Clayton Foundation Laboratories for Peptide Biology
J.W. Kieckhefer Foundation Chair
Marc Montminy is a professor in the Clayton Foundation Laboratories for Peptide Biology. Montminy's lab isolated cDNA clones for the cAMP response element binding protein (CREB) in 1989. cAMP was found to regulate cellular genes via the PKA mediated phosphorylation of CREB at SER133. This modification was shown to promote target gene activation via the recruitment of the coactivator CBP. Structural studies of the CREB/CBP complex revealed that CREB phosphorylation promotes recruitment of CBP via allosteric and direct mechanisms. The structure also suggested the potential for developing small molecules that block target gene activation by disrupting the CREB: CBP complex.
Current work in the lab focuses on the identification of CREB target genes and characterization of agonists and antagonists that may be used to evaluate the importance of CREB in mediating cellular responses to various stimuli. Montminy also conducts research on the genetic basis of diabetes. Using knockout and transgenic approaches, the Montminy laboratory determined that CREB performs a critical role in glucose homeostasis during fasting. They found that CREB triggers the gluconeogenic program via induction of the nuclear hormone receptor coactivator PGC-1a. Following up on these studies, Montminy identified a second family of cAMP regulated CREB coactivators, called TORCs, which are critical for induction of gluconeogenic genes during fasting. They showed that TORC2 activity is inhibited by AMPK-mediated phosphorylation, providing an important link between energy-sensing and hormonal pathways. Indeed, oral hypoglycemic agents such as metformin, which activate AMPK, were found to reduce hepatic glucose production by inhibiting TORC2 activity. Future work using mice with knockouts in TORC family members will reveal the extent to which these coactivators promote energy balance in other insulin-sensitive tissues.
When a person's blood sugar level is high even when the person hasn't recently eaten— known as an "elevated fasting glucose level"—it provides a first clue that he or she is at risk of developing type 2 diabetes.
Finding ways to lower blood glucose offers great promise for diabetes treatment because doing so reduces the risk of the many diabetes complications that substantially affect the quality of life. The need for new drugs is accelerating as almost 26 million Americans have type 2 diabetes, and an estimated 79 million people are at risk of developing the condition.
During the day, when we feed, we use highoctane glucose from the food we take in to get around. And at night, when we fast, our body shifts to burning the fat from adipose stores, which provide a lower-power but longer-lasting source of energy.
Although most organs in the body can use glucose or fat as a source of energy, the brain requires glucose during both night and day. The liver assumes this task during fasting, when it becomes a glucose-producing organ. Obese individuals with insulin resistance produce too much glucose, leading to elevated glucose levels in the bloodstream that contribute to the development of type 2 diabetes.
The Montminy lab identified the function of a genetic switch, called CRTC2, which controls the production of glucose by the liver during fasting and in diabetes. The researchers found that the CRTC2 switch is turned on in liver cells during fasting in response to a hormone called glucagon. Glucagon flips the CRTC2 switch on in liver cells by causing a chemical change in CRTC2 known as de-phosphorylation. The group showed that inactivating the CRTC2 switch blocked the hormone's ability to stimulate glucose production by the liver during fasting.
In recent studies, the Montminy lab has determined that the CRTC2 switch controls glucose production through an enzyme that associates with the switch. Inactivating this enzyme with a small molecule inhibitor was sufficient to lower blood glucose levels in obese, insulin-resistant mice. These findings may offer new targets for drug development and provide effective therapies for the treatment of type 2 diabetic individuals.