In diabetes β-cell failure causes decreased insulin action because of impaired insulin secretion and insulin resistance. While symptoms usually do not appear before 80 per cent of the β-cell mass has been destroyed, absolute destruction of these cells leads to the dependence on exogenous insulin injections. Although insulin-dependent diabetes is generally associated with type 1 diabetes (T1D), as the immune system mediates β-cell destruction, the phenomenon is shared in type 2 diabetes (T2D). The progressive exhaustion of β-cells means that over 75 per cent of type 2 diabetics will eventually rely on insulin injections. While current pharmaceutical options for diabetes treatment help control blood glucose levels they do not prevent, retard or reverse the decline in insulin-secreting β-cells. Consequently, research has focussed on β-cell replacement which remains medical need unmet.
Inhibition of the EZH2 histone methyltransferase restores insulin gene expression by way of human pancreatic ductal cell-driven β-cell regeneration. Results from these studies will contribute to the design of therapies to generate more insulin-producing cells as an effective cure for insulin dependency in T2D. The objective of the project is to be able to regenerate functional glucose-responsive insulin-producing β-cells in vivo through alternate delivery of EZH2 inhibitors.
This project will identify key epigenetic modifications such as sites of histone modification that suppress the ability of pancreatic progenitor cells to synthesise insulin. By elucidating and then targeting these pathways driven by specific enzymes such as EZH2 it will be possible to generate a new more productive source insulin producing cells leading to a potentially new therapeutic strategy to combat insulin dependency in diabetes
Until now, the regenerative process has been incidental, lacking human studies, which have predominantly been in mice. The rare opportunity to examine fresh donor tissue and the availability of FDA approved small molecule inhibitors allow our team to better characterise treatment refractory genes emphasising the regenerative barrier of ductal cells derived from the pancreas. Researchers are focussed on restoring insulin competency.
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