Evaluating insulin secretagogues in a humanized mouse model with functional human islets.
Metabolism
; 62(1): 90-9, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-22982177
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 ß cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicemia
/
Transplante das Ilhotas Pancreáticas
/
Ilhotas Pancreáticas
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Diabetes Mellitus Tipo 2
/
Incretinas
/
Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Metabolism
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos