Is there a connection between pregnancy, diabetes and diabetic retinopathy?

- Shveta Garg, Pune, India

Diabetes refers to a condition in which the body cannot adequately use the sugars and starches (carbohydrates) it takes in as food to make energy. The body either makes too little insulin in the pancreas, or the insulin it makes is not sufficient to change those sugars and starches into energy. As a result, the body collects extra sugar in the blood. This extra sugar, if allowed to collect in the body for too long, can damage organs such as the heart, eyes and kidneys.

Three types of diabetes are known: Type 1, Type 2, and Gestational (pregnancy-related). Type 1 is due to lack of insulin in the body, while resistance to action of insulin leads to Type 2. This article discusses the connection between pregnancy and diabetes.

Diabetes is often detected in women during their childbearing years and can affect the health of both the mother and her unborn child. Diabetes and fertility are also related. Young women with diabetes, either Type 1 or 2, tend to start their periods a little bit later in life than women without diabetes. On the other end of the spectrum, women with diabetes tend to go through menopause slightly earlier, so this provides a slightly smaller window of fertility for them. In addition, many women with Type 2 diabetes have an underlying syndrome called 'polycystic ovarian disease, in short referred to PCOD. Because of the effects of PCOD on the ovaries, women with Type 2 diabetes and PCOD may take longer to conceive than women without diabetes.

Now, if a woman has diabetes, and wants to get pregnant, it is critically important for her to be in good control of her blood glucose levels before she goes off any contraceptive agents, and starts trying to get pregnant. It is a good idea to be in good blood glucose control three to six months before she conceives. Also, the blood glucose levels should be kept under control during pregnancy and, of course, after as well.

The early weeks of pregnancy are important for the baby. Since most women do not know of their pregnancy until the baby has been growing for about two to four weeks, one needs to really plan the pregnancy. Also, a treatment plan has to be put in place to balance meals, exercise & intake of insulin. This plan will, of course, change as the pregnancy progresses as per the recommendations of your doctor and a dietician. You will also need to check your blood glucose often, and keep a record of your results. With your blood glucose in the target range and good medical care, the chances of a trouble-free pregnancy and a healthy baby are almost as good as they are for a woman without diabetes

Pregnancy in women with pre-existing diabetes is generally considered to be high-risk. It does not necessarily mean problems, but your doctor may have to work with other specialists to help you have a healthy pregnancy and baby.

Gestational diabetes is a type of diabetes that is first diagnosed in a pregnant woman. It can often be controlled by a proper diet and regular exercise regimen alone, but sometimes a woman with gestational diabetes may need to take medications. In most cases, this condition goes away after pregnancy. Many women who have had gestational diabetes have an increased chance of developing Type 2 diabetes later, but with healthy diet, regular exercise and weight control, it can be delayed or prevented completely.

If a woman has medical conditions caused by her diabetes, pregnancy can make these conditions worse. Miscarriage and stillbirth are more common in pregnant women with diabetes. Hence the need to be cautious.

After delivery, it is as important to keep check on blood glucose level as it was during pregnancy. Some new mothers have better blood glucose control in the first few weeks after delivery, while for most, it is a period of fluctuating blood glucose level. During the first few weeks at home with the baby, most mothers are tired and stressed from lack of sleep, and with odd sleep patterns, the chances of napping at mealtime or snack time increase, which can potentially cause a dangerous lowering of blood glucose. It is important to check your blood glucose level often during this time, to avoid blood glucose reactions that may not be good for the baby or the mother. Breastfeeding is equally good for women with diabetes, but it may make your blood glucose a little harder to predict. To help prevent low blood glucose levels during breastfeeding, it is a good idea to have a snack, water or a caffeine-free drink at frequent intervals.

Diabetic retinopathy is referred to retinal damage caused by complications of diabetes mellitus, which may eventually lead to blindness. Diabetic retinopathy is one of the major causes of preventable blindness around the world in those aged between 24 and 64 years. For a significant number of diabetic women, the first half of this period coincides with peak fertility and childbearing years. Diabetic eye disease may develop for the first time during pregnancy, and visual loss at this stage can have serious implications for both the patient and her family.

