Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Glucose Tolerance Test
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High-Throughput Screening Assays
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Humans
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Insulin / metabolism*
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Insulin Secretion
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Islets of Langerhans / metabolism
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Male
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Mice
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Rats
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Rats, Zucker
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / genetics
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Small Molecule Libraries
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Zinc / metabolism
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Zinc / pharmacology
Substances
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Blood Glucose
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GPR39 protein, human
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GPR39 protein, mouse
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GPR39 protein, rat
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Insulin
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Receptors, G-Protein-Coupled
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Small Molecule Libraries
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Zinc
Grants and funding
AstraZeneca, Mitsubishi Tanabe Pharma Corporation and Molecular Sensing Inc. provided the funding for this research. All authors are or were employees of either AstraZeneca, Mitsubishi Tanabe Pharma Corporation and Molecular Sensing, Inc. AstraZeneca and Mitsubishi Tanabe Pharma Corporation provided the funding for this research. AstraZeneca, Mitsubishi Tanabe Pharma Corporation and Molecular Sensing, Inc. provided support in the form of salaries for authors OF, NL, AM, CWH, DH, AJ, SL, JB, SG, LB, CP, AT, SY, TT, TO, HF, YY, RJI, and DB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.