ESPEYB20 8. Type 1 Diabetes New Mechanisms (3 abstracts)
8.12. ZnT8 loss-of-function accelerates functional maturation of hESC-derived beta cells and resists metabolic stress in diabetes
Ma Q , Xiao Y , Xu W , Wang M , Li S , Yang Z , Xu M , Zhang T , Zhang ZN , Hu R , Su Q , Yuan F , Xiao T , Wang X , He Q , Zhao J , Chen ZJ , Sheng Z , Chai M , Wang H , Shi W , Deng Q , Cheng X & Li W
Nat Commun 2022;13(1):4142.PMID: 35842441
Brief summary: In this experimental study, genome editing and in vitro pancreatic differentiation of human pluripotent stem cells (SC) were used to generate ZNT8 loss-of-function (LOF) SC-β-cells. These cells showed accelerated functional maturation, increased insulin secretion and improved resistance to metabolic stress. Transplantation of ZnT8 LOF SC-β-cells into mice with preexisting diabetes significantly improved their glucose levels.
Use of human embryonic SC-β-cells is a potential therapy that holds great promise for the treatment of type 1 diabetes (T1D) (1). The unlimited source provided by SC-β-cells could overcome the scarcity in cadaveric donor tissues for islet transplantation. However, the widespread use of SC-β cells is still limited by their immature function and fragility in a hostile environment. In this respect, the use of gene editing has been proposed as a tool to enhance engraftment, function, and survival of SC-β cells (1).
In this study, gene editing was applied and directed to the ZnT8 gene. This target was chosen based on genetic findings that LOF mutations in ZNT8 decrease the risk of diabetes and improve insulin secretion (2). ZnT8 is a zinc transporter, mainly expressed in pancreatic β cells, which regulates zinc influx into insulin granules and facilitates insulin hexamer formation (3). There is evidence suggesting that excessive zinc disrupts the homeostasis of the endoplasmic reticulum (ER) and mitochondrial function, resulting in impaired cell function and viability. Therefore, acting on zinc levels, through ZNT8 gene editing, could represent a way of improving SC-β cells function and survival. Indeed, the generated ZnT8 LOF SC-β cells showed greater insulin secretion capacity, as well as resistance to glucotoxicity/lipotoxicity-triggered cell death, by alleviating ER stress through modulation of zinc levels. ZnT8 LOF also led to improved glycemic control in a mouse model of diabetes.
Overall, these findings highlight the beneficial effects of ZnT8 LOF on the functional maturation and survival of SC-β cells, which are a potential source for cell replacement therapies. Several aspects remain to be clarified through further research, such as how decreased intracellular zinc alleviates ER and mitochondrial dysfunction, and also the effect of different variants of the ZnT8 gene, which previously showed discordant associations with zinc levels and protection from diabetes.
References: 1. Nair GG, Tzanakakis ES, Hebrok M. Emerging routes to the generation of functional β-cells for diabetes mellitus cell therapy. Nat Rev Endocrinol. 2020;16(9):506–518. 2. Dwivedi OP, Lehtovirta M, Hastoy B, et al. Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nature Genetics. 2019;51(11):1596–1606. 3. Daniels MJ, Jagielnicki M, Yeager M. Structure/function analysis of human ZnT8 (SLC30A8): A diabetes risk factor and zinc transporter. Current Research in Structural Biology. 2020;2:144–155.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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