The road to diabetes
In two separate studies from Salk labs, both published in Nature, new information about metabolic switches in fat and the liver suggest new avenues for treating diabetes.
A team led by Ronald M. Evans has discovered that a simple and long-ignored protein known as fibroblast growth factor 1 (FGF1) may be the secret to surviving long bouts of famine. "Facts do not cease to be important just because they are ignored," Evans says. His team found that FGF1 activity is triggered when we eat sugar and fat, and it helps the body to save this energy for lean times. Mice lacking the protein cannot expand their fat and thus swiftly develop diabetes. Evans suggests that FGF1 is crucial for the ebb and flow of energy throughout our bodies and is needed to maintain normal levels of sugar in the blood.
"The discovery of FGF1 as a missing nutrient switch was unexpected—and intriguing—because it was believed to do nothing," says Jae Myoung Suh, a postdoctoral researcher in Evans's laboratory. "If you deplete FGF1 from the body, nothing happens, which is why it was considered uninteresting and ignored. Yet when given a high-fat, 'Western-style' diet, mice develop an uncontrollable form of diabetes and experience a systemwide breakdown of their metabolic health."
Michael Downes, a senior staff scientist working with Evans, says that "without FGF1 abdominal or stomach fat becomes inflamed— an important finding because inflamed visceral fat increases risk for diabetes and other obesity-related diseases, such as heart disease and stroke."
If FGF1 deficiency makes the metabolism worse, then perhaps increasing its levels could make things better. Evans and his colleagues next plan to explore whether FGF1 "therapy" might offer a new way to control diabetes that avoids the side effects of the drug Actos, which regulates FGF1, and thus provide an improved and safer means of increasing insulin sensitivity.
Researchers in Marc Montminy's lab have discovered a pair of molecules that regulate the liver's production of glucose. His team found that controlling the activity of these two molecules, which work together to allow more or less glucose production, could potentially offer a new way to lower blood sugar in type 2 diabetes.
During the day, humans burn glucose, derived from food. At night, when we sleep, we revert to stored fat as a source of very dependable but slowly released energy. But certain parts of the body, most notably the brain, require glucose as a source of energy, even when we fast.
Pancreatic islet cells control both sides of this energy equation, producing glucagon, a hormone released during fasting, to tell the liver to make glucose for the brain. This process is reversed when we eat, when the islets release insulin, which tells the liver to stop making glucose.
Earlier, Montminy found that glucagon turns on a genetic switch (CRTC2) that ramps up production of glucose in the blood. Conversely, when insulin is increased in the blood, activity of CRTC2 is inhibited, and the liver produces less glucose. The new findings identify a relay system that explains how glucagon activates the CRTC2 switch during fasting, and how that system is compromised during diabetes. The scientists say this relay system involves a molecular receptor that they call a "molecular spigot." Glucagon opens the spigot during fasting, allowing an increase in calcium, a common cellular signaling molecule. This stimulates a molecular gas pedal, of sorts, which revs up CRTC2, activating genes that allow the liver to drive the metabolic engine by producing more glucose.
The findings suggest that agents that can selectively damp down activity of the spigot and the accelerator might help to shut down the CRTC2 switch and lower blood sugar in type 2 diabetic patients.