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GPR39 receptors and actions of trace metals on pancreatic beta cell function and glucose homoeostasis

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Abstract

Aims

G-protein-coupled receptor 39 (GPR39) has been implicated in glucose homoeostasis, appetite control and gastrointestinal tract function.

Methods

This study used clonal BRIN-BD11 cells and mouse pancreatic islets to assess the insulin-releasing actions of trace metals believed to act via GPR39, and the second messenger pathways involved in mediating their effects. Micromolar concentrations of Zn2+, Cu2+, Ni2+ and Co2+ were examined under normoglycaemic and hyperglycaemic conditions. Mechanistic studies investigated changes of intracellular Ca2+, cAMP generation and assessment of cytotoxicity by LDH release. Cellular localisation of GPR39 was determined by double immunohistochemical staining.

Results

All trace metals (7.8–500 µmol/l) stimulated insulin release with Cu2+ being the most potent in isolated islets, with an EC50 value of 87 μmol/l. Zn2+ was the most selective with an EC50 value of 125 μmol/l. Enhancement of insulin secretion was also observed with Ni2+ (179 μmol/l) and Co2+ (190 μmol/l). These insulin-releasing effects were confirmed using clonal BRIN-BD11 cells which exhibited enhanced intracellular Ca2+ (p < 0.05–p < 0.001) and cAMP generation (p < 0.05–p < 0.001) in response to trace metals. Oral administration of Zn2+, Ni2+ and Cu2+ (50 µmol/kg together with 18 mmol/kg glucose) decreased the glycaemic excursion (p < 0.05–p < 0.01) and augmented insulin secretion (p < 0.05–p < 0.01) in NIH Swiss mice.

Conclusions

This study has demonstrated the presence of GPR39 and the insulinotropic actions of trace metals on BRIN-BD11 cells and pancreatic beta cells, together with their antihyperglycaemic actions in vivo. These data suggest that development of agonists capable of specifically activating GPR39 may be a useful new therapeutic approach for diabetes management.

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Acknowledgments

These studies were supported by the Department of Education and Learning, Northern Ireland.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

This study was approved by the University of Ulster Animal Ethics Review Committee. All animal experiments were carried out in accordance with the UK Animal (Scientific Procedures) Act 1986.

Human and animal rights

All procedures followed were in accordance with the UK Animal (Scientific Procedures) Act 1986 and the ARRIVE guidelines for reporting experiments involving animals. No clinical studies were carried out in this study.

Informed consent

No informed consent was required as no patients or clinical studies were involved in this study.

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Authors and Affiliations

  1. Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK

    Brian. M. Moran, Yasser H. A. Abdel-Wahab, Srividya Vasu, Peter R. Flatt & Aine M. McKillop

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  1. Brian. M. Moran
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  2. Yasser H. A. Abdel-Wahab
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  3. Srividya Vasu
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  4. Peter R. Flatt
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  5. Aine M. McKillop
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Correspondence to Aine M. McKillop.

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Moran, B.M., Abdel-Wahab, Y.H.A., Vasu, S. et al. GPR39 receptors and actions of trace metals on pancreatic beta cell function and glucose homoeostasis. Acta Diabetol 53, 279–293 (2016). https://doi.org/10.1007/s00592-015-0781-5

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  • DOI: https://doi.org/10.1007/s00592-015-0781-5

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