title: Evaluating insulin secretagogues in a humanized mouse model with functional human islets.
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.
  
  
  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.
authors.affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, CA 94080, USA. jluo@ngmbio.com
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Kathy
authors.initials: K
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.forename: Than
authors.initials: T
authors.lastname: Tran
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hao
authors.forename: Bole
authors.initials: B
authors.lastname: Tian
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Rulifson
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Edwin
authors.initials: E
authors.lastname: Lopez
authors.forename: Daniel C-H
authors.initials: DC
authors.lastname: Lin
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ma
authors.forename: Jonathan
authors.initials: J
authors.lastname: Houze
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D054795:Incretins / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000077715:Nateglinide; D010455:Peptides / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D013047:Specific Pathogen-Free Organisms; D014230:Triazoles / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D003510:Cyclohexanes; D054795:Incretins; D007328:Insulin; D010455:Peptides; D011719:Pyrazines; D014230:Triazoles; D014688:Venoms; D000077715:Nateglinide; D010649:Phenylalanine; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D005905:Glyburide; D000068900:Sitagliptin Phosphate