1 new epigenetic approach for treating diabetes. Going from A to B.

Any new approach to treating and managing diabetes is to be welcomed. The condition affects tens of million people worldwide, and will likely increase as obesity levels in the developed and developing world increase. However the hope of transplanting beta cells have failed to live up to expectations, and this new angle, reprogramming alpha cells to behave as beta cells may end up in a similar way. I don’t want to rain on this parade, but urge caution on any expectation of a quick return from this exciting new research.

What follows below is gobbledygook to most people but is yet another sign that the concept of epigenetics is helping scientists and clinicians find new approaches to treating chronic problems. In this case diabetes. The summary of the research recently published by the Perelman School of Medicine at the University of Pennsylvania is in block text below.

Insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type–specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes.

Epigenetic changes can alter PDX1 expression. It is an essential transcription factor for ...

Let me try and make some sense of the above for those who have skimmed or skipped the summary.

There are two types of cells in the pancreas that have an effect on your blood sugar. They do this by releasing chemical messengers – hormones – in response the level and rate of change of glucose – sugar – in your blood. They cluster together as islets of cells in the pancreas, one being called alpha – A, and the second being beta – B.

Alpha cells release a hormone called glucagon when your blood sugar is low. This hormone acts on organs that store sugar such as the liver, and cause a release of glucose into the blood in an attempt to normalise the glucose level. Beta cells release the hormone insulin, in response to a rise in blood glucose levels. In diabetes it is the beta cells that are the problem. They are either absent, as in Type 1 diabetes or compromised and unable to function correctly as in Type 2 diabetes.

Attempts at beta cell replacement therapy have been the core of research for at least 40 years or more. When stem cells were able to be harvested from diabetic patients, further research was done hoping to find out how to activate the stem cells as beta cells. However this area of technical medicine has not yet borne fruit, due to problems with the immuno-suppression needed if some else’s beta cells are injected into you – in the liver, or not being able to create beta cells that are able to thrive, from a patient’s own stem cells.

So what is new here? Remember that any cell in the body with DNA could become every type of cell in your body. It all hinges on how the DNA in the cell is managed; what genes are turned on and off and when, what are shut down and “in storage” and how the cell knows what is expected of it.

A group of chemicals called histones are known to work in switching genes on and off. The team at Perelman using this group among others including doxorubicin, an anticancer drug, have managed to make alpha cells change their tune and behave like beta cells.

They have made it clear that the reprogramming of alpha cells to act as beta cells is only partial, and that the reprogrammed cells have yet to show an ability to divide and maintain their new genetic signature. This is unlikely to change. The theory goes that if a recipe of existing and new drugs is found that can keep reprogramming the alpha cells to behave as beta cells, then it does not guarantee a possible treatment for diabetes.

I think the next problems beyond where the team are now are;

        1. Are the alpha cells that are programmed as beta cells going to function once the reprogramming has occurred, or will they revert to alpha cells one the epigenetic alchemy is no longer present?
        2. What is the risk of cancerous change in the alpha cell population?
        3. Is the alpha cell population fixed or do the cells divide if the population is reprogrammed?
        4. the possibility of alpha cell depletion.Are the risks of having to use the reprogramming drugs continuously or intermittently more than the use of insulin or other existing drugs used in Type 2 diabetes?

I hate to put a dampener on this important advance but as one of the researchers themselves has commented “…reprogramming was initiated in a substantial sub-population of α cells, but was nearly completed in only a few”.

So be excited, but then sit down and think about the idea of a lifetime of taking drugs that have their own risks, and the possibility of alpha cell depletion.

 

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