1. Academic Validation
  2. Evaluating insulin secretagogues in a humanized mouse model with functional human islets

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

  • Metabolism. 2013 Jan;62(1):90-9. doi: 10.1016/j.metabol.2012.07.010.
Jian Luo 1 Kathy Nguyen Michael Chen Than Tran Jianqiang Hao Bole Tian Ingrid C Rulifson Ying Zhang Lei Tian Yu Zhang Edwin Lopez Daniel C-H Lin Yingcai Wang Zhihua Ma Jonathan Houze Zhiguang Guo
Affiliations

Affiliation

  • 1 NGM Biopharmaceuticals, Inc., South San Francisco, CA 94080, USA. jluo@ngmbio.com
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.

Figures
Products