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Health & Medicine for Senior Citizens

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

July 12, 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 journal Science.

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.

Two years ago, a team headed by Steve Kay, dean of the Division of Biological Sciences at UC San Diego, discovered the first biochemical link between the biological clock and diabetes.

Why Hypertension Damages Eyes of Diabetics

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 vision.

"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."

The article is available online.

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 liver.

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 bloodstream.

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.

 

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Links to more archived stories below this news report


 
 

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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."


Notes:

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.

Heart Disease, Stroke Deaths Drop for People with Diabetes: Often Seniors

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Older Adults with Diabetes Live Long Enough to Benefit from Interventions

‘…with the exception of patients over age 76 with the poorest health status, all showed strong survival rates’ - U-M study - May 2, 2012


Lifestyle Changes Reduced Type 2 Diabetes Risk 58%; Highly Effective for Seniors

Over 10 years, the lifestyle and metformin interventions resulted in health benefits and reduced the costs of inpatient and outpatient care and prescriptions…

March 22, 2012


Diabetes Drug TAX-875 Improves Glucose Control Without Increasing Hypoglycemia

Researchers say it is as effective as glimepiride with lower risk of drop in blood sugar - good news for about 11 million seniors with type 2 diabetes

Feb. 27, 2012


Older Women with Diabetes Have Greater Hearing Loss as They Age

Men lose even more hearing regardless of diabetes or age; women lose less if diabetes controlled

Jan. 26, 2012


Statins of Any Kind May Increase Risk of Diabetes in Postmenopausal Women

Researchers say current recommendations by diabetes association nor statin guidelines should change - Jan. 10, 2012


Diabetes Drugs, Blood Thinners Cause 2/3 of Senior Citizen Adverse Events, Hospitalizations

Almost half of cases are in elderly aged 80 plus; overdoses, stronger than expected effect most common causes - Nov. 26, 2011


Raising 'Good' Cholesterol Reduces Heart Attack, Stroke Risk in Diabetes Patients

And, risks of heart attack and stroke increase when 'good' cholesterol levels go down - Oct. 7, 2011


Dieting Beats Exercise for Diabetes Prevention in Older Women, Combo Is Best

Strengthening exercise appears to have greater benefits for insulin resistance than aerobic exercise - Sept. 2, 2011


Older Diabetes Patients with Very Low Glucose Have Slightly Higher Risk of Death

Well controlled blood sugar level lowers risk of heart attack, amputation, kidney disease - April 18, 2011


Senior Citizens Lead the Way as Diabetes Spreads to 26 Million in New U.S. Estimate

Estimates in U.S. have risen since CDC estimated in 2008 that 23.6 million (7.8) had diabetes and 57 million adults had prediabetes - Jan. 27, 2011


Older Women with Diabetes and Depression Have Twice the Risk of Death

Both problems linked to unhealthy behaviors such as smoking, poor diet and a sedentary lifestyle - Jan. 3, 2011


Fat Distribution Plays Key Role in Weight Loss Success in Patients at Risk of Diabetes

‘Abdominal and liver fat are the two most important factors in predicting whether a lifestyle intervention will be successful’

Aug. 24, 2010


An Old Antibiotic Appears to Reduce Stroke Risk, Injury for Diabetics

Almost 70% of Americans dying with diabetes found to show a major vascular event such as a stroke or heart attack as a cause of death

Aug. 23, 2010


Getting Fat After Age 50 Greatly Increases Diabetes Risk that Already Escalates for Seniors

‘Participants with a greater than 4 inch increase in waist size from baseline to the third follow-up visit had a 70 percent higher risk of type 2 diabetes…’

June 22, 2010


Study Pinpoints Atrial Fibrillation Risk at 40 Percent for Those with Diabetes, Maybe Higher

Nearly nine in 100 people over age 80 - have atrial fibrillation; risk rises by 3% for each additional year patients have diabetes – watch video

April 23, 2010


Considering Type 2 Diabetes Treatment, Experts Say 1 Size Does Not Fit All

International group recommends individualized therapies; Almost one of every four senior citizens has diabetes

April 5, 2010


Senior Women at High Risk of Bone Fractures After Taking Diabetes Drugs Avandia or Actos

TZDs have previously been linked to bone loss, increasing fracture risk; type 2 diabetes and insulin also increase risk for fractures

Feb. 10, 2010


Victoza (liraglutide) Gets FDA Approval as New Treatment for Type 2 Diabetes

Seniors aged 60 with type 2 diabetes are about one-third of all adults with this chronic disease

Jan. 27, 2010


Harvard Scientists Move Closer to Correcting Cellular Defects That Lead to Diabetes

Report says the G6PD protein, which produces essential antioxidant NAPDH, could prevent the death of pancreatic beta cells, the root cause of diabetes

Jan. 4, 2010


Seniors May Reduce Risk of Type 2 Diabetes by Half with More Exercise, Less Weight

Modest weight loss or taking anti-diabetic drug for 10 years lowers risk of type 2 diabetes in high risk people of all ages

Nov. 2, 2009


Diabetes Patients May Have Wrong Idea About Taking Insulin: Should be Front-Line Defense

Common fears of weight gain, developing low blood-sugar, decline in quality of life are largely unfounded, researchers find

Aug. 11, 2009

 

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