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Metformin, beta-cell development, and novel processes following beta-cell ablation in zebrafish

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Abstract

Purpose

Type 1 and 2 diabetes are characterized by a loss of insulin-producing beta-cells. Current treatments help maintain blood glucose levels but cannot provide a cure. As such, a vital target for the cure of diabetes is a way to restore beta-cell mass.

The drug metformin can protect cultured beta-cells/islets from hyperglycemia-induced dysfunction and death. Further, treatment of pregnant mice with metformin results in an enhanced beta-cell fraction in the embryos; however, whether this occurs via a direct effect is unknown.

Methods

We utilized the external embryogenesis of the zebrafish to determine the direct effect of metformin treatment on the pancreas of the developing embryo and following beta-cell ablation.

Results

During development metformin did not alter beta-cell or alpha-cell mass but had a small effect to increase delta-cell mass as measured by in situ hybridization. Further metformin significantly increased beta-cell number. Following beta-cell ablation, both glucagon and somatostatin expression were upregulated (>2-fold). Additionally, while metformin showed no effect to alter beta-cell mass or number, somatostatin expression was further increased (>5-fold).

Conclusions

We showed that direct exposure to metformin during embryogenesis does not increase insulin-expressing area but does increase beta-cell number. Further, we identified novel consequences of beta-cell ablation to alter the expression of other pancreatic hormones that were enhanced by metformin. Therefore, this study provides a greater understanding of the beta-cell development/regenerative processes and the effect of metformin, bringing us closer to identifying how to increase beta-cells in humans.

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Acknowledgements

We thank Deakin University School of Medicine and Centre for Molecular and Medical Research and Monash Medical Micro Imaging Facility and Fish Core for excellent support.

Funding

This project did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector. J.K. and H.C. were supported by an NHMRC project grant (GNT1068411), Monash University Faculty of Medicine and Nursing strategic grant and Operational Infrastructure Support from the Victorian Government, H.C. was supported by a fellowship from CNPq (202130/2015-0).

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Correspondence to Kathryn Aston-Mourney.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Studies were approved by the Deakin University Animal Welfare Committee (AWC G17-2015).

Additional information

Georgia Wyett and Yann Gibert contributed equally to this work.

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Wyett, G., Gibert, Y., Ellis, M. et al. Metformin, beta-cell development, and novel processes following beta-cell ablation in zebrafish. Endocrine 59, 419–425 (2018). https://doi.org/10.1007/s12020-017-1502-3

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  • DOI: https://doi.org/10.1007/s12020-017-1502-3

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