanatsuka, A.; Yamaguchi, T.; Makino, H.; Yoshida, S. Islet Amyloid Polypeptide Inhibits Glucose-Stimulated Insulin Secretion from Isolated Rat Pancreatic Islets. Biochem. Biophys. Res. Commun. 1989, 160, 961–967.
  23. Natori, S.; Huttner, W.B. Chromogranin B (secretogranin I) Promotes Sorting to the Regulated Secretory Pathway of Processing Intermediates Derived from a Peptide Hormone Precursor. Proc. Natl. Acad. Sci. USA 1996, 93, 4431–4436.
  24. Carmon, O.; Laguerre, F.; Riachy, L.; Delestre-Delacour, C.; Wang, Q.; Tanguy, E.; Jeandel, L.; Cartier, D.; Thahouly, T.; Haeberlé, A.-M.; et al. Chromogranin A Preferential Interaction with Golgi Phosphatidic Acid Induces Membrane Deformation and Contributes to Secretory Granule Biogenesis. FASEB J. 2020.
  25. Bartolomucci, A.; Possenti, R.; Mahata, S.K.; Fischer-Colbrie, R.; Loh, Y.P.; Salton, S.R.J. The Extended Granin Family: Structure, Function, and Biomedical Implications. Endocr. Rev. 2011, 32, 755–797.
  26. Hutton, J.C.; Peshavaria, M. Proton-Translocating Mg2+-Dependent ATPase Activity in Insulin-Secretory Granules. Biochem. J. 1982, 204, 161–170.
  27. Schoonderwoert, V.T.; Holthuis, J.C.; Tanaka, S.; Tooze, S.A.; Martens, G.J. Inhibition of the Vacuolar H+-ATPase Perturbs the Transport, Sorting, Processing and Release of Regulated Secretory Proteins. Eur. J. Biochem. 2000, 267, 5646–5654.
  28. Lemaire, K.; Chimienti, F.; Schuit, F. Zinc Transporters and Their Role in the Pancreatic β-Cell. J. Diabetes Investig. 2012, 3, 202–211.
  29. Hutton, J.C.; Penn, E.J.; Peshavaria, M. Low-Molecular-Weight Constituents of Isolated Insulin-Secretory Granules. Bivalent Cations, Adenine Nucleotides and Inorganic Phosphate. Biochem. J. 1983, 210, 297–305.
  30. Hur, Y.S.; Yoo, S.H. Distribution Profile of Inositol 1,4,5-Trisphosphate Receptor/Ca2+ Channels in α and β Cells of Pancreas: Dominant Localization in Secretory Granules and Common Error in Identification of Secretory Granule Membranes. Pancreas 2015, 44, 158–165.
  31. Mitchell, K.J.; Pinton, P.; Varadi, A.; Tacchetti, C.; Ainscow, E.K.; Pozzan, T.; Rizzuto, R.; Rutter, G.A. Dense Core Secretory Vesicles Revealed as a Dynamic Ca(2+) Store in Neuroendocrine Cells with a Vesicle-Associated Membrane Protein Aequorin Chimaera. J. Cell Biol. 2001, 155, 41–51.
  32. Klumperman, J.; Kuliawat, R.; Griffith, J.M.; Geuze, H.J.; Arvan, P. Mannose 6-Phosphate Receptors Are Sorted from Immature Secretory Granules via Adaptor Protein AP-1, Clathrin, and Syntaxin 6-Positive Vesicles. J. Cell Biol. 1998, 141, 359–371.
  33. Ericson, L.E.; Håkanson, R.; Lundquist, I. Accumulation of Dopamine in Mouse Pancreatic B-Cells Following Injection of L-DOPA. Localization to Secretory Granules and Inhibition of Insulin Secretion. Diabetologia 1977, 13, 117–124.
  34. Ekholm, R.; Ericson, L.E.; Lundquist, I. Monoamines in the Pancreatic Islets of the Mouse. Subcellular Localization of 5-Hydroxytryptamine by Electron Microscopic Autoradiography. Diabetologia 1971, 7, 339–348.
  35. Lundquist, I.; Ekholm, R.; Ericson, L.E. Monoamines in the Pancreatic Islets of the Mouse. 5-Hydroxytryptamine as an Intracellular Modifier of Insulin Secretion, and the Hypoglycaemic Action of Monoamine Oxidase Inhibitors. Diabetologia 1971, 7, 414–422.
  36. Sakamoto, S.; Miyaji, T.; Hiasa, M.; Ichikawa, R.; Uematsu, A.; Iwatsuki, K.; Shibata, A.; Uneyama, H.; Takayanagi, R.; Yamamoto, A.; et al. Impairment of Vesicular ATP Release Affects Glucose Metabolism and Increases Insulin Sensitivity. Sci. Rep. 2014, 4, 6689.
  37. Henquin, J.-C. Paracrine and Autocrine Control of Insulin Secretion in Human Islets: Evidence and Pending Questions. Am. J. Physiol. Endocrinol. Metab. 2021, 320, E78–E86.
