Time-Telling Medicines for Diabetes and Obesity?

Nature has its own rhythm. Mimosa plants unfurl their leaves at day and shut them tight come nighttime. Bioluminescent bacteria flare up at nightfall and dim their lights when morning arrives. Our bodies also dance to a unique beat that is kept in time by internal circadian clocks.

For the past 50 years, the study of these clocks, known as chronobiology, looked at people with disrupted sleepwake cycles or sleep disorders. Now, researchers are developing new tools to look at the role circadian clocks play in diseases such as cancer, diabetes, and metabolic syndrome, with the possibility that certain medications could help control these diseases.

“There’s a master synchronizing clock in the hypothalamus and a clock in every cell in your body that keeps track of the time of day,” explains psychiatrist David Welsh, MD, PhD, of the Center for Chronobiology at the University of California, San Diego. “Circadian clocks are really enmeshed in all of physiology.”

Timing Is Everything

By dismantling the pieces of the circadian clock, researchers have identified numerous genes, such as CLOCK and BMAL1. These genes encode transcription factors that regulate physiological activities such as cell proliferation and glucose control.

Taking these genes into account is important in cancer cells that run amok from a sped-up clock. Chronobiology is considered when oncologists determine how to deliver cancer chemotherapy, because time of dosing matters. As such, clinicians try to gauge when the chemotherapeutic drug dose would be most effective and least toxic to patients, according to the June 2003 issue of Integrated Cancer Therapies.

Chronobiology has also entered the realm of diabetes. For instance, pancreatic islet cells contain functioning CLOCK and BMAL1 circadian clock genes. Th e July 2010 issue of Nature stated that mice with impairments in either of these genes displayed impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation in pancreatic beta cells that worsen with age. In short, disruption of the pancreatic clock can trigger the onset of diabetes.

Later in an article in the December 2011 issue of Nature, the authors proposed that in mice the circadian clock genes Cryptochrome 1 and 2 (Cry1 and Cry2) interact with glucocorticoid receptors to regulate glucose and steroid production but not inflammation. Th ese results point to a possible therapeutic strategy for metabolic syndrome, which is plagued by chronic inflammation and poorly controlled glucose homeostasis. This strategy would try to counter the side effects of glucocorticoids used in treating inflammation in these patients (e.g., weight gain, hyperglycemia, compromised immune system) by altering the timing of treatment or combining them with agents that stabilize Cry1 and/or Cry2 proteins.

Time Will Tell

Because the clock system influences physiology across many tissues and not just one in particular, developing chronobiology-based therapeutics might be tough.

But there are believers amongst the field

Joseph Bass, MD, PhD, chief of the Division of Endocrinology, Metabolism and Molecular Medicine at Northwestern University, Chicago, who studies sleep, feeding, and metabolism — all components of the circadian clock — is a scientific advisor for Reset Therapeutics, Inc., a biotechnology firm involved in developing small molecules that manipulate the circadian clocks so as to help eradicate metabolic and related disorders such as diabetes, obesity, and cardiovascular disease.

“The circadian clock system is not so general as to be non-targetable,” says Bass. “We’re still in the early stages in therapeutics, but circadian clock drugs are a definite possibility.”

Drug companies have now developed various highthroughput screens for small molecules that affect clocks. These systems involve recording 24-hour clock gene expression in cells seeded in 384 well plates and subjected to a library of thousands of small molecules, some chemically synthesized, others borrowed from nature, such as plants and bacteria.

—Oberst is a freelance writer based in Bethesda, Md.

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