Several studies on the progression of diabetic retinopathy in women have tried to explain if it is the natural tendency of the disease, or some unique factors that operate during pregnancy, which cause deterioration. That retinopathy worsens during pregnancy is now undisputed, although the mechanism by which progression occurs depend on a variety of factors. The major factors influencing progression of retinopathy during pregnancy include; the state of pregnancy itself, duration of diabetes prior to the pregnancy, degree of retinopathy at time of conception, metabolic control before and during pregnancy, as well as the presence of coexisting hypertension.

There are certain recommendations that are widely accepted for the management of diabetic patients with retinopathy who are planning pregnancy or are already pregnant. Since the risk of progression of retinopathy during pregnancy is greater in women who have had diabetes for longer periods of time, it is beneficial to counsel women in their childbearing years about planning their pregnancies early if possible.

When planning pregnancy, women with preexisting diabetes should have a comprehensive eye examination and should be aware of the risk of development and/or progression of diabetic retinopathy. Women with diabetes who become pregnant should have the eye examination in the first trimester, and close follow-up throughout life.

Pregnancy in a diabetic woman brings about many changes that can lead to the development of diabetic retinopathy or worsening of pre-existing disease. In some patients this may develop into sight threatening disease which, if not treated adequately, can cause devastating visual impairment.

If you wish to read more on the above topic, please click here, here, here, here or here.

New tools in search of treatments for Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a cluster of genetically determined eye disorders that cause visual defects such as night blindness and narrowing of the field of vision, due to progressive loss of rod photoreceptors. As many as 45 different genes have been linked to the inheritance of this disease, which suggests diversity in etiology and makes development of a standardized animal model problematic. Thus, despite a range of clinical trials of nutritional and drug-based interventions for RP, the disease currently remains untreatable. Better platforms for modeling the disease and testing drug candidates in vitro are urgently needed.

Editor's note: Those who want to learn more about the genetic variations in RP and other diseases, please click here for more information.

New work by Zi-Bing Jin and colleagues in the Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan, looks to add a set of powerful new tools for those searching for treatments for RP. In an article published in PLoS One, the team reports the generation of induced pluripotent stem cells (iPSCs) from patients carrying mutations in several RP-associated genes, and the subsequent differentiation and characterization of rod photoreceptors from these genetically distinct, patient-derived pluripotent cells.

After obtaining informed consent from five RP patients with distinct mutations in the RP1, RP9, PRPH2, or RHO gene, the team took samples of skin cells and used the fibroblasts as a starting point for generating iPSCs. Using the classic reprogramming cocktail of Oct4, Sox2, Klf4, and c-Myc delivered via a retroviral vector, Jin and colleagues generated cell lines from each patient and verified their conversion by tests for appropriate morphology, genetic and karyotypic integrity, and teratoma formation.

Using these iPSCs, the team next generated photoreceptors carrying the genetic signatures of each of the five patient donors using a previously established stepwise protocol that steered the cells over four months in culture from an undifferentiated ES cell-lie state through retinal progenitor, and photoreceptor precursor stages to the desired rod photoreceptor phenotype. The differentiated cells were shown to express the rod photoreceptor marker rhodopsin at high levels, and to have similar electrophysiological function.

Interestingly, rod photoreceptor cells generated from iPSC colonies carrying RP-linked mutations showed a tendency to degenerate, while cone photoreceptors and bipolar cells derived from the same iPSCs were stable. The mechanisms underlying this instability turned out to be dependent on the affected gene. Rod photoreceptors generated from iPSCs with a mutation in the RP9 gene showed evidence of DNA oxidation, while those from iPSCs with a mutation in the rhodopsin gene showed signs of stress on the endoplasmic reticulum, the site of protein synthesis.

As an initial proof-of-concept test of their suite of RP-specific rod photoreceptors in drug validation, Jin and colleagues examined the effects of antioxidant vitamins in preventing degeneration of these cells in vitro. Ascorbic acid, α-tocopherol, and β–carotene have all been tested in clinical trials as anti-oxidant therapies for RP, but all had not proved very effective. When the team tested these on individual cells lines by treating them with one of the three antioxidants for seven days at around the stage at which rod photoreceptor degeneration occurs, they found that α-tocopherol increased cell survival in the lines generated from two patients both carrying mutations in RP9. The same treatment was ineffective in cells from other patients, and ascorbic acid and β–carotene had no effect in any of the lines. These results, which show the efficacy of α-tocopherol in promoting survival in RP9 rod photoreceptors, highlights the potential of patient-derived induced pluripotent stem cells in the study of disease mechanisms and in vitro testing of treatment approaches.

