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Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents.

Fjellström O, Larsson N, Yasuda S, Tsuchida T, Oguma T, Marley A, Wennberg-Huldt C, Hovdal D, Fukuda H, Yoneyama Y, Sasaki K, Johansson A, Lundqvist S, Brengdahl J, Isaacs RJ, Brown D, Geschwindner S, Benthem L, Priest C, Turnbull A - PLoS ONE (2015)

Bottom Line: A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists.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.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.

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.

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Related in: MedlinePlus

Insulin secretion assays in mouse islets.Effect on insulin secretion by each compound. Islets were treated with 1 and 10 μM of AZ7914 (A), AZ4237 (B), AZ1395 (C). The assays were performed in the absence or presence of 5 μM of Zn2+. Values were calculated as the ratio of insulin concentration compared to the basal control and expressed as the average of three separate measurements ± SEM.
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pone.0145849.g006: Insulin secretion assays in mouse islets.Effect on insulin secretion by each compound. Islets were treated with 1 and 10 μM of AZ7914 (A), AZ4237 (B), AZ1395 (C). The assays were performed in the absence or presence of 5 μM of Zn2+. Values were calculated as the ratio of insulin concentration compared to the basal control and expressed as the average of three separate measurements ± SEM.

Mentions: Two biological effect assays were developed to measure glucose stimulated insulin secretion (GSIS), one in rat INS-1E β-cells and one in mouse islets. Fig 5 displays the INS-1E data in the absence and presence of Zn2+. AZ7914, AZ4237 and AZ1395 all showed increases in GSIS in the presence of Zn2+. In the islet GSIS experiments none of the compounds in the presence and absence of Zn2+ displayed significantly increased GSIS effects at the 1 and 10 μM compound concentrations tested (Fig 6).


Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents.

Fjellström O, Larsson N, Yasuda S, Tsuchida T, Oguma T, Marley A, Wennberg-Huldt C, Hovdal D, Fukuda H, Yoneyama Y, Sasaki K, Johansson A, Lundqvist S, Brengdahl J, Isaacs RJ, Brown D, Geschwindner S, Benthem L, Priest C, Turnbull A - PLoS ONE (2015)

Insulin secretion assays in mouse islets.Effect on insulin secretion by each compound. Islets were treated with 1 and 10 μM of AZ7914 (A), AZ4237 (B), AZ1395 (C). The assays were performed in the absence or presence of 5 μM of Zn2+. Values were calculated as the ratio of insulin concentration compared to the basal control and expressed as the average of three separate measurements ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697807&req=5

pone.0145849.g006: Insulin secretion assays in mouse islets.Effect on insulin secretion by each compound. Islets were treated with 1 and 10 μM of AZ7914 (A), AZ4237 (B), AZ1395 (C). The assays were performed in the absence or presence of 5 μM of Zn2+. Values were calculated as the ratio of insulin concentration compared to the basal control and expressed as the average of three separate measurements ± SEM.
Mentions: Two biological effect assays were developed to measure glucose stimulated insulin secretion (GSIS), one in rat INS-1E β-cells and one in mouse islets. Fig 5 displays the INS-1E data in the absence and presence of Zn2+. AZ7914, AZ4237 and AZ1395 all showed increases in GSIS in the presence of Zn2+. In the islet GSIS experiments none of the compounds in the presence and absence of Zn2+ displayed significantly increased GSIS effects at the 1 and 10 μM compound concentrations tested (Fig 6).

Bottom Line: A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists.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.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.

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.

Show MeSH
Related in: MedlinePlus