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.
Ian Harper (Manager), Stephen Firth (Manager), Alex Fulcher (Operator), Oleks Chernyavskiy (Operator), Margaret Rzeszutek (Other), David Potter (Manager), Volker Hilsenstein (Operator), Juan Nunez-Iglesias (Other), Stephen Cody (Manager), Irena Carmichael (Operator), Betty Kouskousis (Other), Chad Johnson (Operator), Sarah Creed (Manager) & Giulia Ballerin (Operator)Office of the Vice-Provost (Research and Research Infrastructure)