Biochemical Link Found Between Biological Clock and Diabetes

A new study has discovered that a key protein that regulates the circadian rhythms of mammals also regulates glucose production (gluconeogenesis) in the liver.

Researchers at the University of California San Diego (UCSD; USA), the Chinese Academy of Sciences (Shanghai), the Salk Institute (San Diego, CA, USA), and other institutions discovered that the biological clock protein, known as cryptochrome, regulates gluconeogenesis in the liver. The connection is made via the signaling molecule cyclic adenosine monophosphate (cAMP) via two transcriptional activators that stimulate cryptochrome, and period repressors that feed back on this activity, all of which modulate glucagon-mediated increases in intracellular cAMP concentrations and in the phosphorylation of Creb, a transcription factor that binds to cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes.

In this way, the researchers concluded, the production of glucose in the liver is tied to daily eating, sleeping, and fasting activities controlled by the biological clock. The results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes. The researchers also speculate the cryptochrome may be regulating other cell functions outside the nucleus. The study was published early online on September 19, 2010, in the journal Nature Medicine.

"That is how our energy metabolism evolved to function in concert with our diurnal activity, or in the case of the mice, their nocturnal activity,” said lead author Steve Kay, dean of the division of biological sciences at UCSD. "This molecular mechanism involving cryptochrome presumably evolved to coordinate our energy metabolism with our daily activity and feeding levels. There's a wide role that the biological clock may be playing in influencing other hormones, not just glucagon, that are important for metabolism.”

There are many health problems associated with disturbances of the human circadian rhythm, such as seasonal affective disorder (SAD), delayed sleep phase syndrome (DSPS), and other circadian rhythm disorders. Circadian rhythms also play a part in the reticular activating system, which is crucial for maintaining a state of consciousness.

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University of California
Chinese Academy of Sciences
Salk Institute