  38. Liu, M.; Lara-Lemus, R.; Shan, S.-O.; Wright, J.; Haataja, L.; Barbetti, F.; Guo, H.; Larkin, D.; Arvan, P. Impaired Cleavage of Preproinsulin Signal Peptide Linked to Autosomal-Dominant Diabetes. Diabetes 2012, 61, 828–837.
  39. Huang, X.F.; Arvan, P. Intracellular Transport of Proinsulin in Pancreatic Beta-Cells. Structural Maturation Probed by Disulfide Accessibility. J. Biol. Chem. 1995, 270, 20417–20423.
  40. Haataja, L.; Snapp, E.; Wright, J.; Liu, M.; Hardy, A.B.; Wheeler, M.B.; Markwardt, M.L.; Rizzo, M.; Arvan, P. Proinsulin Intermolecular Interactions during Secretory Trafficking in Pancreatic β Cells. J. Biol. Chem. 2013, 288, 1896–1906.
  41. Frank, B.H.; Veros, A.J. Interaction of Zinc with Proinsulin. Biochem. Biophys. Res. Commun. 1970, 38, 284–289.
  42. Kuliawat, R.; Arvan, P. Distinct Molecular Mechanisms for Protein Sorting within Immature Secretory Granules of Pancreatic Beta-Cells. J. Cell Biol. 1994, 126, 77–86.
  43. Kiselar, J.G.; Datt, M.; Chance, M.R.; Weiss, M.A. Structural Analysis of Proinsulin Hexamer Assembly by Hydroxyl Radical Footprinting and Computational Modeling. J. Biol. Chem. 2011, 286, 43710–43716.
  44. Bailyes, E.M.; Bennett, D.L.; Hutton, J.C. Proprotein-Processing Endopeptidases of the Insulin Secretory Granule. Enzyme 1991, 45, 301–313.
  45. Davidson, H.W.; Hutton, J.C. The Insulin-Secretory-Granule Carboxypeptidase H. Purification and Demonstration of Involvement in Proinsulin Processing. Biochem. J. 1987, 245, 575–582.
  46. Weiss, M.; Steiner, D.F.; Philipson, L.H. Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships. In Endotext; Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., Dungan, K., Grossman, A., Hershman, J.M., Kaltsas, G., Koch, C., Kopp, P., et al., Eds.; MDText.com, Inc.: South Dartmouth, MA, USA, 2014.
  47. Norrman, M.; Schluckebier, G. Crystallographic Characterization of Two Novel Crystal Forms of Human Insulin Induced by Chaotropic Agents and a Shift in pH. BMC Struct. Biol. 2007, 7, 83.
  48. Steiner, D.F. Cocrystallization of Proinsulin and Insulin. Nature 1973, 243, 528–530.
  49. Landreh, M.; Alvelius, G.; Willander, H.; Stukenborg, J.-B.; Söder, O.; Johansson, J.; Jörnvall, H. Insulin Solubility Transitions by pH-Dependent Interactions with Proinsulin C-Peptide. FEBS J. 2012, 279, 4589–4597.
  50. Verchere, C.B.; Paoletta, M.; Neerman-Arbez, M.; Rose, K.; Irminger, J.C.; Gingerich, R.L.; Kahn, S.E.; Halban, P.A. Des-(27–31)C-Peptide. A Novel Secretory Product of the Rat Pancreatic Beta Cell Produced by Truncation of Proinsulin Connecting Peptide in Secretory Granules. J. Biol. Chem. 1996, 271, 27475–27481.
  51. Gold, G.; Grodsky, G.M. Kinetic Aspects of Compartmental Storage and Secretion of Insulin and Zinc. Experientia 1984, 40, 1105–1114.
  52. Chan, S.J.; Seino, S.; Gruppuso, P.A.; Schwartz, R.; Steiner, D.F. A Mutation in the B Chain Coding Region Is Associated with Impaired Proinsulin Conversion in a Family with Hyperproinsulinemia. Proc. Natl. Acad. Sci. USA 1987, 84, 2194–2197.
  53. Carroll, R.J.; Hammer, R.E.; Chan, S.J.; Swift, H.H.; Rubenstein, A.H.; Steiner, D.F. A Mutant Human Proinsulin Is Secreted from Islets of Langerhans in Increased Amounts via an Unregulated Pathway. Proc. Natl. Acad. Sci. USA 1988, 85, 8943–8947.
  54. Halban, P.A.; Irminger, J.-C. Mutant Proinsulin That Cannot Be Converted Is Secreted Efficiently from Primary Rat Beta-Cells via the Regulated Pathway. Mol. Biol. Cell 2003, 14, 1195–1203.
  55. Sizonenko, S.; Irminger, J.C.; Buhler, L.; Deng, S.; Morel, P.; Halban, P.A. Kinetics of Proinsulin Conversion in Human Islets. Diabetes 1993, 42, 933–936.
  56. Sizonenko, S.V.; Halban, P.A. Differential Rates of Conversion of Rat Proinsulins I and II. Evidence for Slow Cleavage at the B-chain/C-Peptide Junction of Proinsulin II. Biochem. J. 1991, 278, 621–625.
  57. Schechter, I.; Berger, A. On the Size of the Active Site in Proteases. I. Papain. Biochem. Biophys. Res. Commun. 1967, 27, 157–162.
