Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Biologists discover biochemical link between biological clock and diabetes

20.09.2010
Biologists have found that a key protein that regulates the biological clocks of mammals also regulates glucose production in the liver and that altering the levels of this protein can improve the health of diabetic mice.

Their discovery, detailed in this week's advanced online publication of the journal Nature Medicine, provides an entirely new biochemical approach for scientists to develop treatments for obesity and type 2 diabetes. It also raises the interesting possibility that some of the rise in diabetes in the U.S. and other major industrialized countries could be a consequence of disturbances in sleep-wake cycles from our increasingly around-the-clock lifestyles.

"We know that mice that don't have good biological clocks tend to develop diabetes and obesity," said Steve Kay, Dean of the Division of Biological Sciences at UC San Diego and one of the lead authors of the research study. "And we know that mice that have developed diabetes and obesity tend not to have very good biological clocks. This reciprocal relationship between circadian rhythm and the maintenance of a constant supply of glucose in the body had been known for some time. But what we found that's so significant is that a particular biological clock protein, cryptochrome, is actually regulating how the hormone that regulates glucose production in the liver works in a very specific way."

"We used to think that our metabolism was regulated primarily by hormones that are released from the pancreas during fasting or feeding. This work shows that the biological clock determines how well these hormones work to regulate metabolism," says Marc Montminy, a professor in the Clayton Foundation Laboratories for Peptide Biology at the Salk Institute for Biological Studies. "The study may explain why shift workers, whose biological clocks are often out of kilter, also have a greater risk of developing obesity and insulin resistance."

Cryptochrome was first discovered by scientists as a key protein regulating the biological clocks of plants. It was later found to have the same function in fruit flies and mammals. But its role in regulating glucose production in the liver came as a complete surprise to the UCSD and Salk team, which included scientists from the Genomics Institute of the Novartis Research Foundation in San Diego, the University of Memphis and the Chinese Academy of Sciences in Shanghai.

"What was incredibly surprising is that cryptochrome has a new function that nobody had predicted," said Eric Zhang, the first author of the study and a researcher in Kay's UCSD laboratory. "Until now, cryptochrome had been known as a protein inside the nucleus of mammalian cells that switches genes on and off in a rhythmic way. What we showed was that cryptochrome has a role outside the nucleus as well."

That additional function of cryptochrome in mammalian cells, the scientists discovered, is to regulate a process known as "gluconeogenesis," in which our bodies supply a constant stream of glucose to keep our brain and the rest of our organs and cells functioning. When we're awake and eating, sufficient glucose is supplied to our bloodstream. But when we're asleep or fasting, glucose needs to be synthesized from the glycogen stored in our liver to keep our glucose levels up.

"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 Kay. "This molecular mechanism involving cryptochrome presumably evolved to coordinate our energy metabolism with our daily activity and feeding levels. So could some instances of diabetes be the result of a faulty circadian clock? And if that's the case, can we find ways of fixing the clock to treat this disease? Such an approach would be a whole new way of thinking about how to develop new treatments for diabetes."

In their study, the scientists found evidence that such an approach would be feasible. "Our experiments show very nicely that modulating cryptochrome levels in the liver of mice can actually give diabetic animals a benefit," Kay added.

The researchers discovered cryptochrome's role in gluconeogenesis while studying how a signaling molecule known as cyclic AMP interacted with the biological clock.

"It had been known for some time now that there was a connection between cyclic AMP signaling and circadian rhythm regulation and that's where we started," said Kay, "by asking the question: How are those two connected?"

Zhang and his UCSD colleagues conducted a series of experiments that found that the production of the next step after cyclic AMP, a protein called Creb, ebbed and flowed rhythmically in the livers of mice. That led the scientists to their initial discovery that cryptochrome was regulating the production of Creb in the liver.

In their studies with fasting and insulin-resistant mice at the Salk Institute, the scientists found that cryptochrome was regulating how the hormone glucagon, which controls gluconeogenesis, works in a very specific way. By controlling the production of cyclic AMP, crytochrome regulates the activity of Creb in the liver. In this way, the production of glucose in the liver is tied through our daily eating, sleeping and fasting activities through the biological clock.

The scientists say their discovery may open up a whole new area of research into how cryptochrome may be regulating other cell functions outside the nucleus.

"There's a wide role that the biological clock may be playing in influencing other hormones, not just glucagon, that are important for metabolism," said Kay.

In addition, studies on human populations have found links between disturbances in the biological clock, such as shift work and chronic jet lag, and the propensity to develop certain kinds of cancers as well as diabetes. Because of this, the scientists plan to continue their research into cryptochrome, looking for compounds that may enhance or diminish the activity of this critical biological clock protein.

The research was funded by grants from the National Institutes of Health. Other co-authors of the paper include Tsuyoshi Hirota, Dmitri A Nusinow, Pagkapol Pongsawakul and Andrew Liu of UCSD's Division of Biological Sciences; David Brenner and Yuzo Kodama of the UCSD School of Medicine; Yi Liu, Renaud Dentin and Severine Landais of The Salk Institute; and Xiujie Sun of the Chinese Academy of Sciences.

Kim McDonald | EurekAlert!
Further information:
http://www.ucsd.edu

More articles from Life Sciences:

nachricht Closing in on advanced prostate cancer
13.12.2017 | Institute for Research in Biomedicine (IRB Barcelona)

nachricht Visualizing single molecules in whole cells with a new spin
13.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

A whole-body approach to understanding chemosensory cells

13.12.2017 | Health and Medicine

Water without windows: Capturing water vapor inside an electron microscope

13.12.2017 | Physics and Astronomy

Cellular Self-Digestion Process Triggers Autoimmune Disease

13.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>