A new study shows that it is possible to cure type 1 diabetes (T1D) using two drugs that the FDA has already approved for the treatment of sarcomas1-2. This study demonstrated how insulin-producing cells in the pancreas can regenerate. Drugs called GSK126 and Tazemetostat (Taz) treat cancer by silencing the gene that encodes a key enzyme, called Enhancer of zeste homolog 2 (EZH2).3.
Diabetes affects around 400 million people worldwide and is responsible for 9.9% of deaths.1. It is caused by the destruction of the insulin-producing β cells of the islets of Langerhans of the pancreas. This causes an inability to properly regulate blood glucose and a dependency on insulin. Current treatments help control blood glucose levels, but do not prevent, slow, or reverse the decline in insulin-secreting β cells. Still, it may be possible to transplant a completely new pancreas or islet. However, there is a shortage of available donors. Even when a donor is available, immunosuppressive medications are necessary. They can cause very adverse side effects.
So it’s interesting that a totally new approach to treating T1D has emerged. The idea is to correct the defect that exists, not in the genome, but in the epigenome. That is, our genome (all our genes) is not a blueprint, but a part of a larger dynamic system that allows the appropriate genes (DNA) to be transcribed into messenger RNA (mRNA) and then translated into proteins. For an organism to survive, it must be able to adapt to changes in its environment. To do this, genes, mRNA and proteins can be activated or deactivated by a control layer that is above the genome, as a complement to genetics. This layer is called the epigenome. Epigenetics is the study of how behavior and the environment cause changes that affect how genes function. One way to control DNA transcription is through positively charged histone proteins, which wrap around double-stranded DNA and neutralize about 50% of it. If the negatively charged DNA were not surrounded by histones, the DNA would not be able to compact in the small space offered by the cell nucleus, due to electrostatic repulsion. The arginine and lysine residues of histones are ideal targets for part of the epigenetic control of transcription. One way to modify them is by adding a methyl group.
Methylation of histones lysine and arginine is dynamically regulated at individual genes through the recruitment of enzymes called methyltransferases and demethylases. These enzymes catalyze the addition or removal of methyl groups. The lysine residues of histones can be methylated with one, two or three methyls, without affecting their charge. Arginine can be mono- or dimethylated. Methylation does not affect the ionic bonds between histones and DNA, but creates tags that can be identified by coregulatory proteins. In differentiated cells, inactive portions of the genome are divided between different forms of repressive chromatin. Repressive structures with a compact structure are not accessible to enzymes that can catalyze the transcription of DNA into RNA. They can affect large regions of the chromosomes. The tightly packed mixture of DNA and histones forms a structure called chromatin. The structure and function of chromatin are modulated by proteins associated with it. Improper control of chromatin structure can lead to T1D, cancer, and many other diseases. A group of proteins that can do this combine to form a complex that is important in the development of plants and animals. Polycomb proteins 1 and 2 (PRC1 and PRC2) can form complex structures that repress transcription. It is essential that transcription of the appropriate genes is turned off and on at the right times for an embryo to develop properly into a healthy baby and subsequently into an infant, child and adult.
A part of PRC2 is the enhancer of the catalytic subunit EZH23. It is a histone methyltransferase. It catalyzes the methylation of histone number 3 at arginine number 27 (H3K27). This causes transcriptional silencing of target genes. Other proteins of the polycomb group bind to H3K27 that forms the repressive state of chromatin. Overexpression of EZH2 occurs in many types of cancer and is correlated with tumorigenesis, metastasis, and poor prognosis. The drug EPZ-6438 (tazemetostat) inhibits EZH2. It was approved by the FDA for the treatment of epithelioid sarcoma in 2020.
Fortunately, researchers have discovered that this same drug is capable of inhibiting EZH2 in β cells found in pancreatic islets. These synthesize, store and release insulin. In T1D, T cells of the immune system selectively destroy insulin-producing β cells. This leads to a lifelong dependence on insulin for survival. The main function of EZH2 is to catalyze histone H3 methylation of H3K27Me3, which inhibits the transcription of target genes, such as tumor suppressor genes. EZH2 also forms complexes with transcription factors or binds directly to the promoters of target genes, leading to regulation of gene transcription. Pancreatic ductal progenitor cells were already known to be a promising source of β-cell regeneration for T1D due to their inherent differentiation capacity. Transcriptional suppression by default tightly controls regenerative potential. In a recent study, exocrine cells derived from young and adult donors with T1D treated with Tazemetostat showed a phenotypic shift toward a cellular identity similar to that of β cells. EZH2 treatment was necessary for the regenerative potential of β cells. Reprogrammed pancreatic ductal cells produced insulin and secretion in response to glucose administration1.
This is not the only promising advance in the treatment of diabetes. Tirzepatide, marketed under the name Mounjaro, was approved for the treatment of type 2 diabetes (T2D) on May 13, 2022. It is a synthetic combination of two peptides called GLP-1 (glucagon-like peptide). 1) and GIP (glucose-dependent insulinotropic polypeptide). They are called incretin hormones. They are secreted in the intestine after consuming nutrients. They stimulate the production of insulin and decrease the concentration of glucose in the blood. So the work continues, as researchers, doctors, and even pharmaceutical companies collaborate to develop treatments and cures for T1D, T2D, and many other diseases.
Grades
1 Al-Hasani, K. et al. (2024). EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors. Signal Transduction and Targeted Therapy.
2 Nield, D. (2024). Diabetes Breakthrough: FDA-Approved Drugs Regenerate Insulin Production in 48 Hours. Science Alert.
3 Zhang, T. et al. (2022). Dysregulated lipid metabolism blunts the sensitivity of cancer cells to EZH2 inhibitor. EBioMedicine.