UMMS Affiliation

Program in Molecular Medicine; Diabetes Center of Excellence; Department of Medicine

Publication Date

8-20-2015

Document Type

Article

Disciplines

Endocrine System Diseases | Endocrinology | Endocrinology, Diabetes, and Metabolism

Abstract

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.

Rights and Permissions

Citation: Diabetes Metab Syndr Obes. 2015 Aug 20;8:387-98. doi: 10.2147/DMSO.S87253. eCollection 2015. Link to article on publisher's site

DOI of Published Version

10.2147/DMSO.S87253

Comments

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.

Related Resources

Link to Article in PubMed

Keywords

GLP-1 receptor agonist, lixisenatide, human islet transplant, beta cells, glucose tolerance tests, plasma insulin

Journal/Book/Conference Title

Diabetes, metabolic syndrome and obesity : targets and therapy

PubMed ID

26316789

Creative Commons License

Creative Commons Attribution-Noncommercial 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 License

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.