Watching The Eye for Signs of Diabetes Changes

Watching The Eye for Signs of Diabetes Changes

ANN ARBOR, Mich. — A new vision screening device, already shown to give an early warning of eye disease, could give doctors and patients a head start on treating diabetes and its vision complications, a new study shows.

The instrument, invented by two scientists at the University of Michigan Kellogg Eye Center, captures images of the eye to detect metabolic stress and tissue damage that occur before the first symptoms of disease are evident.

For people with diabetes — diagnosed or not — the new device could offer potentially significant advantages over blood glucose testing, the “gold standard” for diabetes detection.

The device takes a specialized photograph of the eye and is non-invasive, taking about five minutes to test both eyes.

In the July issue of Archives of Ophthalmology, Victor M. Elner, M.D., Ph.D., and Howard R. Petty, Ph.D., report on the potential of the new instrument to screen for diabetes and determine its severity. If further testing confirms the results to date, the new instrument may be useful for screening people who are at risk of diabetes but haven’t been diagnosed.

“Our objective in performing this study was to determine whether we could detect abnormal metabolism in the retina of patients who might otherwise remain undiagnosed based on clinical examination alone,” says Elner, professor, Department of Ophthalmology and Visual Sciences at U-M Medical School.

Metabolic stress, and therefore disease, can be detected by measuring the intensity of cellular fluorescence in retinal tissue. In a previous study, Petty and Elner reported that high levels of flavoprotein autofluorescence (FA) act as a reliable indicator of eye disease.

In their new study, Elner and Petty measured the FA levels of 21 individuals who had diabetes and compared the results to age-matched healthy controls. The Kellogg scientists found that FA activity was significantly higher for those with diabetes, regardless of severity, compared to those who did not have the disease. The results were not affected by disease severity or duration and were elevated for diabetics in each age group: 30 to 39 years, 40 to 49 years, and 50 to 59 years.

Given the increasing prevalence of diabetes, the FA device holds the potential to help address a leading and growing public health concern.

Some 24 million Americans have diabetes and an additional 57 million individuals have abnormal blood sugar levels that qualify as pre-diabetes, according to the latest report from the Centers for Disease Control and Prevention. In addition, 4.1 million people over the age of 40 suffer from diabetic retinopathy, an eye-related complication of diabetes that is the leading cause of blindness among working-age adults.

Twelve individuals in the study were known to have diabetic retinopathy, a disease in which blood vessels in the eye are damaged. The individuals with diabetic retinopathy in at least one eye had significantly greater FA activity than people with diabetes who do not have any visible eye disease.

“The abnormal readings indicated that it may be possible to use this method to monitor the severity of the disease,” says Elner.

Petty, a biophysicist and imaging expert, explains that hyperglycemia — or high blood sugar — is known to induce cell death in diabetic tissue soon after the onset of disease but before symptoms can be detected clinically.

“Increased FA activity is the earliest indicator that cell death has occurred and tissue is beginning to break down,” says Petty, professor of Ophthalmology and Visual Sciences, and professor of Microbiology and Immunology at the U-M Medical School. “FA serves as a ‘spectral-biomarker’ for metabolism gone awry, and we can use the results to detect and monitor disease.”

Petty also observes that unlike glucose monitoring, elevation of FA levels reflects ongoing tissue damage. That knowledge, he says, could motivate patients to intensify their efforts to manage the disease.

The Michigan researchers also note that elevated FA does not always mean that an individual has diabetes. “Because of the prevalence of diabetes in our population, individuals with abnormally high FA would be prompted to undergo glucose tolerance testing,” says Elner. “If the findings were negative for diabetes, we would look for other causes of ocular tissue dysfunction.”

Both Elner and Petty agree that the device has great potential as a tool for diabetes screening and management. “So much damage occurs before the disease can be detected by a doctor,” says Elner. “Early diagnosis will allow us to reduce organ damage and prevent many complications that accompany this disease.”

Elner and Petty have filed for patents and have formed a company, OcuSciences, Inc., to commercialize the metabolic imaging instrument.

Objective To test whether subjects with diabetes mellitus (DM) have enhanced retinal flavoprotein autofluorescence compared with age-matched control subjects using a rapid, noninvasive clinical imaging method.