  58. Kaufmann, J.E.; Irminger, J.C.; Halban, P.A. Sequence Requirements for Proinsulin Processing at the B-chain/C-Peptide Junction. Biochem. J. 1995, 310 Pt 3, 869–874.
  59. Halban, P.A. Proinsulin Processing in the Regulated and the Constitutive Secretory Pathway. Diabetologia 1994, 37 (Suppl. 2), S65–S72.
  60. Rhodes, C.J.; Lincoln, B.; Shoelson, S.E. 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. 1992, 267, 22719–22727.
  61. Kaufmann, J.E.; Irminger, J.C.; Mungall, J.; Halban, P.A. Proinsulin Conversion in GH3 Cells after Coexpression of Human Proinsulin with the Endoproteases PC2 And/or PC3. Diabetes 1997, 46, 978–982.
  62. Irminger, J.C.; Vollenweider, F.M.; Neerman-Arbez, M.; Halban, P.A. Human Proinsulin Conversion in the Regulated and the Constitutive Pathways of Transfected AtT20 Cells. J. Biol. Chem. 1994, 269, 1756–1762.
  63. Neerman-Arbez, M.; Sizonenko, S.V.; Halban, P.A. Slow Cleavage at the Proinsulin B-Chain/connecting Peptide Junction Associated with Low Levels of Endoprotease PC1/3 in Transformed Beta Cells. J. Biol. Chem. 1993, 268, 16098–16100.
  64. Neerman-Arbez, M.; Cirulli, V.; Halban, P.A. Levels of the Conversion Endoproteases PC1 (PC3) and PC2 Distinguish between Insulin-Producing Pancreatic Islet Beta Cells and Non-Beta Cells. Biochem. J. 1994, 300 Pt 1, 57–61.
  65. Zhu, X.; Orci, L.; Carroll, R.; Norrbom, C.; Ravazzola, M.; Steiner, D.F. Severe Block in Processing of Proinsulin to Insulin Accompanied by Elevation of Des-64,65 Proinsulin Intermediates in Islets of Mice Lacking Prohormone Convertase 1/3. Proc. Natl. Acad. Sci. USA 2002, 99, 10299–10304.
  66. Furuta, M.; Carroll, R.; Martin, S.; Swift, H.H.; Ravazzola, M.; Orci, L.; Steiner, D.F. 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. 1998, 273, 3431–3437.
  67. Ramzy, A.; Asadi, A.; Kieffer, T.J. Revisiting Proinsulin Processing: Evidence That Human β-Cells Process Proinsulin with Prohormone Convertase (PC) 1/3 but Not PC2. Diabetes 2020, 69, 1451–1462.
  68. Irminger, J.C.; Meyer, K.; Halban, P. Proinsulin Processing in the Rat Insulinoma Cell Line INS after Overexpression of the Endoproteases PC2 or PC3 by Recombinant Adenovirus. Biochem. J. 1996, 320 Pt 1, 11–15.
  69. Shennan, K.I.; Taylor, N.A.; Jermany, J.L.; Matthews, G.; Docherty, K. Differences in pH Optima and Calcium Requirements for Maturation of the Prohormone Convertases PC2 and PC3 Indicates Different Intracellular Locations for These Events. J. Biol. Chem. 1995, 270, 1402–1407.
  70. Muller, L.; Zhu, X.; Lindberg, I. Mechanism of the Facilitation of PC2 Maturation by 7B2: Involvement in ProPC2 Transport and Activation but Not Folding. J. Cell Biol. 1997, 139, 625–638.
  71. Zhu, X.; Rouille, Y.; Lamango, N.S.; Steiner, D.F.; Lindberg, I. Internal Cleavage of the Inhibitory 7B2 Carboxyl-Terminal Peptide by PC2: A Potential Mechanism for Its Inactivation. Proc. Natl. Acad. Sci. USA 1996, 93, 4919–4924.
  72. Hwang, J.R.; Lindberg, I. Inactivation of the 7B2 Inhibitory CT Peptide Depends on a Functional Furin Cleavage Site. J. Neurochem. 2001, 79, 437–444.
  73. Lamango, N.S.; Apletalina, E.; Liu, J.; Lindberg, I. The Proteolytic Maturation of Prohormone Convertase 2 (PC2) Is a pH-Driven Process. Arch. Biochem. Biophys. 1999, 362, 275–282.
  74. Ostrega, D.; Polonsky, K.; Nagi, D.; Yudkin, J.; Cox, L.J.; Clark, P.M.; Hales, C.N. Measurement of Proinsulin and Intermediates. Validation of Immunoassay Methods by High-Performance Liquid Chromatography. Diabetes 1995, 44, 437–440.
  75. Clark, P.M.; Levy, J.C.; Cox, L.; Burnett, M.; Turner, R.C.; Hales, C.N. Immunoradiometric Assay of Insulin, Intact Proinsulin and 32–33 Split Proinsulin and Radioimmunoassay of Insulin in Diet-Treated Type 2 (non-Insulin-Dependent) Diabetic Subjects. Diabetologia 1992, 35, 469–474.
