Research

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.

"In order to develop new and effective treatments for diabetes, researchers need to understand the complex and delicate biology behind human metabolism as well as the disorders that develop when this finely tuned system is out of balance."

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.

Left to right:
Wolfgang Fischer, Sandra Guerra, Talitha Van der Meulen, Emilie Blanchett, Jose Paz, Dandan Chen, Run Shen, Young-Sil Yoon, Wenwei Tsai, Jeong Ho Kim, Marc Montminy, Biao Wang, Ezra Wiater, Hongbo Wang, Susie Hedrick, Kim Ravenskjaer, Meghan Hogan, Jeniffer Hernandez, Sam Van de Velde, Debbie Doan, Vera Nies

Salk News Releases

• Sugar production switch in liver may offer target for new diabetes therapies
  April 8, 2012
• Discovery of insulin switches in pancreas could lead to new diabetes drugs
  September 26, 2011
• Evolutionary conservation of fat metabolism pathways: Scientists say "if they ain't broke, don't fix 'em"
  May 12, 2011
• Feast, famine, and the genetics of obesity: you can't have it both ways
  December 15, 2010
• Biologists Discover Biochemical Link Between Biological Clock and Diabetes
  September 19, 2010
• The battle for CRTC2: how obesity increases the risk for diabetes
  June 21, 2009
• Salk scientist Marc Montminy elected to National Academy of Sciences
  April 28, 2009
• Salk Launches Center for Nutritional Genomics with $5.5 Million Grant from Helmsley Trust
  April 22, 2009
• Salk scientists detect molecular obesity link to insulin resistance, type II diabetes
  March 3, 2009
• Food for thought–regulating energy supply to the brain during fasting
  October 6, 2008
• Salk researchers find master switch in the brain that regulates desire for food and ability to reproduce
  September 2, 2008
• Salk Institute partners with the Foundation for Prader-Willi Research to study extreme obesity-related genetic disorder
  June 25, 2008
• Life without TORC is one big struggle
  May 7, 2008
• Chronically elevated blood sugar levels disable "fasting switch"
  March 7, 2008
• How insulin TORCs blood sugar levels: Glowing mice light the way
  September 5, 2007
• Salk scientists hammer out a pathway that promotes muscle cell survival in mice
  April 30, 2007
• Chewing up a key regulator of fat synthesis keeps mice lean despite a high-fat diet
  June 23, 2006
• Key regulator of blood glucose levels discovered
  September 9, 2005
• Salk Scientists Unlock Secret of Insulin Release
  October 4, 2004
• Molecular first steps to adult diabetes found
  November 12, 2003
• Salk scientists find new potential target for diabetes treatment
  September 13, 2001

Awards and Honors

• McKnight Neuroscience Development Award, 1991
• Richard E. Weitzman Award, Endocrine Society, 1990

Links

Montminy lab

Montminy technologies available for licensing

Sugar production switch in liver may offer target for new diabetes therapies

April 08, 2012

In their extraordinary quest to decode human metabolism, researchers at the Salk Institute for Biological Studies have discovered a pair of molecules that regulates the liver's production of glucose—the simple sugar that is the source of energy in human cells and the central player in diabetes. Read more>>

Biologists discover biochemical link between biological clock and diabetes

September 19, 2010

Biologists have found that a key protein that regulates the biological clocks of mammals also regulates glucose production in the liver and that altering the levels of this protein can improve the health of diabetic mice.

Their discovery, published in the September 19 advance online edition of the journal Nature Medicine, provides an entirely new biochemical approach for scientists to develop treatments for obesity and type 2 diabetes. It also raises the interesting possibility that some of the rise in diabetes in the U.S. and other major industrialized countries could be a consequence of disturbances in sleep-wake cycles from our increasingly around-the-clock lifestyles. Read more>>