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Autocrine effect of Zn2+ on the glucose-stimulated insulin secretion

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Abstract

It is well known that zinc (Zn2+) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta (β)-cells, and that changes in Zn2+ levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn2+ and insulin with similar kinetics. However, we do not know whether Zn2+ regulates insulin availability and secretion. Here we investigated the effect of Zn2+ on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn2+ alone (control) had no effect on the basal secretion of insulin, it significantly inhibited GSIS. The application of CaEDTA, by removing the secreted Zn2+ from the extracellular milieu of the islets, resulted in significantly increased GSIS, suggesting an overall inhibitory role of secreted Zn2+ on GSIS. The inhibitory action of Zn2+ was mostly mediated through the activities of KATP/Ca2+ channels. Furthermore, during brief paired-pulse glucose-stimulated Zn2+ secretion (GSZS), Zn2+ secretion following the second pulse was significantly attenuated, probably by the secreted endogenous Zn2+ after the first pulse. Such an inhibition on Zn2+ secretion following the second pulse was completely reversed by Zn2+ chelation, suggesting a negative feedback mechanism, in which the initial glucose-stimulated Zn2+ release inhibits subsequent Zn2+ secretion, subsequently inhibiting insulin co-secretion as well. Taken together, these data suggest a negative feedback mechanism on GSZS and GSIS by Zn2+ secreted from β-cells, and the co-secreted Zn2+ may act as an autocrine inhibitory modulator.

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Acknowledgments

We thank Dr. Calvin James for his advice of preparing pancreatic islets, Dr. Peter Drain for mCherry-tagged insulin fusion protein, and Dr. Tomohiko Sugiyama for helping with propagation and purification of construct DNA kindly gifted to us by Dr. Drain. We also wish to thank the Imaging Facility of the Ohio University Neuroscience Program for their support.

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The authors declare that they have no conflict of interest.

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  1. Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA

    Kira G. Slepchenko & Yang V. Li

  2. Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA

    Nigel A. Daniels & Aili Guo

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  1. Kira G. Slepchenko
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Slepchenko, K.G., Daniels, N.A., Guo, A. et al. Autocrine effect of Zn2+ on the glucose-stimulated insulin secretion. Endocrine 50, 110–122 (2015). https://doi.org/10.1007/s12020-015-0568-z

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