Using iPSCs from cells donated by RP patients with different underlying genetic mutations, the authors were able to show that rod photoreceptors generated from these cells underwent apoptosis in vitro, and showed differing responses in a genetically determined manner to drug treatment. According to them, this is one of the first reports to demonstrate that patient-derived iPSCs may be useful in personalized medicine, as differential responses within a genetically diverse study group will tend to be lost in the crowd. Future improvements in differentiation protocols, screening techniques, cost and efficiency and the establishment of methods for isolating photoreceptors may open up new possibilities for the use of these cells in drug screening.

Reference: PLoS One. 2011 Feb 10;6(2):e17084. Modeling retinal degeneration using patient-specific induced pluripotent stem cells. By Jin ZB, Okamoto S, Osakada F, Homma K, Assawachananont J, Hirami Y, Iwata T, Takahashi M.

Researchers find life in blood-starved retinas

Like all tissues in the body, the eye needs a healthy blood supply to function properly. Poorly developed or damaged blood vessels can lead to visual impairment or even blindness. This is commonly seen in diseases such as diabetic retinopathy, vascular occlusions such as central retinal venous occlusion (CRVO) and Branch retinal venous occlusion (BRVO) (click here for more information about CRVO or BRVO), etc. While many of the molecules involved in guiding the development of the intricate blood vessel architecture are known, only now are the scienitists learning how these molecules work, and more importantly, how they affect sight.

Reporting in the Oct. 16 issue of Cell, researchers at the Johns Hopkins School of Medicine in Baltimore, Maryland, US, find that when some cells in the mouse retina are not properly fed by blood vessels, they can yet remain alive for many months and can later recover some or all of their normal function, suggesting that similar conditions in people may also be reversible.

Three genes -- named Fz4, Ndp and Lrp5 -- previously were suspected to be involved in blood vessel development in the human retina. Defects in any of these genes cause hypovascularization -- a lack of sufficient blood vessels -- in the retina. Similarly, eliminating any of these genes in mice can lead to hypovascularized retinas.

Mice lacking functional Fz4 have poor blood vessel growth in the retina and are blind, but it was not known whether the blood vessel deficiency was the cause of blindness or whether the absence of Fz4 leads to some other defect that causes blindness. The team found that Fz4 function is required only in blood vessels, where it senses a signal produced by the Ndp gene in other retinal cells.

When the team measured electrical responses in retinal cells of mice lacking Fz4, they found a defect in electrical signaling in the middle layer of the retina -- the same region lacking blood vessels.

The researchers then bathed the Fz4 mutant retinas in oxygen and nutrients to mimic a normal blood supply, and measured electrical signaling in response to light. They found that when provided with oxygen and nutrients, the retinas were able to sense light and generate signals similar to those generated by normal retinas. The team suggests that in the absence of Fz4 the defective blood vessels provide the retinas with only enough oxygen and nutrients to keep the retinal cells alive, but not enough for them to function normally to send electrical signals.

Since these experiments have not been tried in humans, it is difficult to say what may happen when such experiements are undertaken some time later. But if the human retina responds to a decrease in blood supply in the same way that the mouse retina has been seen to have responded, then these results may have a significant relevance for those patients with vision loss due to vascular damage, such as diabetic retinopathy and vascular occlusions.

Expert Talk: Dr Subhadra Jalali of LV Prasad Eye Hospital, Hyderabad, India

The following is an interview with Dr Subhadra Jalali, an Ophthalmologist and a Retina Specialist, who heads the Smt. Kanuri Santhamma Retina Vitreous Centre at the L V Prasad Eye Institute in Hyderabad. Dr Jalali is also significantly involved in the scientific work of Retina India as a member of its Scientific Board.

Arun & Rani: Dr Jalali, thank you for taking time from your very busy schedule to respond to our questions.

