Scientists have long suspected that metabolic disorders, such as type 2 diabetes and obesity, could be linked to our circadian rhythm or biological clock. For example, laboratory mice with altered biological clocks often become obese and develop diabetes. Now biologists at UC San Diego have discovered that a chemical, which affects the activity of a key protein that regulates our biological clock, can repress the production of glucose by the liver, offering a promising new direction for the development of a new class of drugs to treat diabetes.

A team headed by Steve Kay, dean of the Division of Biological Sciences at UC San Diego, had previously found that altering the levels of a key protein, called cryptochrome – which regulates the biological clocks of plants, insects and mammals and also regulates glucose production in the liver – could improve the health of diabetic mice. Building on that research, the team has now discovered that a small molecule, which they say can be easily developed into a drug, controls the timekeeping mechanisms of cryptochrome to repress the production of glucose in the liver.

This offers a different approach for treating diabetes as the disease is caused by an accumulation of glucose in the blood – either as a result of the destruction of insulin producing cells in the pancreas in the case of type 1 diabetes, or due to a gradual resistance to insulin because of obesity of other problems for type 2 diabetes (which accounts for around 90 percent of cases).

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

Kay’s lab found that the molecule, dubbed KL001, slowed down the biological clock by preventing the cryptochrome protein from being sent to the proteasomes, whose function is to degrade unneeded (or damaged) proteins.

Molecular model of KL001 (Image: Tsuyoshi Hirota, UC San Diego)

To understand how KL001 worked to control the biological clock, Kay’s team collaborated with a team at UC Santa Barbara led by Frank Doyle to construct a mathematical model of cryptochrome’s role in the biological clock. Based on that model, the scientists predicted that adding KL001 to mouse liver cells should stabilize cryptochrome and that the increased level of the protein would inhibit the production of enzymes in the liver that stimulate the generation of glucose (gluconeogenesis) during fasting. Experiments later confirmed this prediction.

The next step for the team is to understand how KL001 and similar molecules that affect cryptochrome function in living systems, such as laboratory mice. They also plan to examine how these compounds affect other processes besides the liver that may tie the biological clock to metabolic diseases.

The team’s discovery is detailed in a paper published in the journal Science.

The video below provides a brief explanation of K001 and it's potential in providing a new avenue for researchers to pursue in developing a new class of drugs to treat diabetes.

Source: UC San Diego

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