Chemical that Affects Biological Clock Offers New Way to Treat Diabetes
Fishing with ‘longdaysin’ found new chemical to slow biological clock; inhibits production of enzymes in liver – Second
study finds why hypertension and diabetes damage eyes
2012 - A chemical that offers a completely new and promising direction for the development of drugs to treat metabolic disorders such as type
2 diabetes does not directly control glucose production but it can regulate our circadian rhythm or biological clock.
The discovery by biologists at UC San Diego is detailed in a paper published July 13 in an advance online issue of the
It initially came as a surprise because the chemical they isolated does not directly control glucose production in the
liver, but instead affects the activity of a key protein that regulates the internal mechanisms of our daily night and day activities, which
scientists call our circadian rhythm or biological clock.
Scientists had long suspected that diabetes and obesity could be linked to problems in the biological clock. Laboratory
mice with altered biological clocks, for example, often become obese and develop diabetes.
July 12, 2012 - Hypertension frequently
coexists in patients with diabetes. A new University of Georgia study shows why the co-morbid conditions can result in impaired
"Results showed early signals of cell
death in eyes from diabetic animals within the first six weeks of elevated blood pressure. Later, the tiny blood vessels around the
optic nerve that nourish the retina and affect visual processing showed signs of decay as early as 10 weeks after diabetic animals
develop hypertension," said Azza El-Remessy, assistant professor in the UGA College of Pharmacy and director of the UGA clinical and
experimental therapeutics program.
The study examined animals with early
and established stages of diabetes that also had hypertension. The results, which highlight the importance of tight glycemic control
and blood pressure control to delay diabetes-related vision loss, were published in the June issue of the Journal of Molecular
Vision. The study was the first to understand or explain why combining increased blood pressure with diabetes would hurt blood
vessels in the eye.
"The fact that controlling blood
pressure in diabetic patients is beneficial has been shown through many major clinical trials," said Islam Mohamed, a third-year
clinical and experimental therapeutics graduate student who co-authored the paper with El-Remessy.
"Our study highlights the synergistic
and immediate interaction between systemic hypertension and diabetes as two independent risk factors for persistent retina damage
known as retinopathy. This emphasizes the importance of addressing different cardiovascular risk factors in a holistic approach for
improving management and prevention of retinopathy."
According to the Centers for Disease
Control and Prevention, 45 percent of adults in the U.S. suffer from diabetes, hypertension or high levels of cholesterol in the blood
called hypercholesterolemia. Approximately 13 percent of U.S. adults suffer from a combination of two of the conditions, and 3 percent
have all three.
Early intervention is a key factor in
improving the outcome for patients.
"Health care providers, including
pharmacists, should stress the importance of the tight control of blood sugar and blood pressure levels for their patients," El-Remessy
said. "Providing patient education and counseling on how each of these metabolic problems independently can have accelerated
devastating effects is critical and can result in better prevention and outcomes for the patients."
It found that a key protein, cryptochrome, that regulates the biological clocks of plants, insects and mammals also
regulates glucose production in the liver and that altering the levels of this protein could improve the health of diabetic mice.
Now Kay and his team have discovered a small molecule - one that can be easily developed into a drug—that controls the
intricate molecular cogs or timekeeping mechanisms of cryptochrome in such a manner that it can repress the production of glucose by the
Like mice and other animals, humans have evolved biochemical mechanisms to keep a steady supply of glucose flowing to the
brain at night, when we're not eating or otherwise active.
"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."
Diabetes is caused by an accumulation of glucose in the blood, which can lead to heart disease, strokes, kidney failure
and blindness. In type 1 diabetes, destruction of insulin producing cells in the pancreas results in the high blood sugar. In type 2 diabetes,
which makes up 90 percent of the cases, gradual resistance to insulin because of obesity or other problems, leads to high blood sugar.
Kay and his collaborators discovered in 2010 that cryptochrome plays a critical role in regulating the internal timing of
our cyclical eating patterns, timing our fasting at night with our eating during the day to maintain a steady supply of glucose in our
Other researchers have recently discovered that cryptochrome also has the potential to reduce high blood sugar from
asthma medication by adjusting the time of day a patient takes their medication.
"We found that if we increased cryptochrome levels genetically in the liver we could inhibit the production of glucose by
the liver," said Kay.
What he and his team found in their most recent discovery was that a much smaller molecule, dubbed "KL001" (for the first
such compound from the Kay Lab), can regulate that activity as well. It slowed down the biological clock by stabilizing the cryptochrome
protein—that is, it essentially prevented crypotochrome from being sent to the cellular garbage can, the proteasomes.
The discovery of KL001 was serendipitous, a complete surprise to the scientists that came about from a parallel effort in
Kay's laboratory to identify molecules that lengthen the biological clock. Two years ago, Tsuyoshi Hirota, a postdoctoral fellow in Kay's
laboratory found a compound that had the greatest effect ever seen on circadian rhythm, a chemical the biologists dubbed "longdaysin" because
it lengthened the daily biological clocks of human cells by more than 10 hours.
