Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
Autor: | Stefan Geschwindner, Andrew V. Turnbull, Sara Lundqvist, Anna Marley, Kazuyo Sasaki, Niklas Larsson, Ola Fjellström, Charlotte Wennberg-Huldt, Richard J. Isaacs, Anders Johansson, Claire Priest, Lambertus Benthem, Yukimi Yoneyama, Johan Brengdahl, Daniel Hovdal, Shin-ichiro Yasuda, Hajime Fukuda, Takuma Tsuchida, Daniel G. Brown, Takahiro Oguma |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Blood Glucose
Male medicine.medical_specialty medicine.medical_treatment lcsh:Medicine Type 2 diabetes Biology Receptors G-Protein-Coupled Small Molecule Libraries Islets of Langerhans Mice Insulin resistance In vivo Internal medicine Insulin receptor substrate Drug Discovery Insulin Secretion Blood plasma medicine Animals Humans Insulin Receptor lcsh:Science Glucose tolerance test Multidisciplinary Dose-Response Relationship Drug medicine.diagnostic_test lcsh:R Glucose Tolerance Test medicine.disease High-Throughput Screening Assays Rats Rats Zucker Zinc Endocrinology lcsh:Q Research Article |
Zdroj: | PLoS ONE, Vol 10, Iss 12, p e0145849 (2015) PLoS ONE |
ISSN: | 1932-6203 |
Popis: | Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents. |
Databáze: | OpenAIRE |
Externí odkaz: |