October 4, 2004
La Jolla, CA – A Salk Institute research team has made a discovery that provides valuable insight into a complication that is common among organ transplant patients and could eventually lead to new therapies for diabetes.
The team, led by Professor Marc Montminy, discovered a molecular connection linking two key chemical pathways that are essential for blood sugar regulation.
The team published its findings in the Oct. 1 issue of Cell.
The findings emerged as result of Montminy’s ongoing research into a pivotal chemical regulator called CREB, which Montminy’s group originally discovered, that is found inside the insulin-producing beta cells of the pancreas. When activated, CREB works to prolong the life of beta cells and helps promote insulin release. As such, it is the focus of intense interest for researchers understanding how diabetes arises-and how it can be treated.
The research discovered that CREB is ‘turned on’ by two distinct chemical pathways that, in turn, are responding to two types of signal – rising levels of blood glucose and hormones released by the digestive system during a meal. Until recently it was unclear how exactly CREB was able to respond to both these chemical pathways. Montminy’s laboratory has now provided part of the answer by showing that CREB is able to respond to these two pathways with the assistance of a ‘coactivator’ protein also found in islet cells called TORC (transducer of regulated CREB activity).
“In our work to determine how CREB coordinated the efforts of these two pathways, we found that TORC played a key role in mediating regulation of the body’s response to blood sugar,” Montminy said. “Because TORC enhances islet cell function and therefore insulin production, this finding may prove useful for people with adult diabetes. Since TORC also appears to promote the production of islet cells, it may be useful in the future for transplanting new islet cells into patients with type I diabetes, (who lose islet cells through an auto-immune process.”
In addition, the researchers found that cyclosporine, a drug frequently used to prevent rejection of transplanted organs, interfered with the ability of TORC to assist CREB, thus providing one explanation for the islet cell failure and diabetes that is often seen as a complication of transplant surgery.
“This work illustrates the importance of cellular switches like TORC to coordinate the body’s response to dietary glucose,” said Montminy. “We now need to know the extent TORC is active in other parts of the body, and how we might develop methods that enhance its activity, particularly in the pancreas, to maintain healthy blood sugar levels.”
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes.