Beta Cell Reactivation May Be Viable Treatment for Patients With Type 1 Diabetes

Investigators in Australia have reactivated pancreatic stem cells from a donor with type 1 diabetes (T1D) to become insulin-expressing, showing the possibility that a drug could jump start beta cell production in patients with diabetes.

The study from Monash University represents a major breakthrough toward new treatments for (T1D) and type 2 diabetes (T2D). The findings, appearing in Signal Transduction and Targeted Therapy, could lead to a shift from insulin replacement to helping the body to produce insulin once again.

The study involved GSK126, a drug approved by FDA but not indicated for diabetes treatment.

Researchers sought to investigate the specific regulation of the H3K27me3 writing enzyme EZH2, which is considered responsible for silencing genes needed to allow ductal progenitor cells to eventually function as insulin secreting beta cells. If researchers could block this gene silencing with an EZH2 inhibitor, they might understand how to trigger pancreatic beta-cell regeneration, which could be a treatment for T1D.

The findings of the study showed that the action of the EZH2 inhibitor may aid development of epigenetic compounds for beta cell regeneration. This highlights the potential for new mechanisms of gene regulation, using EZH2 as a drug target.

As the first example of restoring transcription of the insulin gene, the study has clinical implications for regenerative medicine within the context of T1D.

The authors also note that this work determines that human pancreatic progenitor cells retain their capacity to differentiate into neo-beta-cells from the exocrine compartment that were derived from an insulin devoid donor with T1D. These findings show that pharmacological alteration of cell fate decisions through the epigenetic induction of progenitor genes holds promise for the treatment of T1D by promoting ex vivo beta cell regeneration through assisted epigenetic lineage reprogramming.

If this concept is successful, it would mean beta cells among those with insulin-dependent diabetes could be retrained to function, thus eliminating the need for lifetime testing of blood glucose and daily insulin injections.

“Patients rely on daily insulin injections to replace what would have been produced by the pancreas. Currently, the only other effective therapy requires pancreatic islet transplantation and while this has improved health outcomes for individuals with diabetes, transplantation relies on organ donors, so it has limited widespread use,” said Assam El-Osta, PhD, an epigeneticist and professor at Monash University in a statement.

About the current study, El-Osta noted, “We consider the research novel and an important step forward towards developing new therapies.”

However, the study faced limitations. The authors of the study describe the case as isolated, involving 1 child with T1D with hallmark islet damage and significant destruction of beta cells. Therefore, the results of the case cannot be generalized without further research.

Additionally, it is unclear whether classic silencing of progenitor genes can be restored in long-standing diabetes, though the ability to inhibit EZH2 and influence exocrine beta-cell progenitor transcription o near non-diabetic mRNA levels suggests this is highly likely.

The authors encourage further research to better understand the benefits and potential pharmacological interactions associated with exocrine regeneration.

“Before you get to patients, there are many issues to be resolved,” Keith Al-Hasani, PhD, pancreatic beta cell specialist at Monash University said in a statement. “More work is required to define the properties of these cells and establish protocols to isolate and expand them. I would think therapy is pretty far away, however, this represents an important step along the way to devising a lasting treatment that might be applicable for all types of diabetes.”

Reference

Al-Hasani L, Khurana I, Mariana L, et al. Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor. Signal Transduct Target Ther. 2022. Published July 21, 2022. Accessed July 21, 2022.