We have heard about the amazing work that you and your team are involved in at the LV Prasad Eye Institute, with a focus on finding a long term and viable treatment for retinal degenerative diseases. As we all know, retinal ailments have taken a heavy toll of patients all over our country, and have devastating consequences in terms of leading to total blindness.

Dr Jalali: Thank you for giving me this opportunity.

Question: Which form of treatment is your team specifically targeting for treating retinal degenerative diseases? Is it stem cell treatment, gene therapy or artificial retina? What reasons would you attribute to pursuing a specific method?

Dr SJ: All options are open. Scientific evidence and rigor are the key factors targeting treatment major retinal degenerative diseases.

Question: Is your treatment methodology applicable to a wide range of retinal ailments?

Dr SJ: Not necessarily in all cases. It depends on the clinical situation and the actual results of treatment being given.

Question In your experience, what are the most common retinal ailments among Indian patients and what are the important challenges you face in their rehabilitation?

Dr SJ: Common retinal ailments include diabetic retinopathy and other vascular retinal occlusions, rhegmatogenous retinal detachments, trauma to the eye and the retina, congenital ocular anamolies (like coloboma), retinal vasculitis, retinal degenerations including generalised conditions such as Retinitis Pigmentosa, Leber’s Congenital Anaurosis, Rod monochromat, Congenital stationary night blindness, etc., and localized conditions like Staargardts, cone dystrophy, as well as conditions such as Age-related Macular Degeneration, Parafoveal Telengiectesia and Idiopathic Polypoidal Choroidal Vasculopathy (IPCV) and pediatric retinal diseases like Retinopathy of Prematurity and Familial Exudative Vitreoretinopathy (FEVR).

Question By when do you propose to start full fledged clinical trials at your Institute?

Dr SJ: We wait to see the safety results from Phase I of a clinical trial. As and when they go to Phase II or beyond with good scientific evidence, and the rigor of safety with some efficacy demonstrated in phase I, we can begin with the clinical trials.

Editor's note: If you wish to know more about clinical trials and how they are conducted, please click here.

Question: We had heard in the news that last year, there was some breakthrough in your Institute, regarding implementing stem cell treatment for retinitis pigmentosa and there was also news of starting clinical trials for the same. What has happened to that particular development?

Dr SJ: It is an ongoing study in various phases of development. The scientific study is not conclusive yet.

Question Every research requires funding. What are your major sources of funding? How is the Government cooperating in this regard?

Dr SJ: There are multiple sources of funding for us. Major funding comes both from Indian Government, as well as international collaborations from American, European, Australian and Japanese Governments and trusts. We are appreciative of the substantial support from the Indian Government.

Question Could you please describe to us in brief, the exact methodology of your work/research in treating retinal degenerative diseases?

Dr SJ: We are in various phases of scientific study and trials from basic science to animal studies and human trials. All completed work is published/presented at various scientific fora in peer review journals and meetings

Question What problems and shortcomings do you have to overcome, medically, in implementing your work on a full fledged basis?

Dr SJ: Mainly, it is the lack of time due to overwhelming clinical work

Question: Are you satisfied with your current level of work, and what would be your goal in the long term, as far as finding a viable treatment is concerned?

Dr SJ: Yes I am very much satisfied. This is ongoing work, with the long term goal of providing scientific evidence based treatment to my patients.

Question We also heard that your Institute is doing a lot for rehabilitation of visually impaired patients. Could you throw some more light on this aspect?

Dr SJ: We care for low vision and blind patients in all areas of care. This includes social, vocational, educational, government schemes, awareness, advocacy and medical care. (Please click here for more details. )

Question What specific measures do you plan to take in the near future, as far as making more progress in your current research work is concerned?

Dr SJ: I would like to be being involved with various ongoing research areas in retinal treatments, so as to keep abreast with latest technologies and trends on sound scientific foundations.

Question How long do you feel it might take to find full fledged treatment for retinal degenerative diseases?

Dr SJ: I feel it would take about 3- 5 years for a start. I also think we will reach substantial progress in next 10 years where treatments match expectations and needs of the patients.

Question: What are the criteria laid down by your Institute to participate in clinical trials, as and when they take place?

