| Calcium-activated calpain-2 is a mediator of beta cell dysfunction and apoptosis in type 2 diabetes. | |
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MedLine Citation:
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PMID: 19861418 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The islet in type 2 diabetes (T2DM) and the brain in neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, and accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) in T2DM). Excessive activation of the Ca(2+)-sensitive protease calpain-2 has been implicated as a mediator of oligomer-induced cell death and dysfunction in neurodegenerative diseases. To establish if human IAPP toxicity is mediated by a comparable mechanism, we overexpressed human IAPP in rat insulinoma cells and freshly isolated human islets. Pancreas was also obtained at autopsy from humans with T2DM and nondiabetic controls. We report that overexpression of human IAPP leads to the formation of toxic oligomers and increases beta cell apoptosis mediated by increased cytosolic Ca(2+) and hyperactivation of calpain-2. Cleavage of alpha-spectrin, a marker of calpain hyperactivation, is increased in beta cells in T2DM. We conclude that overactivation of Ca(2+)-calpain pathways contributes to beta cell dysfunction and apoptosis in T2DM. |
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Authors:
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Chang-jiang Huang; Tatyana Gurlo; Leena Haataja; Safia Costes; Marie Daval; Sergey Ryazantsev; Xiuji Wu; Alexandra E Butler; Peter C Butler |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-10-27 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-12-28 Completed Date: 2010-01-26 Revised Date: 2011-12-13 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 339-48 Citation Subset: IM |
Affiliation:
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Larry Hillblom Islet Research Center, David Geffen School of Medicine, California Nano Systems Institute, UCLA, Los Angeles, California 90024-2852, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Aged, 80 and over Amyloid / toxicity Animals Apoptosis* / drug effects Calcium / metabolism* Calpain / metabolism* Cell Line, Tumor Cell Survival / drug effects Cytosol / drug effects, metabolism Diabetes Mellitus, Type 2 / enzymology*, pathology, physiopathology* Dipeptides / pharmacology Enzyme Activation / drug effects Female Humans Insulin-Secreting Cells / drug effects, enzymology*, pathology*, ultrastructure Islet Amyloid Polypeptide Male Middle Aged Protein Transport / drug effects Rats Recombinant Fusion Proteins / metabolism Spectrin / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK059579/DK/NIDDK NIH HHS; R01 DK059579-11/DK/NIDDK NIH HHS; R01 DK059579-12/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid; 0/Dipeptides; 0/Islet Amyloid Polypeptide; 0/Recombinant Fusion Proteins; 117591-20-5/calpeptin; 12634-43-4/Spectrin; 7440-70-2/Calcium; EC 3.4.22.-/Calpain; EC 3.4.22.4/calpain 2, human |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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