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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

IPGTT in C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds (black triangles: 30 mg/kg, black circles: 100 mg/kg, grey circles: exendin-4, 1 μg/kg) or vehicle (white circles) were IP administered to fasted C57BL/6J mice at -30 min. Glucose solution (1.5 g/kg) was given IP at 0 min. Values are mean ± SEM (n = 7). #P<0.05, ##P<0.01, ###P<0.001 versus vehicle (repeated measures ANOVA followed by student’s t-test).*P<0.05, **P<0.01, ***P<0.001 versus vehicle (repeated measures ANOVA followed by Dunnett).
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pone.0145849.g007: IPGTT in C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds (black triangles: 30 mg/kg, black circles: 100 mg/kg, grey circles: exendin-4, 1 μg/kg) or vehicle (white circles) were IP administered to fasted C57BL/6J mice at -30 min. Glucose solution (1.5 g/kg) was given IP at 0 min. Values are mean ± SEM (n = 7). #P<0.05, ##P<0.01, ###P<0.001 versus vehicle (repeated measures ANOVA followed by student’s t-test).*P<0.05, **P<0.01, ***P<0.001 versus vehicle (repeated measures ANOVA followed by Dunnett).

Mentions: IPGTT was chosen as the key experiment for assessing the acute in vivo utility of GPR39 agonists. First, the three compounds were tested by IP administration to fasted lean mice 30 min before IP administration of 1.5 g/kg glucose. The GLP-1 agonist exendin-4 [18] was used as positive control, in this and all presented in vivo studies. Effect data on glucose and insulin levels are shown in Fig 7. The three agonists showed neither significant glucose lowering effects nor significant insulinotropic effects.


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)

IPGTT in C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds (black triangles: 30 mg/kg, black circles: 100 mg/kg, grey circles: exendin-4, 1 μg/kg) or vehicle (white circles) were IP administered to fasted C57BL/6J mice at -30 min. Glucose solution (1.5 g/kg) was given IP at 0 min. Values are mean ± SEM (n = 7). #P<0.05, ##P<0.01, ###P<0.001 versus vehicle (repeated measures ANOVA followed by student’s t-test).*P<0.05, **P<0.01, ***P<0.001 versus vehicle (repeated measures ANOVA followed by Dunnett).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145849.g007: IPGTT in C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds (black triangles: 30 mg/kg, black circles: 100 mg/kg, grey circles: exendin-4, 1 μg/kg) or vehicle (white circles) were IP administered to fasted C57BL/6J mice at -30 min. Glucose solution (1.5 g/kg) was given IP at 0 min. Values are mean ± SEM (n = 7). #P<0.05, ##P<0.01, ###P<0.001 versus vehicle (repeated measures ANOVA followed by student’s t-test).*P<0.05, **P<0.01, ***P<0.001 versus vehicle (repeated measures ANOVA followed by Dunnett).
Mentions: IPGTT was chosen as the key experiment for assessing the acute in vivo utility of GPR39 agonists. First, the three compounds were tested by IP administration to fasted lean mice 30 min before IP administration of 1.5 g/kg glucose. The GLP-1 agonist exendin-4 [18] was used as positive control, in this and all presented in vivo studies. Effect data on glucose and insulin levels are shown in Fig 7. The three agonists showed neither significant glucose lowering effects nor significant insulinotropic effects.

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