Potential Breakthrough in the Treatment of Type 1 Diabetes
Image: ‘Diabetes 2/4’ by Dennis Skley is licensed under CC BY-ND 2.0 DEED
The novel method of producing insulin in type 1 diabetes-affected pancreatic cells depends on restoring β-like cell function in the pancreas, opening up the pathway for potential regenerative treatment strategies.
In a first, scientists have successfully restored insulin production through β (beta)-like cells in the pancreas by regulating gene behaviour, paving the way for a novel treatment of type 1 diabetes (T1D). Current treatment strategies mainly include a lifelong dependence on exogenous insulin through injections or a pump, so this discovery of a new potential treatment option comes with promise and hope for patients suffering from the incurable disease.
With over 8.4 million cases worldwide and a prediction of over 17 million cases by 2040, T1D is a cause for concern. It is an autoimmune disease wherein the insulin-producing β-cells in the pancreas are attacked by one’s own immune cells. Because of this, the pancreas either becomes incapable of producing insulin or makes very little of it. Since insulin is vital for the uptake of blood glucose by cells, an absence of insulin leads to the buildup of glucose in the bloodstream. This dysregulation of blood glucose levels gives rise to the complications associated with T1D, like heart disease and stroke, kidney problems, and foot and circulation problems, to name a few.
Unfortunately, there is no cure for T1D. It can only be managed with a regular intake of insulin in the body through injections or an insulin pump, which can be challenging. In some cases, a transplant to restore β-cell mass can also be done. However, these therapies can face donor shortages or have side effects from immunosuppressive drugs that have to be consumed after transplantation. Therefore, there is an urgent need for new treatment strategies.
A recent study published in the Signal Transduction and Targeted Therapy journal demonstrates that it is possible to restore insulin expression in pancreatic ductal cells by regulating gene expression. “Our research has shown an unprecedented effect on β-cell regeneration in preclinical work. It is a potential breakthrough in regenerative therapy aimed at restoring pancreatic function,” said Sam El-Osta, the corresponding author of the study.
The team of scientists at the Baker Heart and Diabetes Institute in Melbourne, Australia, surgically obtained two pancreatic tissue samples from T1D patients and one healthy tissue sample from a healthy participant as a control and stimulated them for 48 hours using two FDA-approved cancer drugs, GSK126 and Tazemetostat (Taz), which are used for inhibiting EZH2, a gene that has recently gained attention as a target in cancer therapy. They found that the ductal cells in the pancreatic tissue samples, which don’t normally produce insulin and remain unaffected in T1D, started behaving like β-cells and produced insulin on drug stimulation, followed by high glucose exposure.
The mechanism of action behind this is the genetic alteration of the EZH2 gene by the two drugs. The EZH2 gene produces the EZH2 methyltransferase enzyme, which is responsible for trimethylation of lysine 27 on the histone 3 (H3K27me3) of chromatin, a complex of DNA and proteins that forms chromosomes. H3K27me3 is, therefore, an epigenetic (a change in the DNA that regulates whether genes are turned on or off) modification associated with “silencing” specific genes, which simply means preventing their expression. Inhibition of EZH2 by the drugs does not allow production of the EZH2 methyltransferase enzyme, and subsequently, the H3K27me3 modification does not take place. As a result, the ductal cells in the pancreas that house EZH2 remain activated and produce insulin in response to glucose, behaving like β-cells.
The team has now patented this method of producing insulin-producing cells. El-Osta, who is also the head of the Epigenetics in Human Health and Disease lab at the Baker Heart and Diabetes Institute, said, “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. This advance in methodology harnesses the patients’ remaining pancreatic cells to increase insulin-producing β-cells to modify the course of diabetes, potentially eliminating the need for round-the-clock insulin injections in some people living with T1D. This could potentially lead to the development of a regenerative strategy that avoids transplantation.”
Given the small sample size of the study and the fact that the experiments involved testing pancreatic tissue in a lab, El-Osta said: “[that] further preclinical work is necessary to test the approach using alternative models.” However, there is no doubt that this advancement takes us one step closer to a potential breakthrough in the treatment of T1D. El-Osta is also hopeful for the use of these findings in developing treatments for type 2 diabetes in the future.