  76. Lukinius, A.; Wilander, E.; Westermark, G.T.; Engström, U.; Westermark, P. Co-Localization of Islet Amyloid Polypeptide and Insulin in the B Cell Secretory Granules of the Human Pancreatic Islets. Diabetologia 1989, 32, 240–244.
  77. Nakazato, M.; Miyazato, M.; Asai, J.; Mitsukawa, T.; Kangawa, K.; Matsuo, H.; Matsukura, S. Islet Amyloid Polypeptide, a Novel Pancreatic Peptide, Is a Circulating Hormone Secreted under Glucose Stimulation. Biochem. Biophys. Res. Commun. 1990, 169, 713–718.
  78. Stridsberg, M.; Sandler, S.; Wilander, E. Cosecretion of Islet Amyloid Polypeptide (IAPP) and Insulin from Isolated Rat Pancreatic Islets Following Stimulation or Inhibition of Beta-Cell Function. Regul. Pept. 1993, 45, 363–370.
  79. Lutz, T.A. The Role of Amylin in the Control of Energy Homeostasis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010, 298, R1475–R1484.
  80. Hull, R.L.; Westermark, G.T.; Westermark, P.; Kahn, S.E. Islet Amyloid: A Critical Entity in the Pathogenesis of Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2004, 89, 3629–3643.
  81. Westermark, P.; Grimelius, L. The Pancreatic Islet Cells in Insular Amyloidosis in Human Diabetic and Non-Diabetic Adults. Acta Pathol. Microbiol. Scand. A 1973, 81, 291–300.
  82. Westermark, P.; Wilander, E. The Influence of Amyloid Deposits on the Islet Volume in Maturity Onset Diabetes Mellitus. Diabetologia 1978, 15, 417–421.
  83. Zhao, H.-L.; Lai, F.M.M.; Tong, P.C.Y.; Zhong, D.-R.; Yang, D.; Tomlinson, B.; Chan, J.C.N. Prevalence and Clinicopathological Characteristics of Islet Amyloid in Chinese Patients with Type 2 Diabetes. Diabetes 2003, 52, 2759–2766.
  84. Westermark, P.; Andersson, A.; Westermark, G.T. Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus. Physiol. Rev. 2011, 91, 795–826.
  85. Haataja, L.; Gurlo, T.; Huang, C.J.; Butler, P.C. Islet Amyloid in Type 2 Diabetes, and the Toxic Oligomer Hypothesis. Endocr. Rev. 2008, 29, 303–316.
  86. Raleigh, D.; Zhang, X.; Hastoy, B.; Clark, A. The β-Cell Assassin: IAPP Cytotoxicity. J. Mol. Endocrinol. 2017, 59, R121–R140.
  87. Wang, J.; Xu, J.; Finnerty, J.; Furuta, M.; Steiner, D.F.; Verchere, C.B. The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing pro-Islet Amyloid Polypeptide at the NH2-Terminal Cleavage Site. Diabetes 2001, 50, 534–539.
  88. Marzban, L.; Soukhatcheva, G.; Verchere, C.B. Role of Carboxypeptidase E in Processing of Pro-Islet Amyloid Polypeptide in β-Cells. Endocrinology 2005, 146, 1808–1817.
  89. Marzban, L.; Trigo-Gonzalez, G.; Verchere, C.B. Processing of pro-Islet Amyloid Polypeptide in the Constitutive and Regulated Secretory Pathways of Beta Cells. Mol. Endocrinol. 2005, 19, 2154–2163.
  90. Marzban, L.; Trigo-Gonzalez, G.; Zhu, X.; Rhodes, C.J.; Halban, P.A.; Steiner, D.F.; Verchere, C.B. Role of Beta-Cell Prohormone Convertase (PC)1/3 in Processing of pro-Islet Amyloid Polypeptide. Diabetes 2004, 53, 141–148.
  91. Chen, Y.-C.; Taylor, A.J.; Verchere, C.B. Islet Prohormone Processing in Health and Disease. Diabetes Obes. Metab. 2018, 20 (Suppl. 2), 64–76.
  92. Rulifson, I.C.; Cao, P.; Miao, L.; Kopecky, D.; Huang, L.; White, R.D.; Samayoa, K.; Gardner, J.; Wu, X.; Chen, K.; et al. Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate. PLoS ONE 2016, 11, e0147254.
  93. Courtade, J.A.; Wang, E.Y.; Yen, P.; Dai, D.L.; Soukhatcheva, G.; Orban, P.C.; Verchere, C.B. Loss of Prohormone Convertase 2 Promotes Beta Cell Dysfunction in a Rodent Transplant Model Expressing Human pro-Islet Amyloid Polypeptide. Diabetologia 2017, 60, 453–463.
  94. Westermark, P.; Engström, U.; Johnson, K.H.; Westermark, G.T.; Betsholtz, C. Islet Amyloid Polypeptide: Pinpointing Amino Acid Residues Linked to Amyloid Fibril Formation. Proc. Natl. Acad. Sci. USA 1990, 87, 5036–5040.