Continuing his search, Hirota resumed his efforts to find more chemicals that lengthened or slowed down circadian
rhythms, enabling the scientists to understand more about the intricate chemical and genetic machinery of the biological clock.
He and his colleagues in Kay's lab did this by screening thousands of compounds from a chemical library with human cells
in individual micro-titer wells in which a luciferase gene from fireflies is attached to the biological clock machinery, enabling the
scientists to detect a glow whenever the biological clock is activated. Their molecular fishing expedition came up with a number of other
compounds, one of which was KL001.
"We found other compounds that like longdaysin slowed down the biological clock," said Kay. "But unlike longdaysin, these
compounds did not inhibit the protein kinases that longdaysin inhibits so we knew this compound must be working differently.
"What we needed to
know was what is this compound interacting with? And we were absolutely stunned when we discovered that what was binding most specifically to
our compound, KL001, was the clock protein cryptochrome that our lab has worked on in plants, flies and mammals for the last 20 years."
Kay's team turned to biological chemists in Peter Schultz's laboratory at The Scripps Research Institute to characterize
the compound and understand better chemically how it affected cryptochrome to lengthen the biological clock.
"Those biochemical studies showed us that KL001 prevents cryptochrome from being degraded by the proteasome system, which
was another big surprise," said Kay. "It essentially interferes with the signal to send cryptochrome to the garbage can."
To understand how KL001 worked mechanistically with cryptochrome to control the biological clock, the team initiated a
collaboration with Frank Doyle and his group at UC Santa Barbara. "They constructed a beautiful mathematical model of cryptochrome's role in
the clock," said Kay.
"That model was essential in allowing us to understand the action of the compound because the biological clock is very
complicated. It's like opening the back of a Rolex and seeing the hundreds of tiny little cogs that are tightly integrated."
Based on that mathematical model, the scientists predicted that adding KL001 to mouse liver cells should stabilize
cryptochrome and that the increased level of cryptochrome would inhibit the production of enzymes in the liver that stimulate the process of
gluconeogenesis - the generation of glucose during fasting. Experiments done together with the laboratory of David Brenner, dean of the UC San
Diego School of Medicine and Vice Chancellor for Health Sciences, confirmed that prediction to be true.
"In mouse liver cells," said Kay, "we showed that KL001 inhibited gene expression for gluconeogenesis that is induced
when exposed to the hormone glucagon, which promotes glucose production by the liver. It's a hormone we all produce in fasting states. And our
compound, in a dose dependent way, inhibits hepatic gluconeogenesis, the actual production of glucose by those liver cells."
Kay said the next step for the research group is to understand how KL001 and similar molecules that affect cryptochrome
function in living systems, such has laboratory mice. The scientists also plan to probe how such compounds affect other processes besides the
liver that may tie the biological clock to metabolic diseases. "As with any surprise discovery," he notes, "this opens the door to more
opportunities for novel therapeutics than we can currently imagine."
Besides Kay, Hirota, Schultz, Doyle and Brenner, other scientists involved in the discovery were Mariko
Sawa, Pagkapol Y. Pongsawakul and Tim Sonntag of UC San Diego's Division of Biological Sciences; Jae Wook Lee of TSRI; Peter St. John of UC
Santa Barbara; Keiko Iwaisako, Takako Noguchi and David Welsh of UC San Diego's School of Medicine.
The study was supported by grants from the National Institutes of Health.
Links to Archived Reports on Diabetes
Should YOU be tested for diabetes?
Anyone 45 years old or older should consider getting tested for diabetes. If you are 45 or older and overweight-see the
BMI chart -getting tested is strongly recommended. If you are younger than 45,
overweight, and have one or more of the
risk factors, you should consider getting tested. Ask your doctor for a fasting
blood glucose test or an oral glucose tolerance test. Your doctor will tell you if you have normal blood glucose, prediabetes, or diabetes.
● Among U.S. residents ages 65 years and older, 10.9 million, or 26.9 percent, had diabetes in 2010.
● Diabetes affects 25.8 million people of all ages - 8.3 percent of the U.S. population
> DIAGNOSED - 18.8 million people
●> UNDIAGNOSED - 7.0 million people
● About 215,000 people younger than 20 years had diabetes—type 1 or type 2—in the United States in 2010.
● About 1.9 million people ages 20 years or older were newly diagnosed with diabetes in 2010 in the United States.
● In 2005–2008, based on fasting glucose or hemoglobin A1C (A1C) levels, 35 percent of U.S. adults ages 20 years or
older had prediabetes - 50 percent of adults ages 65 years or older. Applying this percentage to the entire U.S. population in 2010 yields an
estimated 79 million American adults ages 20 years or older with prediabetes.
● Diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness
among adults in the United States.
● Diabetes is a major cause of heart disease and stroke.
● Diabetes is the seventh leading cause of death in the United States.