期刊
ENDOCRINE
卷 59, 期 2, 页码 419-425出版社
SPRINGER
DOI: 10.1007/s12020-017-1502-3
关键词
Zebrafish; Beta-cell; Diabetes; Metformin; Development; Regeneration
资金
- NHMRC [GNT1068411]
- Monash University Faculty of Medicine and Nursing strategic grant
- Victorian Government
- CNPq [202130/2015-0]
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. 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. 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). 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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