  95. Yonemoto, I.T.; Kroon, G.J.A.; Dyson, H.J.; Balch, W.E.; Kelly, J.W. Amylin Proprotein Processing Generates Progressively More Amyloidogenic Peptides That Initially Sample the Helical State. Biochemistry 2008, 47, 9900–9910.
  96. Jaikaran, E.T.A.S.; Nilsson, M.R.; Clark, A. Pancreatic Beta-Cell Granule Peptides Form Heteromolecular Complexes Which Inhibit Islet Amyloid Polypeptide Fibril Formation. Biochem. J. 2004, 377, 709–716.
  97. Westermark, P.; Li, Z.C.; Westermark, G.T.; Leckström, A.; Steiner, D.F. Effects of Beta Cell Granule Components on Human Islet Amyloid Polypeptide Fibril Formation. FEBS Lett. 1996, 379, 203–206.
  98. Brender, J.R.; Hartman, K.; Nanga, R.P.R.; Popovych, N.; de la Salud Bea, R.; Vivekanandan, S.; Marsh, E.N.G.; Ramamoorthy, A. Role of Zinc in Human Islet Amyloid Polypeptide Aggregation. J. Am. Chem. Soc. 2010, 132, 8973–8983.
  99. Khemtémourian, L.; Doménech, E.; Doux, J.P.F.; Koorengevel, M.C.; Killian, J.A. Low pH Acts as Inhibitor of Membrane Damage Induced by Human Islet Amyloid Polypeptide. J. Am. Chem. Soc. 2011, 133, 15598–15604.
  100. Janciauskiene, S.; Eriksson, S.; Carlemalm, E.; Ahrén, B. B Cell Granule Peptides Affect Human Islet Amyloid Polypeptide (IAPP) Fibril Formation in Vitro. Biochem. Biophys. Res. Commun. 1997, 236, 580–585.
  101. Kudva, Y.C.; Mueske, C.; Butler, P.C.; Eberhardt, N.L. A Novel Assay in Vitro of Human Islet Amyloid Polypeptide Amyloidogenesis and Effects of Insulin Secretory Vesicle Peptides on Amyloid Formation. Biochem. J. 1998, 331 Pt 3, 809–813.
  102. Johnson, K.H.; O’Brien, T.D.; Jordan, K.; Westermark, P. Impaired Glucose Tolerance Is Associated with Increased Islet Amyloid Polypeptide (IAPP) Immunoreactivity in Pancreatic Beta Cells. Am. J. Pathol. 1989, 135, 245–250.
  103. Gurlo, T.; Ryazantsev, S.; Huang, C.-J.; Yeh, M.W.; Reber, H.A.; Hines, O.J.; O’Brien, T.D.; Glabe, C.G.; Butler, P.C. Evidence for Proteotoxicity in Beta Cells in Type 2 Diabetes: Toxic Islet Amyloid Polypeptide Oligomers Form Intracellularly in the Secretory Pathway. Am. J. Pathol. 2010, 176, 861–869.
  104. Lin, C.-Y.; Gurlo, T.; Kayed, R.; Butler, A.E.; Haataja, L.; Glabe, C.G.; Butler, P.C. Toxic Human Islet Amyloid Polypeptide (h-IAPP) Oligomers Are Intracellular, and Vaccination to Induce Anti-Toxic Oligomer Antibodies Does Not Prevent H-IAPP-Induced Beta-Cell Apoptosis in H-IAPP Transgenic Mice. Diabetes 2007, 56, 1324–1332.
  105. Yagui, K.; Yamaguchi, T.; Kanatsuka, A.; Shimada, F.; Huang, C.I.; Tokuyama, Y.; Ohsawa, H.; Yamamura, K.; Miyazaki, J.; Mikata, A. Formation of Islet Amyloid Fibrils in Beta-Secretory Granules of Transgenic Mice Expressing Human Islet Amyloid Polypeptide/amylin. Eur. J. Endocrinol. 1995, 132, 487–496.
  106. Wang, H.; Raleigh, D.P. The Ability of Insulin to Inhibit the Formation of Amyloid by pro-Islet Amyloid Polypeptide Processing Intermediates Is Significantly Reduced in the Presence of Sulfated Glycosaminoglycans. Biochemistry 2014, 53, 2605–2614.
  107. Janson, J.; Ashley, R.H.; Harrison, D.; McIntyre, S.; Butler, P.C. The Mechanism of Islet Amyloid Polypeptide Toxicity Is Membrane Disruption by Intermediate-Sized Toxic Amyloid Particles. Diabetes 1999, 48, 491–498.
  108. Brender, J.R.; Lee, E.L.; Cavitt, M.A.; Gafni, A.; Steel, D.G.; Ramamoorthy, A. Amyloid Fiber Formation and Membrane Disruption Are Separate Processes Localized in Two Distinct Regions of IAPP, the Type-2-Diabetes-Related Peptide. J. Am. Chem. Soc. 2008, 130, 6424–6429.
  109. Brender, J.R.; Salamekh, S.; Ramamoorthy, A. Membrane Disruption and Early Events in the Aggregation of the Diabetes Related Peptide IAPP from a Molecular Perspective. Acc. Chem. Res. 2012, 45, 454–462.
