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Biological clock discovery could mean new way to treat diabetes

Kathleen Blanchard's picture
Surprise discovery could mean entirely new approach to treating diabetes

Scientists have uncovered a molecule that affects our biological clock that they say can easily be developed into a drugs to treat metabolic disorders like diabetes and obesity. The molecule plays a major role in regulating the ‘internal clock’, which also controls glucose production. The discovery came as a surprise to researchers who were exploring how circadian rhythm affects cells in the body and the complexities of how molecules interact with each other.

Diabetes, obesity linked to internal clock

Researchers have long surmised diabetes and obesity could be the result of problems with our internal clock, leading biologists at University of California, San Diego to explore whether there is indeed a link.

Two years ago the research team found just such a biochemical link when they isolated a protein called cryptochrome that regulates glucose production in the liver. Cryptochrome is also regulates the biological clock in plants and animals.

They also discovered that the protein cryptochrome regulates the internal workings of our eating cycle in a way that keeps glucose balanced in the bloodstream.

“At the end of the night, our hormones signal that we’re in a fasting state,” said Kay in a press release. “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.”

The cryptochrome discovery was made by Steve Kay, dean of the Division of Biological Sciences at UC San Diego. Kay’s team has been working on finding molecules that lengthen the biological clock for 20 years.

“We found that if we increased cryptochrome levels genetically in the liver we could inhibit the production of glucose by the liver” Kay explains.

Now the same team has further isolated the molecule KL001 that controls cryptochrome and glucose regulation in the liver that can easily be developed into a drug.

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KL001 was accidentally discovered when Tsuyoshi Hirota, a postdoctoral fellow in Kay’s laboratory isolated a compound called “longdaysin” that lengthens it the daily biological clocks of human cells by more than 10 hours.

KL001 slows down the biological clock because it stops crypotochrome from being sent to the proteasomes – protein complexes that degrade damaged cellular material. The purpose of proteasomes is to regulate cellular function by getting rid of ‘garbage’.

The team then asked for help from Frank Doyle and his group at UC Santa Barbara to help them understand the complexities of cryptochrome that Kay likens to “…opening the back of a Rolex and seeing the hundreds of tiny little cogs that are tightly integrated.”

Doyle’s team constructed a mathematical model of the protein’s role in the biological clock. Based on the model, the researchers suspected that if they added KL001 to liver cells in mice, glucose production would stop during periods of fasting. They found out they were right.

“In mouse liver cells,” said Kay, “we showed that KL001 inhibited gene expression for gluconeogenesis that is induced when exposed to the hormone glucagon, which promotes glucose production by the liver. It’s a hormone we all produce in fasting states. And our compound, in a dose dependent way, inhibits hepatic gluconeogenesis, the actual production of glucose by those liver cells.”

The next step is to see how KL001 and similar molecules affect cryptochrome in living systems and how the biological clock affects other metabolic diseases. “As with any surprise discovery, this opens the door to more opportunities for novel therapeutics than we can currently imagine, Kay said.

The finding, published online in the journal Science, means an entirely new way for treating type 2 diabetes and possibly other metabolic diseases like obesity with drugs that reset the biological clock.

UC San Diego
July 12, 2012

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