Researchers investigating whether they can reprogram pancreatic stem cell-like cells into insulin-producing beta-cells for potential diabetes treatment, have found that the genes regulating insulin expression could be reactivated by using a drug previously investigated for treating patients with certain types of cancers. The research findings suggest a possible new treatment option for diabetes patients who rely on daily insulin injections.

According to the World Health Organization, there are around 422 million people with diabetes globally, with some researchers estimating that the figure will reach 700 million by 2045. There are two major types of diabetes: Type 1 diabetes is where the body does not produce the hormone insulin or makes very little of it. This form of diabetes is more common in children and young adults.

Type 2 diabetes is where the body produces insulin but not enough of it, or the body cannot properly utilize the insulin produced. Type 2 is the most common form of diabetes, accounting for nearly 95 percent of all cases, and is often found to begin later in life.

Beta-cells in the pancreas, which typically make up 50-70 percent of the groups of cells in the pancreas referred to as pancreatic islets, are responsible for producing insulin. In both types of diabetes, there is a significant reduction in beta-cells primarily due to autoimmune destruction.

Individuals with Type 1 diabetes, and some people with Type 2 diabetes, must take insulin injections daily to survive. The alternative is whole pancreas or pancreatic islet transplantation, which is limited by the shortage of organ donors and the associated side effects of drugs used to suppress the body’s immune response to the transplanted organ,
Researchers at Monash University in Australia, found that the investigational drug GSK-126, used in treating certain types of cancers, can potentially restore insulin-producing beta-cells in Type 1 diabetes patients. The drugs do this by inhibiting the pancreatic enzyme EZH2, which in turn is responsible for inhibiting the development of insulin-producing beta-cells. The researchers hypothesized that blocking EZH2 activity may restore insulin production.

For their study, the researchers examined the effect of the highly selective EZH2 inhibitor GSK-126 on specific genes related to insulin production using ex vivo human pancreatic tissues from three donors, two non-diabetic and one Type 1 diabetes donor. When the researchers analyzed the pancreas from the Type 1 diabetes donor, as expected, they noted absolute beta-cell destruction. The genes that regulate beta-cell development and insulin production in these pancreatic cells were ‘silenced’.

The researchers then found that by stimulating the pancreatic cells with GSK-126, the hallmark genes responsible for developing pancreatic progenitor cells (stem cell-like cells) into insulin-producing beta-cells, insulin production could be restored.
They observed that GSK-126 also restored expression of the insulin gene in the cells taken from the Type 1 diabetes donor, despite absolute beta-cell destruction. The study is the first reported example of restored insulin gene transcription and provides strong evidence for beta-cell regeneration.

Additionally, the study found that the restoration of insulin production was ‘rapid’, in some cases, by as early as two days of drug treatment compared to three to four months with alternate approaches using embryonic stem-cells. A major advantage of this potential diabetes treatment is that it is less vulnerable to the risks associated with organ or islet transplantation.

Commenting on the limitations of their study, the researchers noted that they used cells from a single Type 1 diabetes donor. They said that additional studies were required to determine if the approach is successful in a broader Type 1 diabetes population.

Moreover, autoimmune attacks on insulin-producing beta-cells also present another hurdle to developing a new therapy. In type 1 diabetes (and some cases of type 2 diabetes) there is quite strong (auto)immune reactivity to the islets and insulin-producing beta cells, which will not be avoided by making more of them.

Although this potential new diabetes treatment offers hope to individuals with Type 1 diabetes, it is not ideally targeted to Type 2 diabetes. In the more common Type 2 diabetes, the biggest problem is generally that insulin does not work very well. Moreover, this treatment may not become available for clinical treatment until another 7 to 10 years, which, while normal for most new therapies, is indeed a long wait for those debilitated by diabetes today.

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