Basic Science| Volume 62, ISSUE 1, P90-99, January 2013

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Evaluating insulin secretagogues in a humanized mouse model with functional human islets

Published:September 17, 2012DOI:



      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.


      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.


      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.


      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.


      GLP-1 (glucagon-like peptide-1), GPR40 (G protein-coupled receptor 40), STZ (streptozotocin), OGTT (oral glucose tolerance test)


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