New Way to Treat Diabetes – Treat the Biological Clock

Their discovery, detailed in a published paper, initially came as a surprise because the chemical they isolated does not directly control glucose production in the liver, but instead affects the activity of a key protein that regulates the internal mechanisms of our daily night and day activities, which scientists call our circadian rhythm or biological clock.

Scientists had long suspected that diabetes and obesity could be linked to problems in the biological clock. Laboratory mice with altered biological clocks, for example, often become obese and develop diabetes. Two years ago, a team headed by Steve Kay, dean of the Division of Biological Sciences at UC San Diego, discovered the first biochemical link between the biological clock and diabetes. It found that a key protein, cryptochrome, that regulates the biological clocks of plants, insects and mammals, also regulates glucose production in the liver and that altering the levels of this protein could improve the health of diabetic mice.

Now they have discovered a small molecule -- one that can be easily developed into a drug -- that controls the intricate molecular cogs or timekeeping mechanisms of cryptochrome in such a manner that it can repress the production of glucose by the liver. Like mice and other animals, humans have evolved biochemical mechanisms to keep a steady supply of glucose flowing to the brain at night, when we're not eating or otherwise active.

Kay stated, "At the end of the night, our hormones signal that we're in a fasting state." "And during the day, when we're active, our biological clock shuts down those fasting signals that tell our liver to make more glucose because that's when we're eating."

Diabetes is caused by an accumulation of glucose in the blood, which can lead to heart disease, strokes, kidney failure and blindness. In type 1 diabetes, destruction of insulin producing cells in the pancreas results in the high blood sugar. In type 2 diabetes, which makes up 90 percent of the cases, gradual resistance to insulin because of obesity or other problems, leads to high blood sugar.

Kay and his collaborators discovered in 2010 that cryptochrome plays a critical role in regulating the internal timing of our cyclical eating patterns, timing our fasting at night with our eating during the day to maintain a steady supply of glucose in our bloodstream. Other researchers have recently discovered that cryptochrome has the potential to reduce high blood sugar from asthma medication by adjusting the time of day a patient takes their medication. "We found that if we increased cryptochrome levels genetically in the liver we could inhibit the production of glucose by the liver," said Kay.

Published July 13, 2012 in an advance online issue of the journal Science