Promising Early Evidence Of The Superior Benefits Of Drug Therapy For Diabetic Eye Disease

April 29, 2008

April 29, 2009 (EurekAlert) - A JDRF collaboration between Johns Hopkins researchers and Genentech has shown that a drug for the treatment of diabetic eye disease has performed better in clinical trials than the current standard treatment using laser surgery.

These findings, representing the six-month end-point evaluation of the READ-2 clinical trial coordinated by The Johns Hopkins University, were presented Monday at the 2008 Annual Meeting of The Association for Research in Vision and Ophthalmology, in Fort Lauderdale, Florida.

According to Barbara Araneo, Ph.D., director of the complications program at JDRF, “These are very encouraging results, showing that drugs we have been testing in human clinical trials can be effective in slowing or stopping the effects of eye disease brought on by diabetes.”

The multi-center READ-2 Study (Ranibizumab for Edema of the mAcula in Diabetes), which began in December 2006, was designed to test the long-term safety and effectiveness of injections of the drug ranibizumab in patients with diabetic macular edema, a condition characterized by swelling of the central portion of the retina, or macula, at the back of the eye. In addition, the trial sought to determine the comparative efficacy of ranibizumab versus conventional treatment – laser photocoagulation therapy – or both together.

Macular edema, one of the most common causes of blindness, occurs when fluid and protein deposits collect on or under the macula, causing it to thicken and swell.

Participating in the clinical trial were 126 diabetic patients (average age 62) with documented Diabetic Macular Edema prior to enrollment; the majority had 20/80 vision in the eye that was treated. Patients were randomly assigned to receive one of three interventions: ranibizumab, laser photocoagulation, or a combination of the two treatments. At each visit over the course of the six-month treatment period, patients were evaluated for vision, retinal thickening, and general eye health. Although the study ended at six months, patients will be monitored for two years.

Patients treated with ranibizumab experienced significantly greater improvements in visual acuity, or clarity of vision, compared with patients receiving either of the other interventions. On average, the vision of ranibizumab-treated patients improved to 20/63 at month six, compared with essentially unchanged acuity scores of about 20/80 in both the laser and the combination treatment groups.

In addition, patients treated with ranibizumab had a 56 percent reduction in excess retinal thickness, whereas only an 11 percent reduction was seen in those receiving laser treatments.

Posted by dlife at 10:24 AM | Comments (0)

Transporters May Help Delay Diabetes-Related Retinal Damage

November 28, 2007

November 28, 2007 (EurekAlert) - Two transporters that deliver alternative energy sources to the eye may help delay retinal damage that can occur in diabetes, researchers say.

The transporters, SMCT1 and SMCT2, can circumvent the eye’s protective blood-retinal barrier, delivering energy sources lactate and ketone bodies to a healthy eye, says Dr. Pamela Martin, biochemist at the Medical College of Georgia.

In diabetes, characterized by plenty of glucose but the inability of cells to use it, the retina may turn to those alternate sources for survival.

“Glucose is your primary energy source,” says Dr. Martin. “But in diabetes, the retina undergoes a lot of stress, there is oxidative damage and a lot of other things going on. These transporters, we believe, may be instrumental in bringing in additional substrates which the cells can use for energy to try and prevent death.”

Diabetic retinopathy, the leading cause of blindness in working-age adults, results in death of retinal neurons, at least in part because glucose availability is compromised for this high-energy-consuming tissue, says Dr. Martin.

She suspects the two transporters work harder in diabetes to increase levels of lactate and ketones bodies, which may help explain why diabetes’ impact on the eye may go undiagnosed for years. “I think what fascinates me so much about the eye is you can have diabetes for more than 20 years before you or your doctor realize that you have diabetic retinopathy,” says Dr. Martin.

Understanding how these transporters work normally and in diabetes may enable early diagnosis of diabetic retinopathy and natural delivery mechanisms for drugs to stop it.

Dr. Martin was a postdoctoral fellow in the lab of Dr. Vadivel Ganapathy, chair of the MCG Department of Biochemistry and Molecular Biology who first cloned the SMCT1 and SMCT2 transporters, before she joined the faculty in 2005. She was first author on a paper published this year in Investigative Ophthalmology and Visual Science that showed the presence of the transporters in the retina.

Now she is one of four investigators nationally to receive a Pathway to Independence Award for new investigators from the National Eye Institute that will help her elucidate these transporters’ activity in healthy and diseased states.

