Lixisenatide accelerates restoration of normoglycemia and improves human beta-cell function and survival in diabetic immunodeficient NOD-scid IL-2rg(null) RIP-DTR mice engrafted with human islets
Authors
Yang, ChaoxingLoehn, Matthias
Jurczyk, Agata
Przewozniak, Natalia
Leehy, Linda
Herrera, Pedro L.
Shultz, Leonard D.
Greiner, Dale L.
Harlan, David
Bortell, Rita
UMass Chan Affiliations
Department of MedicineDiabetes Center of Excellence
Program in Molecular Medicine
Document Type
Journal ArticlePublication Date
2015-08-20Keywords
GLP-1 receptor agonistlixisenatide
human islet transplant
beta cells
glucose tolerance tests
plasma insulin
Endocrine System Diseases
Endocrinology
Endocrinology, Diabetes, and Metabolism
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OBJECTIVE: Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells. To investigate the effects on human beta cells, we used immunodeficient mice transplanted with human islets. The goal was to determine whether lixisenatide, a glucagon-like peptide-1 receptor agonist, improves human islet function and survival in vivo. METHODS: Five independent transplant studies were conducted with human islets from five individual donors. Diabetic human islet-engrafted immunodeficient mice were treated with lixisenatide (50, 150, and 500 microg/kg) or vehicle. Islet function was determined by blood glucose, plasma human insulin/C-peptide, and glucose tolerance tests. Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis. RESULTS: Diabetic mice transplanted with marginal human islet mass and treated with lixisenatide were restored to euglycemia more rapidly than vehicle-treated mice. Glucose tolerance tests, human plasma insulin, and glucose-stimulation indices of lixisenatide-treated mice were significantly improved compared to vehicle-treated mice. The percentages of proliferating or apoptotic beta cells at graft recovery were not different between lixisenatide-treated and vehicle-treated mice. Nevertheless, in one experiment we found a significant twofold to threefold increase in human beta-cell numbers in lixisenatide-treated compared to vehicle-treated mice. CONCLUSION: Diabetic human islet-engrafted immunodeficient mice treated with lixisenatide show improved restoration of normoglycemia, human plasma insulin, and glucose tolerance compared to vehicle-treated mice engrafted with the same donor islets. Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.Source
Diabetes Metab Syndr Obes. 2015 Aug 20;8:387-98. doi: 10.2147/DMSO.S87253. eCollection 2015. Link to article on publisher's siteDOI
10.2147/DMSO.S87253Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39834PubMed ID
26316789Related Resources
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Copyright © 2015 Yang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Distribution License
http://creativecommons.org/licenses/by-nc/3.0/ae974a485f413a2113503eed53cd6c53
10.2147/DMSO.S87253
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Except where otherwise noted, this item's license is described as Copyright © 2015 Yang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at <a href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</a>. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.