Salk Institute - Press Releases - Chronically elevated blood sugar levels disable "fasting switch"
March 07, 2008
La Jolla, CA – Continually revved up insulin production, the kind that results from overeating and obesity, slowly dulls the body's response to insulin. As a result, blood sugar levels start to creep up, setting the stage for diabetes-associated complications such as blindness, stroke and renal failure. To make matters even worse, chronically elevated blood sugar concentrations exacerbate insulin resistance.
The vicious circle gets rolling, researchers at the Salk Institute for Biological Studies discovered, when out-of-control blood sugar levels disable the molecular switch that normally shuts off sugar production in the liver in response to rising levels of insulin.
Their findings, published in the March 7 issue of Science suggest that appropriate inhibitors of the enzymatic pathway that blocks the "sugar-off"-switch might be useful in lowering glucose levels in diabetic individuals and reducing long-term complications associated with the disease.
"The islet cells in the pancreas can compensate with increased insulin production only for so long when confronted with chronic obesity and inactivity," says Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology, who led the study. "As a result glucose levels start to rise causing a host of problems."
Just like a flex-fuel vehicle that can run on either gasoline or ethanol, the human body can switch between different types of fuel: During the day the body mostly burns glucose, and during the night or prolonged fasting, it burns primarily fat. But neither flex-fuel engines nor human brains can run on ethanol or fat alone – a little bit of gasoline or glucose needs to be thrown into the mix to keep either one of them humming.
Three years ago, Montminy discovered a "fasting switch" called CRTC2 (formerly known as TORC2) that flips on glucose production in the liver when blood glucose levels run low during the night. After a meal, the hormone insulin normally shuts down CRTC2 ensuring that blood sugar levels don't rise too high.
In many patients with type II diabetes, however, CRTC2 no longer responds to rising insulin levels and as a result the liver acts like a sugar factory on overtime, churning out glucose throughout the day, even when blood sugar levels are high. The Salk researchers were interested in the molecular mechanism that leads to the breakdown of the normally tightly regulated feedback loop.