Georgia Wyett1, Yann Gibert1, Megan Ellis1, Hozana A Castillo2,3, Kathryn Aston-Mourney4. 1. Metabolic Research Unit, School of Medicine, Deakin University, 75 Pigdons Rd, Waurn Ponds, VIC, 3216, Australia. 2. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, 3800, Australia. 3. Brazilian Biosciences National Laboratory, Brazilian Center of Research in Energy and Materials, Campinas, Brazil. 4. Metabolic Research Unit, School of Medicine, Deakin University, 75 Pigdons Rd, Waurn Ponds, VIC, 3216, Australia. k.astonmourney@deakin.edu.au.
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.
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.
Authors: Lihua Ye; Morgan A Robertson; Daniel Hesselson; Didier Y R Stainier; Ryan M Anderson Journal: Development Date: 2015-04-15 Impact factor: 6.868
Authors: M Masini; M Anello; M Bugliani; L Marselli; F Filipponi; U Boggi; F Purrello; M Occhipinti; L Martino; P Marchetti; V De Tata Journal: Diabetes Res Clin Pract Date: 2014-01-03 Impact factor: 5.602