Saturday, September 22, 2012

Our Internal Clock

Life on the planet has developed in the setting of the rhythmic cycles of day and night – light and dark.  As a result mammals have evolved an internal biological clock referred to as the so-called, "circadian clock."  This clock represents a physiological mechanism that establishes the internal rhythms of many diverse processes such as sleeping and waking patterns, body temperature, hormonal activity and the overall general metabolism.  As one might expect, aberrations in this system can have profound impacts on general health and well-being.

This clock is in effect an inherent mechanism that is driven by regulatory networks of clock genes that control gene expression through transcription factors.  It has been well established that the primary transcription factors are CLOCK and BMAL1 - responsible for the expression of the Period (PER) and Cryptochrome (CRY) genes.  The periodicity of the clock mechanism is established by a feedback loop in which PER and CRY proteins inhibit CLOCK-BMALI.  This feedback mechanism results in rhythmic gene expression.  In fact, it has been clearly shown that essential liver function and processes, for example, are under the control of the circadian clock.

These internal rhythms are so essential to good health that when they are disturbed by genetic mutation or environmental influences, ill-health is often the consequence.  To cite a number of examples of environmental disturbances, jet lag and shift work have been implicated in sleep disorders, and both cardiovascular and metabolic disease.

Through the work of Dr. Tsuyoshi Hirota and colleagues from the Division of Biological Sciences and Center for Chronobiology at the University of California at San Diego and La Jolla, a small molecule that functions as a modulator of the circadian clock has been identified.  This compound referred to as KL001 acts specifically on the protein products of the CRY gene that regulates a particularly critical metabolic pathway in the liver that is responsible for the synthesis of glucose – gluconeogenesis.  This was no meager accomplishment since over 60,000 compounds were analyzed using human cell lines in the laboratory.  Since KL001 is involved in regulating a pathway associated with glucose synthesis, it may prove to have some therapeutic potential in regards to the treatment of type 2 diabetes.

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