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Archive - 11 - 2007

Transporters May Help Delay Diabetes-Related Retinal Damage

Posted by dlife on Wed, Nov 28, 07, 11:12 AM 0 Comment

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 eyes 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 Mller cells.One of the many questions she wants to answer is whether they play different roles in these different cell types.Shes 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.Shell look at the expression, activity and function of these transporters in both models and is optimistic shell 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. Martins 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.

UC Davis Researchers Discover Novel Pathway to Increased Inflammation in Diabetes Patients

Posted by dlife on Wed, Nov 28, 07, 10:40 AM 0 Comment

November 27, 2007 (EurekAlert) - Researchers at UC Davis Health System have discovered a novel pathway that results in increased inflammation of blood vessels in patients with type 1 diabetes. Their findings suggest that, with good diabetes control, this inflammation may be reduced, possibly resulting in a reduction of cardiovascular disease as well.In a study now available both in the online edition of the Journal of Clinical Endocrinology & Metabolism as well on the National Institutes of Healths PubMed, the researchers provide the first-ever demonstration of increased expression and signaling in type 1 diabetics of two key receptors within the bodys innate immune system. Called TLR2 and TLR4, they are part of a family of pattern recognition receptors known as Toll-like receptors (TLRs), so-called because of their similarities to the well-defined Toll gene found in much-studied fruit flies.Type 1 diabetes is a pro-inflammatory state associated with increased cardiovascular mortality. Inflammation plays a pivotal role in all stages of atherosclerosis, the progressive narrowing and hardening of the arteries over time. The UC Davis study found that TLR2 and TLR4 expression and signaling are increased in type 1 diabetes patients and contribute to the pro-inflammatory state.It is not unreasonable to speculate that TLR2 and TLR4 promote atherogenesis by contributing to the pro-inflammatory state in type 1 diabetes, said lead author Ishwarlal Jialal, director of the Laboratory for Atherosclerosis and Metabolic Research and professor of internal medicine at UC Davis. Inflammation is central to heart disease, playing a pivotal role in plaque formation and stroke. We may well find that a serendipitous byproduct of controlling diabetes is the simultaneous control of this new pathway, leading to less inflammation and lower risk of heart problems.The study represents the first-ever demonstration of increased TLR2 and TLR4 activity in type 1 diabetes monocytes, which are part of the bodys immune system, protecting against blood-borne pathogens by moving quickly to sites of infection. The immune system comprises the cells and mechanisms that defend the host from infection by other organisms, accomplishing its defense with the help of such pattern-recognition receptors as TLRs for early detection of specific classes of pathogens.This finding provides us with a totally new insight into the causes of inflammation in diabetics, adds Jialal, who holds the Robert E. Stowell Endowed Chair in Experimental Pathology at UC Davis. Its an exciting development in the emerging area of TLR research that has potentially wide-ranging implications. Further studies will use mice to examine the molecular mechanisms for increased TLR2 and TLR4 expression and determine their contribution to the pro-inflammatory state of diabetes.

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