Dr SJ: Our institute follows the following criteria.

1. We need to get ethics committee approval

2. We want to see compliance with all national and international laws and regulations governing clinical trials.

3. The clinical trial should be relevant to the clinical diseases common in our population.

Question In what ways do you think Retina India, as an organization, can collaborate with your Institution?

Dr SJ: Some of the areas in which Retina India can collaborate would be:

1. Provide patient support group activities, which I believe the group is already involved in.

2. Initiate discussions on needs of this group

3. Raise awareness and support for education and integrated schooling of such children with normal sighted children

4. Prepare patient registries to provide data to bring advocacy and awareness for support for research in retinal diseases

5. Raise funds and bring retina to forefront of public opinion. As of now too many people are unaware that they have a critical organ in their vision called RETINA!

Question Finally, is there anything else you would like to share with our readers?

Dr SJ: I am convinced that in the coming decade, we will definitely meet many challenges in achieving the goal of satisfactory and substantial treatment for patients with progressive retinal dystrophies.

Arun & Rani: Thank you very much Doctor, for having spent your precious time with us. We are sure our readers will greatly benefit from this discussion. We wish you and your Institute all success in your endeavor, and fervently hope that there will soon be a full fledged treatment for retinal degenerative diseases.

The interview was conducted by Mr Arun Torgal from Goa and Ms Rani Ramakrishnan from Coimbatore. Ms Shveta Garg from Pune helped in refining the write-up.

Researchers help blind ‘see’ Facebook photos

Social networking has come to dominate 21st-century culture. But visually impaired people have yet to fully experience this digital community.

Baoxin Li, assistant professor in the School of Computing and Informatics at the Arizona State University (ASU) Tempe campus, is working with several ASU students to develop a way for the visually impaired to “see” images of faces on computers.

“Imagine if a blind user can now get an idea what his [or] her Facebook friends ‘look like’ by touching tactile pictures made from their photos,” Li said in an e-mail.

When Li came to ASU six years ago, similar research was already happening in the Center for Cognitive Ubiquitous Computing (CUbiC), he said. Researchers in CUbiC, which focuses on different applications for cutting-edge research, were developing assistive technologies for the visually impaired.

Li said the researchers narrowed down the list of ways they could make social networks more accessible to the blind.

“Among others, face images were chosen because of their significance in a person’s social and emotional life,” he said.

The concept is similar to text-to-Braille, but differs because unlike words, images don’t have a strict alphabet, Li said. It’s challenging to print a photograph and translate it into an image, but through tactile form, blind participants are able to explore the image with their fingertips and “see” what an image looks like.

“We developed computer-based image analysis techniques to identify major facial landmarks,” Li said.

The analysis first works to identify the image through major facial features, such as the eyes and nose, and then puts them into tactile form.

“A user can then explore the image by touch,” he said.

Zheshen Wang, a fifth-year doctoral student in computer science and engineering, is Li’s key student researcher on the project.

“Some of the blind participants were very excited in touching a graphical human face by hand,” Wang said in an e-mail. “It is a rewarding task.”

Li, Wang and their team are currently working on mastering the technology and printing tactile faces for their participants, Li said, but actual deployment is in the works.

“We will be seeking different embodiments of this technology,” Li said. “Such as its use as software component for tactile printer manufacturers … or a software package for a user at home.”

Wang sees the future of tactile printing as affordable for the blind. She looks forward to the day when visually impaired people can select their friends online, click print and finally know how they look.

Article by Kortney Tenaglia published here.

Lasers may be increasing threat to the eye and the retina

An article in the New York Times by Christine Negroni refers to the increasing threat to vision and damage to the retina, by increasing access to the green laser.

Eye doctors around the world are warning of increasing number of cases of teenagers who suffer permanent eye damage while playing with high-powered green laser pointers.

The pointers, which have also been implicated in a ninefold increase over five years in reports of lasers’ being aimed at airplanes, are easier than ever to order online, even though they are 10 to 20 times as powerful as the legal limit set by the Food and Drug Administration.

A recent case highlights the problem: A high school student complained of a blind spot in his left eye, when a friend waved a green laser pointer in front of his face. The damage, as diagnosed by a retina specialist, was found to be severe and is not likely to completely heal, which means the high school student may end up with a permanent damage to his vision. The same retina specialist found out that the laser put out 50 milliwatts of power, 10 times more than the F.D.A. limit. And as he investigated his patient’s case, the doctor went online and bought a 100-milliwatt pointer for $28 (about Rs 1255) , and was hardly able to believe that he could buy an even more stronger laser without any controls or checks in place.

Like household lights, lasers are measured in watts, but the similarity ends there. A 100-watt incandescent bulb produces about five watts of visible light; the five-milliwatt laser is only one-thousandth as powerful. But because the light from a bulb is diffuse while a laser beam is concentrated, the effect of five milliwatts on the eye is 10,000 times as intense, according to laser experts. (For technical information on lasers, click here.) It also does not help that the eye tends to focus and intensify the laser, causing even more damage to the main part of the retina, the macula or the fovea, which is the center of the retina. The darker pigment present in the region absorbs the light as heat, quickly raising the temperature of the retina.

Some experts feel that the sale of laser pointers more than one milliwatt should be banned to the general public, since the stronger laser put people at risk of permanent visual impairment by the criminally minded or those who are unaware of the risks.

F.D.A., in its update, warned that a higher-powered laser gives less time to look away before injury can occur, and as power increases, eye damage may happen in a microsecond. One company that has come under scrutiny from the FDA is Wicked Lasers from Hong Kong.

Several laser experts feel that the enforcement of regulations is insufficient and ineffective. But any new restrictions being put in to contain the availability of such lasers will certainly meet resistance from the large community of laser enthusiasts, including those who use them professionally (like contractors and astronomers) and hobbyists.

Earlier, red lasers were used as laser pointers, Now, green lasers are more commonly used. But green lasers are also more dangerous. Green is more easily absorbed by the retina than red, so it requires less exposure to cause damage.

As a recommendation, please do not allow lasers to fall into the hands of unsuspecting children, who may find it easy to point the laser light at others, which can potentially be permanently damaging. Also, educate everyone who uses laser pointers to be more careful, including colleagues at work, who have the tendency of using the laser pointer during presentations, and who have the tendency of sweeping their hands around with the laser pointer turned on!

Researchers find novel pathway that helps eyes quickly adapt to darkness

It's almost time for the movie to start. As you hurry from the lobby into the darkened theater, you may have to stop, as the transition from light into darkness renders you temporarily blind. Cells in the eye's retina must adapt before you can begin to distinguish heads from backs of chairs. As the cells adjust, sight will be restored enough to avoid tripping over a chair, or sitting in a stranger's lap!

Scientists have long known that these cells, called photoreceptors, are involved in this adaptive process, but a study from investigators at Washington University School of Medicine in St. Louis and Boston University School of Medicine has uncovered a new pathway in the retina that allows photoreceptor cells to adapt following changes in light exposure.

The discovery could help scientists better understand human diseases that affect the retina, including age-related macular degeneration, the leading cause of blindness in people over the age of 50. That's because the process of adapting to darkness involves the same cells that are affected in macular degeneration and other blinding retinal diseases.

The findings are reported online in the journal Nature Neuroscience and will be the cover story in the March print edition.

The retina's two main light-sensing cells are the rods and cones. Both use similar mechanisms to convert light into vision, but they function differently. Rods are highly sensitive and work well in dim light, but they can quickly saturate with light and stop responding. They don't sense color either, which is why we rarely see colors in dim light.

Cones, on the other hand, allow us to see colors and can adapt quickly to stark changes in light intensity. The research team focused on cone cells, studying their ability to continue functioning in very bright light and to adapt quickly when that light is shut off.

"Rods can take up to an hour to adapt to darkness," says principal investigator Vladimir J. Kefalov, Ph.D., Assistant Professor of Ophthalmology and Visual Sciences. "Cones, by contrast, adapt in three to five minutes."

Scientists have known for years that light-sensing molecules bind together to make up visual pigments. Those pigments are destroyed when they absorb light and must be rebuilt, or recycled, for the cone cells to continue sensing light. In order to be recycled, key components of pigments called chromophores leave the retina, and travel to the eye's retinal pigment epithelium where the chromophore is restored and returned to the retina.

"If the chromophores cannot be recycled, cone cells gradually run out of visual pigment and can't detect light," Kefalov says.

But the process of traveling to and from the pigment epithelium takes too long to explain how cones quickly adapt to darkness following exposure to bright light, so Kevalov's team went looking for a second, supplementary pathway.

Working in salamander eyes, the research team removed the pigment epithelium layer so that pigment molecules could not be recycled using the known pathway. When the scientists exposed the retina to bright light and then to darkness, the cones continued to function, even without the pigment epithelium. That meant the pigment molecules were recycled in spite of the fact that they could not travel to the pigment epithelium.

"So it was clear that a second pathway is being used by the cone cells," Kefalov says.

But where? Biochemical evidence had suggested cells called Müller cells might be involved. Like glial cells in the brain that support and interact with neurons, Müller cells in the retina support and interact with photoreceptors. The researchers treated salamander retinas with a chemical that destroyed the Müller cells.

They repeated the experiment exposing the retina to bright light, followed by darkness. "And by blocking the function of Müller cells, we prevented the recycling of chromophores. The cones ran out of photopigment and could not adapt to dark," Kefalov says.

The group then conducted the same series of experiments in the mouse retina, with the same results, suggesting the second pathway involving Müller cells also is important in the mammalian eye. If it is active in the human eye, Kefalov believes it may be possible one day to manipulate this pathway to improve vision when the other one involving pigment epithelium has been interrupted by injury or disease.

One such disease is age-related macular degeneration, where cone cells begin to malfunction over time. Because the disease and the pathway Kefalov's team identified both involve cones, he says it may be possible someday to target that pathway, rev up its activity and supplement or rescue the function of cones.

Before that happens, he says it will be important to figure out exactly how the Müller cells are interacting with photoreceptors. Although these studies confirmed the existence of the second photoreceptor pathway, they didn't reveal how it works. Kefalov's laboratory has recently received a five-year, $1.9 million National Eye Institute grant to study how this newly identified visual pathway functions in the retina.

If you wish to reacd this paper, please click here.

News from the website of Washington University in St. Louis.

Revised blood sugar levels may predict development of retinal disease in patients with Diabetes

New hyperglycemia thresholds may predict the onset of retinopathy more accurately than the standard benchmarks in patients with diabetes mellitus, a study has found.

The current definition of diabetes is a fasting plasma glucose (FPG) level of 126 mg/dL or higher.

"We propose that thresholds of 108 mg/dL for FPG, and concentration of 6% for [hemoglobin A1C] level could be used to define those who are at risk of retinopathy," the study authors said.

The Data From an Epidemiological Study on Insulin Resistance Syndrome Study included 700 patients, ranging in age from 30 to 65 years. The patients were recruited between 1994 and 1996, and underwent health examinations at 3, 6 and 9 years after enrollment.

At 9 years, 235 patients had been treated for diabetes or had FPG levels of 126 mg/dL or higher, 227 patients had an impaired fasting glucose level of 110 mg/dL to 125 mg/dL at least once, and 238 patients had glucose levels lower than 110 mg/dL.

A non-mydriatic digital retinal camera was used to obtain high-resolution retinal images at 10 years. Retinopathy was identified in 44 patients.

Study results showed that patients with retinopathy had a mean baseline FPG level of 130 mg/dL and hemoglobin A1C level of 6.4%. Patients without retinopathy had a mean baseline FPG of 106 mg/dL and hemoglobin A1C level of 5.7%. Both differences were statistically significant (P < .001).

An FPG level of 108 mg/dL had a positive predictive value of retinopathy at 10 years of 8.4% and a level of 116 mg/dL had a predictive value of 14%.

A hemoglobin A1C level of 6% had a positive predictive value of 6% and a level of 6.5% had a predictive value of 14.8%, the authors reported.

For those who want to read the abstract or the paper, please click here.

Researchers develop snapshot of powerful retinal pigment and its partners

In a Journal of Biological Chemistry, the Berlin-based team reports that it has uncovered surprising new details about a key protein-protein interaction in the retina that contributes to the exquisite sensitivity of vision. Additionally, they say, the proteins involved represent the best-studied model of how other senses and countless other physiological functions are controlled.

