Remaining critical insulin gene is uncovered

For the first time, researchers at the Harvard-affiliated Joslin Diabetes Center have isolated and cloned the third and remaining gene believed to be a key regulator of insulin production. The scientists believe this achievement may now pave the way for researchers to use the trio of genes to encourage stem cells or other cells that do not normally produce insulin to do so, thereby creating a possible new way to treat diabetes.

For the past seven to eight years, scientists have known the identity of two genes (PDX-1 and Neuro-D1) that can influence the ability of insulin genes to trigger insulin production in the beta cells of the pancreas. Through subsequent research it has been demonstrated that these two genes are at least partially responsible for a form of diabetes called maturity onset diabetes of the young (MODY), which causes about 2-3 percent of all diabetes. Absence of either of these genes results in failure of the pancreas to develop or in abnormal development of insulin-producing cells resulting in development of diabetes.

But previous research has also clearly suggested that there was a third gene (termed RIPE3b1 factor) that played a critical role in controlling insulin production. Interestingly, the RIPE3b1 factor also plays a critical role in the ability of insulin-producing cells to sense changes in glucose levels and appropriately regulate the insulin gene to trigger insulin production. But scientists had been unable to isolate and clone this factor to test for its role in insulin production and development of diabetes.

In a paper published in the May 14 issue of the Proceedings of the National Academy of Sciences, Joslin researcher Arun Sharma and colleagues reported that they have been able to identify and clone the RIPE3b1 factor as mammalian MafA factor. “This gene produces a protein in humans that is very similar to a protein that is produced in chickens and quails that can transform undifferentiated cells into lens cells in the eyes,” says Sharma, who is also instructor in medicine at Harvard Medical School. “What we now wonder is whether we can insert this gene – plus the other two genes previously identified as influencing insulin production – into stem cells, or undifferentiated pancreatic duct cells, and convert them into insulin-producing cells.”

An estimated 17 million Americans have diabetes. There are two major types of diabetes – type 1 (previously called juvenile-onset or insulin-dependent diabetes) and type 2 (previously called adult-onset or non-insulin-dependent diabetes). In type 1 diabetes, the body has destroyed the insulin-producing beta cells in the islet cells of the pancreas, and the patient needs daily insulin injections to survive. About 1 million people in the United States have type 1.

In type 2 diabetes, the body is still producing some insulin, but the body’s cells are resistant to insulin’s effects and the body is not producing enough insulin to meet its needs. An estimated 16 million Americans have this form of diabetes, although about a third of those don’t know they have it. In both type 1 and type 2 diabetes, as well as in the far less frequently occurring MODY, glucose from food that is eaten backs up in the bloodstream because of inadequate insulin supply or insulin resistance, causing blood sugars to rise. Poorly controlled diabetes can lead to a host of complications including blindness, heart disease, stroke, nerve damage, and impotence.

Islet cell transplants (islet cells contain insulin-producing beta cells) are hoped to one day be a means of treating people with type 1 diabetes. But while research is gradually improving success rates for this still very experimental procedure, a major barrier looms – an inadequate supply of islet beta cells to transplant. Only about 3,000 to 4,000 pancreases become available for transplant each year, and two pancreases are needed to harvest enough beta cells for a single transplant. With 1 million Americans having type 1 diabetes, and more than 30,000 new cases diagnosed annually, the demand for transplants, once perfected, will far outstrip the supply of transplantable cells – unless research uncovers a way to transform other types of cells into insulin-producing cells.

Sharma speculates that in addition to being able to convert stem cells into insulin-producing cells, this gene might also be capable of boosting the insulin production capacity of beta cells that have been harvested for transplants to treat type 1 diabetes, or for correcting the glucose sensitivity of insulin-producing cell lines that have begun to lose their ability to work as well over time. “Now that we have all three regulatory genes available to us, we can begin testing them in a variety of experiments to see how they may make it possible for us to generate insulin-producing cells that appropriately respond to changes in blood glucose levels and use these cells for the treatment for diabetes.”

Researchers involved in this most recent research include Martin Olbrot, Jonathan Rud, and Sharma of Joslin Diabetes Center, and Larry G. Moss of the Department of Physiology at Tufts University and Tufts University School of Medicine.