September 13, 2001
La Jolla, CA – Salk scientists have identified a new potential drug target for type II diabetes that may offer a specific treatment to complement existing therapies. The new target, a protein called CREB (for cyclic AMP response binding), acts in a pathway independent of that targeted by the thiazolidinediones, currently considered the most effective drugs for managing the condition.
“Attacking the disease on two fronts could make a big difference in patients,” said Salk Professor Marc Montminy, senior author of the study, which appears in the current Nature.
CREB is highly specific in its effects on glucose production; it does not appear to affect other metabolic pathways in the liver
“Liver is also an excellent target for fast-acting drugs that can be cleared quickly, minimizing side effects,” added Montminy.
Approximately 18 million Americans suffer from type II, or non-insulin dependent, diabetes, and about 80 percent of them display a condition called fasting hyperglycemia, in which blood sugar levels remain elevated even under fasting conditions such as sleep.
“Normally, the liver waits for a ‘low fuel’ warning before making more glucose,” said Montminy. “But in patients with type II diabetes, the liver seems to be in overdrive, and it looks like CREB is the accelerator.”
Two molecular pathways are known to control glucose production in the liver during fasting. One is triggered by the hormone glucagon, which is made in the pancreas; the other pathway originates in the adrenal gland, which produces glucocorticoid hormone. Both pathways work cooperatively; that is, they work far better together than individually, although the reason for this synergy between pathways was unknown. Montminy and his colleagues showed that CREB provides the molecular glue that connects these two pathways in the liver and it does so by stimulating the production of an intermediary protein called PGC-1 (PPAR gamma coactivator).
The investigators found that mice made deficient in CREB activity in the liver had lowered levels of both glucose and the enzymes that catalyze its production and release. Interfering with CREB in diabetic hyperglycemic mice restored their blood sugar levels to normal during fasting, indicating the potential of CREB as a drug target.
“We initially thought perhaps CREB activated glucose production directly, but found that it actually stimulates the production of an intermediary, PGC-1, which turns on the enzymes responsible for releasing glucose from its stored form,” said Montminy.
“PGC-1 might eventually make a good drug target,” he added, “but we already know the three-dimensional structure of CREB and this information might allow us to design drugs that can interfere with its activity more effectively.
“Either way, it would give physicians a nice tool to complement the existing drugs, the thiazolidinediones, which target a completely different aspect of the disease, reducing insulin resistance.”
The study, called “CREB regulates hepatic gluconeogenesis via the co-activator PGC-1” was conducted in collaboration with Salk co-authors Stephan Herzig, Fanxin Long, Ulupi Jhala and Susan Hedrick. Authors from other institutions included Rebecca Quinn at the Joslin Diabetes Center in Boston, Mass.; Anton Bauer, Dorothea Rudolph and Gunther Schutz at the Deutsches Krebsforschungzentrum Im Neuenheimerfeld in Heidelberg, German; and Pere Puisgever and Bruce Spiegelman at the Dana-Farber Cancer Center in Boston, Mass. The study was funded by the National Institutes of Health and the Deutsche Forschungs Gemeinshaft.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.