The islet tissue plasminogen activator/plasmin system is upregulated with human islet amyloid polypeptide aggregation and protects beta cells from aggregation-induced toxicity.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE
    • Publication Information:
      Original Publication: Berlin Springer Verlag
    • Subject Terms:
      Islet Amyloid Polypeptide*/metabolism ; Fibrinolysin*/metabolism ; Mice, Transgenic* ; Tissue Plasminogen Activator*/metabolism ; Insulin-Secreting Cells*/metabolism ; Insulin-Secreting Cells*/drug effects; Animals ; Humans ; Mice ; Islets of Langerhans/metabolism ; Islets of Langerhans/drug effects ; Diabetes Mellitus, Type 2/metabolism ; Up-Regulation/drug effects ; Cell Survival/drug effects
    • Abstract:
      Aims/hypothesis: Apart from its fibrinolytic activity, the tissue plasminogen activator (tPA)/plasmin system has been reported to cleave the peptide amyloid beta, attenuating brain amyloid deposition in Alzheimer's disease. As aggregation of human islet amyloid polypeptide (hIAPP) is toxic to beta cells, we sought to determine whether activation of the fibrinolytic system can also reduce islet amyloid deposition and its cytotoxic effects, which are both observed in type 2 diabetes.
      Methods: The expression of Plat (encoding tPA) and plasmin activity were measured in isolated islets from amyloid-prone hIAPP transgenic mice or non-transgenic control islets expressing non-amyloidogenic mouse islet amyloid polypeptide cultured in the absence or presence of the amyloid inhibitor Congo Red. Plat expression was also determined in hIAPP-treated primary islet endothelial cells, bone marrow-derived macrophages (BMDM) and INS-1 cells, in order to determine the islet cell type(s) producing tPA in response to hIAPP aggregation. Cell-free thioflavin-T assays and MS were used to respectively monitor hIAPP aggregation kinetics and investigate plasmin cleavage of hIAPP. Cell viability was assessed in INS-1 beta cells treated with hIAPP with or without plasmin. Finally, to confirm the findings in human samples, PLAT expression was measured in freshly isolated islets from donors with and without type 2 diabetes.
      Results: In isolated islets from transgenic mice, islet Plat expression and plasmin activity increased significantly with the process of amyloid deposition (p≤0.01, n=5); these effects were not observed in islets from non-transgenic mice and were blocked by Congo Red (p≤0.01, n=4). In response to hIAPP exposure, Plat expression increased in BMDM and INS-1 cells vs vehicle-treated cells (p≤0.05, n=4), but not in islet endothelial cells. Plasmin reduced hIAPP fibril formation in a dose-dependent manner in a cell-free system, and restored hIAPP-induced loss of cell viability in INS-1 beta cells (p≤0.01, n=5). Plasmin cleaved monomeric hIAPP, inducing a rapid decrease in the abundance of full-length hIAPP and the appearance of hIAPP 1-11 and 12-37 fragments. hIAPP 12-37, which contains the critical amyloidogenic region, was not toxic to INS-1 cells. Finally, PLAT expression was significantly increased by 2.4-fold in islets from donors with type 2 diabetes (n=4) vs islets from donors without type 2 diabetes (n=7) (p≤0.05).
      Conclusions/interpretation: The fibrinolytic system is upregulated in islets with hIAPP aggregation. Plasmin rapidly degrades hIAPP, limiting its aggregation into amyloid and thus protecting beta cells from hIAPP-induced toxicity. Thus, increasing islet plasmin activity might be a strategy to limit beta cell loss in type 2 diabetes.
      (© 2024. The Author(s).)
    • References:
      Protein Eng Des Sel. 2019 Dec 13;32(2):87-93. (PMID: 31768548)
      J Neurosci. 1997 Jan 15;17(2):543-52. (PMID: 8987777)
      J Biol Chem. 2000 Nov 24;275(47):36621-5. (PMID: 10973971)
      J Mol Biol. 2002 May 3;318(3):697-706. (PMID: 12054816)
      Ups J Med Sci. 1972;77(2):91-4. (PMID: 4116019)
      Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3492-6. (PMID: 8622964)
      J Biol Chem. 1997 Jan 17;272(3):1976-82. (PMID: 8999889)
      Diabetes. 2002 Apr;51(4):1131-7. (PMID: 11916936)
      ACS Appl Mater Interfaces. 2023 Jan 18;15(2):2617-2629. (PMID: 36596222)
      Nat Struct Mol Biol. 2020 Nov;27(11):1048-1056. (PMID: 32929282)
      Nat Immunol. 2010 Oct;11(10):897-904. (PMID: 20835230)
      Diabetes. 1994 Dec;43(12):1457-61. (PMID: 7958499)
      J Proteome Res. 2012 Jul 6;11(7):3520-32. (PMID: 22578083)
      Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. (PMID: 9600986)
      Endocrinology. 1987 Dec;121(6):2238-44. (PMID: 2890516)
      Diabetes. 1999 Mar;48(3):491-8. (PMID: 10078548)
      Diabetologia. 2016 Oct;59(10):2166-71. (PMID: 27393137)
      Amyloid. 2013 Jun;20(2):113-21. (PMID: 23697555)
      Curr Biol. 2002 Oct 29;12(21):1833-9. (PMID: 12419183)
      Proc Natl Acad Sci U S A. 1990 Jul;87(13):5036-40. (PMID: 2195544)
      J Mol Biol. 2012 Aug 10;421(2-3):282-95. (PMID: 22206987)
      Diabetes. 2014 May;63(5):1698-711. (PMID: 24222351)
      J Neurosci. 2003 Oct 1;23(26):8867-71. (PMID: 14523088)
      J Exp Med. 1989 Apr 1;169(4):1509-14. (PMID: 2494295)
      Protein Eng Des Sel. 2019 Dec 13;32(2):67-76. (PMID: 31504890)
      Nature. 1947 May 17;159(4046):681. (PMID: 20342264)
      Metabolism. 1990 Oct;39(10):1044-8. (PMID: 2215252)
      Nature. 1994 Apr 21;368(6473):756-60. (PMID: 8152488)
      J Clin Endocrinol Metab. 2004 Aug;89(8):3629-43. (PMID: 15292279)
      Biochem Biophys Res Commun. 1988 Sep 15;155(2):608-14. (PMID: 3048259)
      Endocrinology. 1992 Jan;130(1):167-78. (PMID: 1370150)
      Kidney Int. 1996 Apr;49(4):1097-104. (PMID: 8691730)
      Endocrinology. 2016 Sep;157(9):3462-8. (PMID: 27404391)
      Biochemistry. 2016 Jan 26;55(3):510-8. (PMID: 26694855)
      Biochemistry. 1999 Feb 9;38(6):1811-8. (PMID: 10026261)
      Nat Struct Mol Biol. 2020 Jul;27(7):660-667. (PMID: 32541895)
      Diabetes. 2003 Feb;52(2):372-9. (PMID: 12540610)
      Diabetologia. 2009 Apr;52(4):626-35. (PMID: 19148619)
      Diabetologia. 2012 Nov;55(11):2989-98. (PMID: 22898766)
      Org Lett. 2010 Nov 5;12(21):4848-51. (PMID: 20931985)
      Diabetologia. 2010 Jun;53(6):1046-56. (PMID: 20182863)
      J Neurosci. 2000 Jun 1;20(11):3937-46. (PMID: 10818128)
      J Biol Chem. 2010 Jun 11;285(24):18177-83. (PMID: 20400513)
      Circulation. 2006 Apr 11;113(14):1753-9. (PMID: 16585388)
      Diabetes Care. 2005 Sep;28(9):2211-6. (PMID: 16123492)
      Proc Natl Acad Sci U S A. 1983 Nov;80(22):6804-8. (PMID: 6580616)
      Diabetologia. 2022 Oct;65(10):1687-1700. (PMID: 35871651)
      Diabetes. 1990 May;39(5):634-8. (PMID: 2185112)
      Biochemistry. 2018 May 29;57(21):3065-3074. (PMID: 29697253)
      Nat Struct Mol Biol. 2021 Sep;28(9):724-730. (PMID: 34518699)
      Acc Chem Res. 2012 Sep 18;45(9):1548-57. (PMID: 22738376)
      Ann N Y Acad Sci. 2001;936:237-46. (PMID: 11460481)
      J Biol Chem. 2015 Dec 18;290(51):30475-85. (PMID: 26483547)
      Diabetes. 2019 Jul;68(7):1380-1393. (PMID: 31221802)
      Cell Metab. 2016 Oct 11;24(4):593-607. (PMID: 27667667)
      Nucleic Acids Res. 2018 Jan 4;46(D1):D624-D632. (PMID: 29145643)
      Am J Pathol. 2011 Jun;178(6):2632-40. (PMID: 21641386)
      Biochem Biophys Res Commun. 2007 Mar 2;354(1):234-9. (PMID: 17222388)
      Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8754-9. (PMID: 18559859)
    • Grant Information:
      T32 HL007028 United States HL NHLBI NIH HHS; T32 DK007247 United States DK NIDDK NIH HHS; 107927/Z/15/Z United Kingdom WT_ Wellcome Trust; T32 HL007028 United States NH NIH HHS; I01 BX001060 United States BX BLRD VA; R01 GM078114 United States NH NIH HHS; I01 BX004063 United States BX BLRD VA; P30 DK017047 United States NH NIH HHS; Julia McAbee Endowed Postdoctoral Fellows Diabetes Research Center, University of Washington; R01 GM078114 United States GM NIGMS NIH HHS; T32 DK007247 United States NH NIH HHS; United Kingdom WT_ Wellcome Trust; Post doctorate Clinical Master Specialist Fonds De La Recherche Scientifique - FNRS; P30 DK017047 United States DK NIDDK NIH HHS; 1-INO-2022-1123-A-N Juvenile Diabetes Research Foundation Australia; IK2 BX004659 United States BX BLRD VA; Dick Diabetes Research Center, University of Washington; Postdoctoral Fellowship 1-18-PDF-174 American Diabetes Association
    • Contributed Indexing:
      Keywords: Amyloid; Beta cell; Fibrinolysis; Human islet; Islet amyloid polypeptide; Plasmin; Tissue plasminogen activator; Type 2 diabetes
    • Accession Number:
      0 (Islet Amyloid Polypeptide)
      EC 3.4.21.7 (Fibrinolysin)
      EC 3.4.21.68 (Tissue Plasminogen Activator)
    • Publication Date:
      Date Created: 20240908 Date Completed: 20240918 Latest Revision: 20240922
    • Publication Date:
      20240922
    • Accession Number:
      PMC11410534
    • Accession Number:
      10.1007/s00125-024-06161-0
    • Accession Number:
      39245780