| Insulin degradation by acinar cell proteases creates a dysfunctional environment for human islets before/after transplantation: benefits of α-1 antitrypsin treatment. | |
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MedLine Citation:
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PMID: 22089666 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Pancreatic acinar cells are commonly cotransplanted along with islets during auto- and allotransplantations. The aims of this study were to identify how acinar cell proteases cause human islet cell loss before and after transplantation of impure islet preparations and to prevent islet loss and improve function with supplementation of α-1 antitrypsin (A1AT). METHODS: Acinar cell protease activity, insulin levels, and percent islet loss were measured after culture of pure and impure clinical islet preparations. The effect of proteases on ultrastructure of islets and β-cell insulin granules were examined by transmission electron microscopy. The number of insulin granules and insulin-labeled immunogold particles were counted. The in vivo effect of proteases on islet function was studied by transplanting acinar cells adjacent to islet grafts in diabetic mice. The effects of A1AT culture supplementation on protease activity, insulin levels, and islet function were assessed in pure and impure islets. RESULTS: Islet loss after culture was significantly higher in impure relative to pure preparations (30% vs. 14%, P<0.04). Lower islet purity was associated with increased protease activity and decreased insulin levels in culture supernatants. Reduced β-cell insulin granules and insulin degradation by proteases were confirmed by transmission electron microscopy. Transplantations in mice showed delayed islet graft function when acinar cells were transplanted adjacent to the islets under the kidney capsule. Supplementation of A1AT to impure islet cultures maintained islet cell mass, restored insulin levels, and preserved islet functional integrity. CONCLUSION: Culture of impure human islet fractions in the presence of A1AT prevents insulin degradation and improves islet recovery. |
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Authors:
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Gopalakrishnan Loganathan; Rajinder K Dawra; Subbiah Pugazhenthi; Zhiguang Guo; Sajjad M Soltani; Alexander Wiseman; Mark A Sanders; Klearchos K Papas; Kumaravel Velayutham; Ashok K Saluja; David E R Sutherland; Bernhard J Hering; A N Balamurugan |
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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 |
Journal Detail:
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Title: Transplantation Volume: 92 ISSN: 1534-6080 ISO Abbreviation: Transplantation Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-11-23 Completed Date: 2012-02-02 Revised Date: 2012-04-19 |
Medline Journal Info:
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Nlm Unique ID: 0132144 Medline TA: Transplantation Country: United States |
Other Details:
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Languages: eng Pagination: 1222-30 Citation Subset: IM |
Affiliation:
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Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN 55455, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acinar Cells
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cytology,
enzymology* Animals Cells, Cultured Diabetes Mellitus, Experimental / chemically induced, surgery Disease Models, Animal Graft Survival / drug effects Humans Insulin / metabolism* Islets of Langerhans / cytology, drug effects*, physiopathology* Islets of Langerhans Transplantation / physiology* Male Mice Mice, Nude Peptide Hydrolases / drug effects, metabolism* Serine Proteinase Inhibitors / pharmacology Streptozocin / adverse effects Transplantation, Heterologous Treatment Outcome alpha 1-Antitrypsin / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK092145-02/DK/NIDDK NIH HHS; R01 DK093047-02/DK/NIDDK NIH HHS; U42 RR16598/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Insulin; 0/Serine Proteinase Inhibitors; 0/alpha 1-Antitrypsin; 18883-66-4/Streptozocin; EC 3.4.-/Peptide Hydrolases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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