  110. Westermark, P.; Engström, U.; Westermark, G.T.; Johnson, K.H.; Permerth, J.; Betsholtz, C. Islet Amyloid Polypeptide (IAPP) and pro-IAPP Immunoreactivity in Human Islets of Langerhans. Diabetes Res. Clin. Pract. 1989, 7, 219–226.
  111. Westermark, G.T.; Steiner, D.F.; Gebre-Medhin, S.; Engström, U.; Westermark, P. Pro Islet Amyloid Polypeptide (ProIAPP) Immunoreactivity in the Islets of Langerhans. Ups. J. Med. Sci. 2000, 105, 97–106.
  112. Zheng, X.; Ren, W.; Zhang, S.; Liu, J.; Li, S.; Li, J.; Yang, P.; He, J.; Su, S.; Li, P. Serum Levels of Proamylin and Amylin in Normal Subjects and Patients with Impaired Glucose Regulation and Type 2 Diabetes Mellitus. Acta Diabetol. 2010, 47, 265–270.
  113. Xu, J.; Wijesekara, N.; Regeenes, R.; Rijjal, D.A.; Piro, A.L.; Song, Y.; Wu, A.; Bhattacharjee, A.; Liu, Y.; Marzban, L.; et al. Pancreatic β Cell-Selective Zinc Transporter 8 Insufficiency Accelerates Diabetes Associated with Islet Amyloidosis. JCI Insight 2021, 6.
  114. Elias, S.; Delestre, C.; Ory, S.; Marais, S.; Courel, M.; Vazquez-Martinez, R.; Bernard, S.; Coquet, L.; Malagon, M.M.; Driouich, A.; et al. Chromogranin A Induces the Biogenesis of Granules with Calcium- and Actin-Dependent Dynamics and Exocytosis in Constitutively Secreting Cells. Endocrinology 2012, 153, 4444–4456.
  115. Montero-Hadjadje, M.; Elias, S.; Chevalier, L.; Benard, M.; Tanguy, Y.; Turquier, V.; Galas, L.; Yon, L.; Malagon, M.M.; Driouich, A.; et al. Chromogranin A Promotes Peptide Hormone Sorting to Mobile Granules in Constitutively and Regulated Secreting Cells: Role of Conserved N- and C-Terminal Peptides. J. Biol. Chem. 2009, 284, 12420–12431.
  116. Inomoto, C.; Umemura, S.; Egashira, N.; Minematsu, T.; Takekoshi, S.; Itoh, Y.; Itoh, J.; Taupenot, L.; O’Connor, D.T.; Osamura, R.Y. Granulogenesis in Non-Neuroendocrine COS-7 Cells Induced by EGFP-Tagged Chromogranin A Gene Transfection: Identical and Distinct Distribution of CgA and EGFP. J. Histochem. Cytochem. 2007, 55, 487–493.
  117. Huh, Y.H.; Jeon, S.H.; Yoo, S.H. Chromogranin B-Induced Secretory Granule Biogenesis: Comparison with the Similar Role of Chromogranin A. J. Biol. Chem. 2003, 278, 40581–40589.
  118. Chanat, E.; Huttner, W.B. Milieu-Induced, Selective Aggregation of Regulated Secretory Proteins in the Trans-Golgi Network. J. Cell Biol. 1991, 115, 1505–1519.
  119. Yoo, S.H.; Albanesi, J.P. High Capacity, Low Affinity Ca2+ Binding of Chromogranin A. Relationship between the pH-Induced Conformational Change and Ca2+ Binding Property. J. Biol. Chem. 1991, 266, 7740–7745.
  120. Sun-Wada, G.-H.; Toyomura, T.; Murata, Y.; Yamamoto, A.; Futai, M.; Wada, Y. The a3 Isoform of V-ATPase Regulates Insulin Secretion from Pancreatic Beta-Cells. J. Cell Sci. 2006, 119 Pt 21, 4531–4540.
  121. Taupenot, L.; Harper, K.L.; O’Connor, D.T. Role of H+-ATPase-Mediated Acidification in Sorting and Release of the Regulated Secretory Protein Chromogranin A: Evidence for a Vesiculogenic Function. J. Biol. Chem. 2005, 280, 3885–3897.
  122. Lissandron, V.; Podini, P.; Pizzo, P.; Pozzan, T. Unique Characteristics of Ca2+ Homeostasis of the Trans-Golgi Compartment. Proc. Natl. Acad. Sci. USA 2010, 107, 9198–9203.
  123. Arvan, P.; Halban, P.A. Sorting Ourselves out: Seeking Consensus on Trafficking in the Beta-Cell. Traffic 2004, 5, 53–61.
  124. Klemm, R.W.; Ejsing, C.S.; Surma, M.A.; Kaiser, H.-J.; Gerl, M.J.; Sampaio, J.L.; de Robillard, Q.; Ferguson, C.; Proszynski, T.J.; Shevchenko, A.; et al. Segregation of Sphingolipids and Sterols during Formation of Secretory Vesicles at the Trans-Golgi Network. J. Cell Biol. 2009, 185, 601–612.
  125. Orci, L.; Montesano, R.; Meda, P.; Malaisse-Lagae, F.; Brown, D.; Perrelet, A.; Vassalli, P. Heterogeneous Distribution of Filipin--Cholesterol Complexes across the Cisternae of the Golgi Apparatus. Proc. Natl. Acad. Sci. USA 1981, 78, 293–297.
  126. von Blume, J.; Hausser, A. Lipid-Dependent Coupling of Secretory Cargo Sorting and Trafficking at the Trans-Golgi Network. FEBS Lett. 2019, 593, 2412–2427.
  127. Wang, Y.; Thiele, C.; Huttner, W.B. Cholesterol Is Required for the Formation of Regulated and Constitutive Secretory Vesicles from the Trans-Golgi Network. Traffic 2000, 1, 952–962.
  128. Wang, T.Y.; Silvius, J.R. Different Sphingolipids Show Differential Partitioning into Sphingolipid/cholesterol-Rich Domains in Lipid Bilayers. Biophys. J. 2000, 79, 1478–1489.
  129. Kreutzberger, A.J.B.; Kiessling, V.; Doyle, C.A.; Schenk, N.; Upchurch, C.M.; Elmer-Dixon, M.; Ward, A.E.; Preobraschenski, J.; Hussein, S.S.; Tomaka, W.; et al. Distinct Insulin Granule Subpopulations Implicated in the Secretory Pathology of Diabetes Types 1 and 2. eLife 2020, 9.
  130. Hussain, S.S.; Harris, M.T.; Kreutzberger, A.J.B.; Inouye, C.M.; Doyle, C.A.; Castle, A.M.; Arvan, P.; Castle, J.D. Control of Insulin Granule Formation and Function by the ABC Transporters ABCG1 and ABCA1 and by Oxysterol Binding Protein OSBP. Mol. Biol. Cell 2018, 29, 1238–1257.
  131. Tsuchiya, M.; Hosaka, M.; Moriguchi, T.; Zhang, S.; Suda, M.; Yokota-Hashimoto, H.; Shinozuka, K.; Takeuchi, T. Cholesterol Biosynthesis Pathway Intermediates and Inhibitors Regulate Glucose-Stimulated Insulin Secretion and Secretory Granule Formation in Pancreatic Beta-Cells. Endocrinology 2010, 151, 4705–4716.
  132. Bogan, J.S.; Xu, Y.; Hao, M. Cholesterol Accumulation Increases Insulin Granule Size and Impairs Membrane Trafficking. Traffic 2012, 13, 1466–1480.
  133. Payet, L.-A.; Pineau, L.; Snyder, E.C.R.; Colas, J.; Moussa, A.; Vannier, B.; Bigay, J.; Clarhaut, J.; Becq, F.; Berjeaud, J.-M.; et al. Saturated Fatty Acids Alter the Late Secretory Pathway by Modulating Membrane Properties. Traffic 2013, 14, 1228–1241.
  134. Yoo, S.H.; Oh, Y.S.; Kang, M.K.; Huh, Y.H.; So, S.H.; Park, H.S.; Park, H.Y. Localization of Three Types of the Inositol 1,4,5-Trisphosphate Receptor/Ca2+ Channel in the Secretory Granules and Coupling with the Ca2+ Storage Proteins Chromogranins A and B*. J. Biol. Chem. 2001, 276, 45806–45812.
  135. Yoo, S.H.; Lewis, M.S. Thermodynamic Study of the pH-Dependent Interaction of Chromogranin A with an Intraluminal Loop Peptide of the Inositol 1,4,5-Trisphosphate Receptor. Biochemistry 1995, 34, 632–638.
  136. Hosaka, M.; Suda, M.; Sakai, Y.; Izumi, T.; Watanabe, T.; Takeuchi, T. Secretogranin III Binds to Cholesterol in the Secretory Granule Membrane as an Adapter for Chromogranin A. J. Biol. Chem. 2004, 279, 3627–3634.
  137. Hosaka, M.; Watanabe, T.; Sakai, Y.; Uchiyama, Y.; Takeuchi, T. Identification of a Chromogranin A Domain That Mediates Binding to Secretogranin III and Targeting to Secretory Granules in Pituitary Cells and Pancreatic Beta-Cells. Mol. Biol. Cell 2002, 13, 3388–3399.
  138. Han, L.; Suda, M.; Tsuzuki, K.; Wang, R.; Ohe, Y.; Hirai, H.; Watanabe, T.; Takeuchi, T.; Hosaka, M. A Large Form of Secretogranin III Functions as a Sorting Receptor for Chromogranin a Aggregates in PC12 Cells. Mol. Endocrinol. 2008, 22, 1935–1949.
  139. Courel, M.; Vasquez, M.S.; Hook, V.Y.; Mahata, S.K.; Taupenot, L. Sorting of the Neuroendocrine Secretory Protein Secretogranin II into the Regulated Secretory Pathway: Role of N- and C-Terminal Alpha-Helical Domains. J. Biol. Chem. 2008, 283, 11807–11822.