Lactate and ketone bodies are substances called monocarboxylates and previously there was no evidence that transporters that typically haul these substances around are elevated in diabetes. But these monocarboxylate transporters, or MCTs, are more passive than the recently discovered, sodium-coupled SMCT1 and SMCT2 which are “driven,” able to go against the concentration gradient and change substrates, like lactate, from low to high concentrations inside the cells, says Dr. Martin.

“If you have these transporters, they can transport these substrates into your retina and hopefully prevent some of the neuronal cell damage that occurs,” Dr. Martin says.

An aggressive vehicle is necessary since, like the brain, the retina has a natural barrier to prevent many substances in the blood from reaching the eye.

The MCG researcher has shown SMCT1 is expressed in retinal neurons and in the retinal pigmented epithelium, one of the back layers of the multi-layer retina that is important in terms of transporting good things in and waste products out. SMCT2 is primarily expressed in supportive retinal Müller cells.

One of the many questions she wants to answer is whether they play different roles in these different cell types.

She’s using two diabetic mouse models, one that develops type 1 diabetes at about three weeks, which is comparable to children developing the disease in their first few years of life. The second is a mouse she makes diabetic, so she will know the precise moment it happens.

She’ll look at the expression, activity and function of these transporters in both models and is optimistic she’ll find them helpful to diabetics.

“The damage still occurs, people still go blind from diabetic retinopathy, but it may delay it,” says Dr. Martin. “But what if we could find some pharmacologic agents they could transport into the eye and save it."

Dr. Ganapathy, who is Dr. Martin’s mentor for the NIH grant, also is working on SMCT1 and its role in the colon where his experimental evidence indicates it has a tumor-suppressive role. In the colon, SMCT1 transports short-chain fatty acids such as butyrate, which is generated by bacterial fermentation of dietary fiber. The transporter is silenced in colon cancer but when colon cancer cells are forced to express it, they die in the presence of butyrate.

“The normal bacteria present in our colon are doing a lot of good things to benefit us,” Dr. Ganapathy says. “These findings may explain the age-old knowledge that dietary intake of fiber is protective against colon cancer.”

Posted by dlifenews at 11:12 AM | Comments (0)

Omega-3 Fatty acids Protect Eyes Against Retinopathy, Study Finds

June 25, 2007

June 25, 2007 (EurekAlert) - Omega-3 polyunsaturated fatty acids protect against the development and progression of retinopathy, a deterioration of the retina, in mice. This is the major finding of a study that appears in the July 2007 issue of the journal Nature Medicine. The study was a collaborative effort by researchers at Children’s Hospital Boston, the primary pediatric teaching affiliate of Harvard Medical School, Brigham and Women’s Hospital, Massachusetts General Hospital, the University of Goteborg in Sweden, and the National Eye Institute (NEI) and National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH).

Paul A. Sieving, M.D., Ph.D., director of the NEI, said, “This study explores the potential benefit of dietary omega-3 fatty acids in protecting against the development and progression of retinal disease. The study gives us a better understanding of the biological processes that lead to retinopathy and how to intervene to prevent or slow disease.”

The researchers studied the effect of the omega-3 fatty acids EPA and DHA, derived from fish, and the omega-6 fatty acid arachidonic acid on the loss of blood vessels, the re-growth of healthy vessels, and the growth of destructive abnormal vessels in a mouse model of oxygen-induced retinopathy. The retinopathy in the mouse shares many characteristics with retinopathy of prematurity (ROP) in humans.

ROP is a disease of the eyes of prematurely born infants in which the retinal blood vessels increase in number and branch excessively, sometimes leading to bleeding or scarring. Infants who progress to a severe form of ROP are in danger of becoming permanently blind. There are also aspects of the disease process that may apply to diabetic retinopathy, a disease in which blood vessels swell and leak fluid or grow abnormally on the surface of the retina, and age-related macular degeneration (AMD), a disease of the macula, the part of the retina responsible for central vision, and a leading cause of vision loss in Americans 60 years of age and older.

The researchers found that increasing omega-3 fatty acids and decreasing omega-6 fatty acids in the diet reduced the area of vessel loss that ultimately causes the growth of the abnormal vessels and blindness. Omega-6 fatty acid contributes to the growth of abnormal blood vessels in the retina.

To further test the apparent beneficial effect of omega-3 fatty acids, the researchers studied mice fed a diet modeled after a traditional Japanese diet (more omega-3 than omega-6 fatty acids) and mice fed a diet modeled after a traditional Western diet (lower amounts of omega-3 fatty acids). In addition, they studied mice genetically altered with a gene which mammals normally lack that converts omega-6 into omega-3 fatty acids. They found that the mice with higher amounts of omega-3 had a nearly 50 percent decrease in retinopathy.

