Transporters may help delay diabetes-related retinal damage

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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."

Dr. Martin is a 2003 graduate of the MCG School of Graduate Studies.

Medical College of Georgia