"Nearly a thousand different types of these proteins are present in the human body, and nearly half of pharmaceutical drugs are targeted to them," explains Martha E. Sommer, a postdoctoral researcher at the Institute for Medicinal Physics and Biophysics at Charité Medical School.

The retina, which is located at the back of the eye, is considered an outgrowth of the brain and is, thus, a part of the central nervous system. Embedded in the retina's 150 million rod-shaped photoreceptor cells are purplish pigment molecules called rhodopsin. It is the rhodopsin protein that is activated by the first glimmer – or photon – of light. Upon activation, the purple molecule binds another protein, known as transducin, to set off a cascade of biochemical reactions that ultimately results in vision.

"After this signaling event, rhodopsin must be shut off. This task is achieved by a third molecule called arrestin, which binds to light-activated rhodopsin and blocks further signaling," Sommer says. When rhodopsin is not properly shut off, overactive signaling can lead to a decrease in sensitivity to light and ultimately cell death. People who lack arrestin have a form of night blindness called Oguchi disease. "They are essentially blind in low light and can suffer retinal degeneration over time."

It is believed that the arrestin molecule silences rhodopsin's signaling by embracing it and elbowing out transducin.

"Since arrestin was first discovered more than 20 years ago, it was assumed that a single arrestin binds a single light-activated rhodopsin," Sommer says. "However, when the molecular structure of arrestin was solved using X-ray crystallography about 10 years ago, it was observed that arrestin is composed of two near-symmetrical parts – like an open clam shell."

The diameter of each side of the arrestin shell is about equal to that of one rhodopsin, she says, so some researchers wondered if a single arrestin might be able to bind to two rhodopsins.

It seemed like a simple enough question: To how many rhodopsins can a single arrestin bind? But, Sommer explains, little experimental work had been published about the topic, and the few studies that had been done seemed to support the one-arrestin-to-one-rhodopsin theory. That is, until now.

Using photoreceptor cells from cows, Sommer's team set out to shine a light on the rhodopsin-arrestin mystery once and for all. They exposed the rhodopsin molecules to low light and to bright light and managed to count how many arrestin molecules bound with them. In the end, it took three to tango.

"Increasing the light intensity increases the percentage of rhodopsins that are activated. Although the number of arrestins that bound per activated rhodopsin appeared to change with the percentage of activated rhodopsins -- with one-to-one binding in very low light and one-to-two binding in very bright light -- we hypothesize that arrestin always interacts with two rhodopsin molecules," Sommer says. "In low light, arrestin interacts with one active rhodopsin and with one inactive rhodopsin; whereas, in bright light, arrestin interacts with two active rhodopsins."

It's just a matter of probability, Sommer says: In brighter light, arrestin interacts with two activated receptors simply because there are more of them around.

"Although there were two fairly clear-cut theories regarding how arrestin binds rhodopsin, what was totally unexpected is that both can occur," she says.

But what does this mean for the other senses and physiological functions controlled by other rhodopsin-like proteins? Rhodopsin is the most-studied member of the large family of G-protein coupled receptors, or GPCRs, and many well-known drugs target GPCRs. For example, when morphine binds to a GPCR, it affects the release of neurotransmitters in the brain and thus reduces pain signals. Meanwhile, beta-blockers, which are used to treat cardiac conditions and hypertension, block the activation of GPCRs by standing in the way of natural activating molecules.

"Nearly all GPCRs are normally bound by arrestin, and arrestin can greatly influence what happens to the GPCRs when they are acted on by drugs," says Sommer. "For example, many GPCR-targeted drugs become less effective with continued use. Part of this is because of arrestin. Arrestin binds to the activated GPCR and tells the cell to remove it from the cell surface. In other words, arrestin causes the cell to become less sensitive to the drug because it loses the receptors that normally catch the drug molecules."

By understanding how arrestin interacts with receptors like rhodopsin under healthy conditions, she says, researchers will be able to design better drugs that avoid such problems as desensitization.

More information: The resulting "Paper of the Week" appears in the March 4 print issue of the Journal of Biological Chemistry.