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

ABSTRACT: Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired ?-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic ?-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve ?-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.

SUBMITTER: Fjellstrom O

PROVIDER: S-EPMC4697807 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Fjellström Ola O Larsson Niklas N Yasuda Shin-Ichiro S Tsuchida Takuma T Oguma Takahiro T Marley Anna A Wennberg-Huldt Charlotte C Hovdal Daniel D Fukuda Hajime H Yoneyama Yukimi Y Sasaki Kazuyo K Johansson Anders A Lundqvist Sara S Brengdahl Johan J Isaacs Richard J RJ Brown Daniel D Geschwindner Stefan S Benthem Lambertus L Priest Claire C Turnbull Andrew A

PloS one 20151231 12

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 st ...[more]

PMID: 26720709

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Project description:Type 2 diabetes mellitus (T2DM) describes a group of metabolic disorders characterized by defects in insulin secretion and insulin sensitivity. Insulin secretion from pancreatic β-cells is an important factor in the etiology of T2DM, though the complex regulation and mechanisms of insulin secretion from β-cells remains to be fully elucidated. High plasma levels of serotonin (5-hydroxytryptamine; 5-HT) have been reported in T2DM patients, though the potential effect on insulin secretion is unclear. However, it is known that the 5-HT receptor 2C (5-HT(2C)R) agonist, mCPP, decreases plasma insulin concentration in mice. As such, we aimed to investigate the expression of the 5-HT(2C)R in pancreatic islets of diabetic mice and the role of 5-HT(2C)R signaling in insulin secretion from pancreatic β-cells. We found that 5-HT(2C)R expression was significantly increased in pancreatic islets of db/db mice. Furthermore, treatment with a 5-HT(2C)R antagonist (SB242084) increased insulin secretion from pancreatic islets isolated from db/db mice in a dose-dependent manner, but had no effect in islets from control mice. The effect of a 5-HT(2C)R agonist (mCPP) and antagonist (SB242084) were further studied in isolated pancreatic islets from mice and Min-6 cells. We found that mCPP significantly inhibited insulin secretion in Min-6 cells and isolated islets in a dose-dependent manner, which could be reversed by SB242084 or RNA interference against 5-HT(2C)R. We also treated Min-6 cells with palmitic acid for 24 h, and found that the expression of 5-HT(2C)R increased in a dose-dependent manner; furthermore, the inhibition of insulin secretion in Min-6 cells induced by palmitic acid could be reversed by SB242084 or RNA interference against 5-HT(2C)R. Taken together, our data suggests that increased expression of 5-HT(2C)R in pancreatic β-cells might inhibit insulin secretion. This unique observation increases our understanding of T2DM and suggests new avenues for potential treatment.

Dataset Information

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

Publications

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

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