  140. Sun, M.; Watanabe, T.; Bochimoto, H.; Sakai, Y.; Torii, S.; Takeuchi, T.; Hosaka, M. Multiple Sorting Systems for Secretory Granules Ensure the Regulated Secretion of Peptide Hormones. Traffic 2013, 14, 205–218.
  141. Hotta, K.; Hosaka, M.; Tanabe, A.; Takeuchi, T. Secretogranin II Binds to Secretogranin III and Forms Secretory Granules with Orexin, Neuropeptide Y, and POMC. J. Endocrinol. 2009, 202, 111–121.
  142. Courel, M.; Soler-Jover, A.; Rodriguez-Flores, J.L.; Mahata, S.K.; Elias, S.; Montero-Hadjadje, M.; Anouar, Y.; Giuly, R.J.; O’Connor, D.T.; Taupenot, L. Pro-Hormone Secretogranin II Regulates Dense Core Secretory Granule Biogenesis in Catecholaminergic Cells. J. Biol. Chem. 2010, 285, 10030–10043.
  143. Glombik, M.M.; Krömer, A.; Salm, T.; Huttner, W.B.; Gerdes, H.H. The Disulfide-Bonded Loop of Chromogranin B Mediates Membrane Binding and Directs Sorting from the Trans-Golgi Network to Secretory Granules. EMBO J. 1999, 18, 1059–1070.
  144. Pimplikar, S.W.; Huttner, W.B. Chromogranin B (secretogranin I), a Secretory Protein of the Regulated Pathway, Is Also Present in a Tightly Membrane-Associated Form in PC12 Cells. J. Biol. Chem. 1992, 267, 4110–4118.
  145. Giordano, T.; Brigatti, C.; Podini, P.; Bonifacio, E.; Meldolesi, J.; Malosio, M.L. Beta Cell Chromogranin B Is Partially Segregated in Distinct Granules and Can Be Released Separately from Insulin in Response to Stimulation. Diabetologia 2008, 51, 997–1007.
  146. Yoo, S.H.; Chu, S.Y.; Kim, K.D.; Huh, Y.H. Presence of Secretogranin II and High-Capacity, Low-Affinity Ca2+ Storage Role in Nucleoplasmic Ca2+ Store Vesicles. Biochemistry 2007, 46, 14663–14671.
  147. Bearrows, S.C.; Bauchle, C.J.; Becker, M.; Haldeman, J.M.; Swaminathan, S.; Stephens, S.B. Chromogranin B Regulates Early-Stage Insulin Granule Trafficking from the Golgi in Pancreatic Islet β-Cells. J. Cell Sci. 2019, 132.
  148. Yoo, S.H.; Lewis, M.S. Effects of pH and Ca2+ on Heterodimer and Heterotetramer Formation by Chromogranin A and Chromogranin B. J. Biol. Chem. 1996, 271, 17041–17046.
  149. Garcia, A.L.; Han, S.-K.; Janssen, W.G.; Khaing, Z.Z.; Ito, T.; Glucksman, M.J.; Benson, D.L.; Salton, S.R.J. A Prohormone Convertase Cleavage Site within a Predicted α-Helix Mediates Sorting of the Neuronal and Endocrine Polypeptide VGF into the Regulated Secretory Pathway *. J. Biol. Chem. 2005, 280, 41595–41608.
  150. Obermüller, S.; Calegari, F.; King, A.; Lindqvist, A.; Lundquist, I.; Salehi, A.; Francolini, M.; Rosa, P.; Rorsman, P.; Huttner, W.B.; et al. Defective Secretion of Islet Hormones in Chromogranin-B Deficient Mice. PLoS ONE 2010, 5, e8936.
  151. Wollam, J.; Mahata, S.; Riopel, M.; Hernandez-Carretero, A.; Biswas, A.; Bandyopadhyay, G.K.; Chi, N.-W.; Eiden, L.E.; Mahapatra, N.R.; Corti, A.; et al. Chromogranin A Regulates Vesicle Storage and Mitochondrial Dynamics to Influence Insulin Secretion. Cell Tissue Res. 2017, 368, 487–501.
  152. Thomsen, S.K.; Raimondo, A.; Hastoy, B.; Sengupta, S.; Dai, X.-Q.; Bautista, A.; Censin, J.; Payne, A.J.; Umapathysivam, M.M.; Spigelman, A.F.; et al. Type 2 Diabetes Risk Alleles in PAM Impact Insulin Release from Human Pancreatic β-Cells. Nat. Genet. 2018, 50, 1122–1131.
  153. Maeda, Y.; Kudo, S.; Tsushima, K.; Sato, E.; Kubota, C.; Kayamori, A.; Bochimoto, H.; Koga, D.; Torii, S.; Gomi, H.; et al. Impaired Processing of Prohormones in Secretogranin III-Null Mice Causes Maladaptation to an Inadequate Diet and Stress. Endocrinology 2018, 159, 1213–1227.
  154. Stephens, S.B.; Edwards, R.J.; Sadahiro, M.; Lin, W.-J.; Jiang, C.; Salton, S.R.; Newgard, C.B. The Prohormone VGF Regulates β Cell Function via Insulin Secretory Granule Biogenesis. Cell Rep. 2017, 20, 2480–2489.
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