Omega-3 fatty acids create chemical compounds known as bioactive mediators, which protect against the growth of abnormal blood vessels, a condition that characterizes some forms of retinopathy. In part, this occurs because these mediators suppress a type of inflammatory protein called tumor necrosis factor alpha (TNF-alpha). TNF-alpha is found in one type of cell, called microglia, that can be closely associated with retinal blood vessels.

“The retina has one of the highest concentrations of omega-3 fatty acids in the body,” said lead author and NEI fellowship recipient Kip M. Connor, Ph.D., a postdoctoral research fellow at Children’s Hospital Boston. “Given this, it is remarkable that with only a two percent change in dietary omega-3 intake, we observed an approximate 40-50 percent decrease in retinopathy severity.”

“Our findings represent new evidence suggesting the possibility that omega-3 fatty acids act as protective factors in diseases that affect retinal blood vessels,” said John Paul SanGiovanni, Sc.D., NEI staff scientist and the other lead author of the study. “This is a major conceptual advance in the effort to identify modifiable factors that may influence inflammatory processes implicated in the development of common sight-threatening retinal diseases.”

These study results, SanGiovanni emphasized, are important because they provide a reasonable biological explanation for findings from a number of human studies on diet and retinal disease, and they identify low-cost and widely available nutrient-based treatment approaches that may show merit in future research on diseases that damage retinal blood vessels and nerve cells.

"The purpose of our study was to discover and describe the scientific basis for any possible protective role of omega-3 fatty acids against retinopathy,” said Lois E. H. Smith, M.D., Ph.D., senior investigator of the study and associate professor of ophthalmology at Children’s Hospital Boston, an affiliate of Harvard Medical School. “By identifying the fatty acids, lipids and growth factors involved in both the disease and protective processes, we hope to translate this work to influence the outcome in patients. Our study results suggest that increasing omega-3 fatty acid intake in premature infants may significantly decrease the occurrence of ROP. This changing of lipids by dietary means may also translate to AMD and diabetic retinopathy. If clinical trials find that supplementing with omega-3 fatty acids is as effective in protecting humans against retinal disease as demonstrated by the findings of this study, this cost effective intervention could benefit millions of people."

The NEI is currently conducting the Age-Related Eye Disease Study 2 (AREDS2) that will, in part, assess the effect of omega-3 fatty acids DHA and EPA on the progression of AMD. In addition, an upcoming clinical trial at Children’s Hospital Boston will test the effects of omega-3 supplements in premature infants.

Posted by dlifenews at 10:50 AM | Comments (0)

Joslin Diabetes Center Reminds People with Diabetes to Schedule Annual Eye Exams to Preserve Vision

March 23, 2007

March 23, 2007 (Joslin) -- Did you know that diabetes is the number one cause of preventable vision loss and blindness? Did you also know that an annual eye exam can lead to early detection of diabetic retinopathy and other eye disease, a frequent complication of diabetes?

On Diabetes Alert Day, March 27 -- a day set aside by the American Diabetes Association to raise public awareness of the rampant incidence of diabetes in our nation -- the care team at the world renowned Joslin Diabetes Center's Beetham Eye Institute reminds the 20.8 million Americans with diabetes to schedule an annual eye exam. Joslin's Beetham Eye Institute clinicians have shown that an annual exam can provide early detection and help prevent or delay 90 percent of cases of vision loss due to diabetic retinopathy. According to the Centers for Disease Control and Prevention, diabetic retinopathy is a leading cause of blindness in adults, resulting in 12,000 to 24,000 new cases of blindness each year.

Diabetic retinopathy, the most common eye disease in people with diabetes, occurs when the small blood vessels in the eye are damaged by high levels of glucose in the blood. Because diabetic retinopathy can progress to advanced stages without the patient knowing it, it is crucial to have annual eye exams to help preserve vision.

Joslin clinicians recommend a three-prong approach to preserving vision:

- Maintain excellent A1C levels. (The A1C is a test that measures average blood glucose levels over the 2 to 3 month period before the test.)
- Keep blood pressure, blood lipids and other health factors in check.
- Have an annual eye exam.

To watch a video on Joslin's Web site about the importance of annual eye exams, click here: http://www.joslin.org/754_871.asp

For more information about eye research and clinical trials at Joslin, click here: http://www.joslin.org/755_3819.asp

Posted by dlife at 12:22 PM | Comments (0)