Abstract
Objective
To develop a rapid, easy and clinically relevant in vivo model to evaluate novel insulin secretagogues on human islets, we investigated the
effect of insulin secretagogues on functional human islets in a humanized mouse model.
Materials/Methods
Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced
diabetic mice with immunodeficiency. Human islet graft function was monitored by measuring
non-fasting blood glucose levels. After diabetes was reversed, human islet transplanted
mice were characterized physiologically by oral glucose tolerance and pharmacologically
with clinically proven insulin secretagogues, glucagon-like peptide-1 (GLP-1), exenatide,
glyburide, nateglinide and sitagliptin. Additionally, G protein-coupled receptor 40
(GPR40) agonists were evaluated in this model.
Results
Long-term human islet graft survival could be achieved in immunodeficient mice. Oral
glucose challenge in human islet transplanted mice resulted in an immediate incremental
increase of plasma human C-peptide, while the plasma mouse C-peptide was undetectable.
Treatments with GLP-1, exenatide, glyburide, nateglinide and sitagliptin effectively
increased plasma human C-peptide levels and improved postprandial glucose concentrations.
GPR40 agonists also stimulated human C-peptide secretion and significantly improved
postprandial glucose in the human islet transplanted mice.
Conclusions
Our studies indicate that a humanized mouse model with human islet grafts could mimic
the in vivo characteristics of human islets and could be a powerful tool for the evaluation of
novel insulin secretagogues or other therapeutic agents that directly and/or indirectly
target human β cells.
Abbreviations:
GLP-1 (glucagon-like peptide-1), GPR40 (G protein-coupled receptor 40), STZ (streptozotocin), OGTT (oral glucose tolerance test)Keywords
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Article info
Publication history
Published online: September 17, 2012
Accepted:
July 17,
2012
Received:
May 18,
2012
Footnotes
Disclosure statement: Jian Luo, Kathy Nguyen, Michael Chen, Than Tran, Ingrid C Rulifson, Ying Zhang, Edwin Lopez, Daniel C. Lin, Yingcai Wang, Zhihua Ma, and Jonathan Houze were employed by and shareholders in Amgen during the study period. Jianqiang Hao, Bole Tian, Lei Tian, Yu Zhang, and Zhiguang Guo were employed by the University of Minnesota during the study period.
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