Methods Twenty-one subjects with DM and 21 healthy age-matched control volunteers were subjected to retinal imaging using 1-ms flashes of 467-nm light. Flavoprotein autofluorescence for each flash at 535 nm was recorded using an electron-multiplying charged-coupled device camera with a 512×512-pixel chip. The average intensity and the average curve width of retinal flavoprotein autofluorescence were determined by analyzing histograms of pixel intensities plotted for each eye.

Results When stratified by age, the mean average intensity and average curve width levels in subjects with DM were significantly greater than those in controls across all 3 consecutive decades of life studied (P ? .004 and P ? .006, respectively). An overall comparison of the mean average intensity and average curve width levels in all subjects with DM vs all controls, with adjustment for age, was consistent with the results found in each age category (P =.001 and P < .001, respectively). Subjects having DM with retinopathy in at least 1 eye had significantly greater average intensity and average curve width than subjects having DM without retinopathy in either eye (P =.002 and P =.005, respectively).

Conclusions Flavoprotein autofluorescence measurements may be clinically useful to rapidly and noninvasively identify diabetic metabolic tissue stress and disease severity. Development of flavoprotein autofluorescence technology is likely to result in a tool that will improve DM screening and disease management.

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Figures in this Article

Hyperglycemia induces mitochondrial stress and apoptotic cell death in diabetic tissues soon after disease onset and before involvement can be detected by any current clinical diagnostic method.1 – 6 This suggests that measurement of mitochondrial metabolic activity can serve as an early indicator of the onset of disease.7 Before apoptosis, mitochondria exhibit impaired electron transport by energy-generating enzymes in the respiratory chain,1 ,8 causing increased percentages of flavoproteins in the chain to be oxidized and rendered capable of absorbing blue light and emitting green autofluorescence.9 – 11 This phenomenon leads to the hypothesis that increased flavoprotein autofluorescence (FA) may be an early indicator of diabetic metabolic tissue stress.

The standard criterion diagnostic method for diabetes mellitus (DM) is the oral glucose tolerance test. However, this method is cumbersome and is often avoided by patients.12 Thus, many subjects with DM may remain undiagnosed until they develop diabetic microvascular and macrovascular complications.12 – 13

A noninvasive method of measuring FA to detect early ocular dysfunction due to disease has been previously described.14 In this study, we compared retinal FA levels in subjects with DM regardless of disease severity or duration with those of age-matched healthy control subjects.

METHODS

ABSTRACT | METHODS | RESULTS | COMMENT | AUTHOR INFORMATION | REFERENCES

To measure retinal FA, a modified fundus camera containing 467-nm excitation and 535-nm emission filters (Omega Optical, Brattleboro, Vermont), 2 back-illuminated electron-multiplying charge-coupled device (EMCCD) cameras (Photometrics 512B; Roper Scientific, Tucson, Arizona), and customized computer hardware and software were used. The equipment has been previously described.14

Twenty-one subjects, aged 30 to 59 years, with established type 1 or type 2 DM and without ophthalmic disease other than retinopathy (hereafter referred to as “cases”) were enrolled consecutively betweenJune 11, 2007, and September 17, 2007, at the University of Michigan, Ann Arbor, during routine funduscopic examinations (Figure 1). Plasma glucose levels (obtained at the examination) were assessed by the glucose oxidase method, and hemoglobin A1c (HbA1c) levels were measured by high-performance liquid chromatography. Twenty-one age-matched healthy controls with normal glucose tolerance,15 normal blood pressure,16 and normal lipid profile17 according to recognized guidelines and standards were recruited as the control population.

Figure 1.

Flow of participants in the study. Subjects were classified as having diabetes mellitus by plasma testing, which served as the reference standard. The index test was retinal flavoprotein autofluorescence (FA) of each subject’s eyes. Results of the index test were then compared with the reference standard.

Image not available.

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This study was approved by the institutional review board at the University of Michigan; all subjects gave written informed consent. The study was organized and was performed according to the Standards for Reporting of Diagnostic Accuracy Initiative.18 – 19

After pupillary dilation, an EMCCD camera was used to visualize the macula using commercially available software (RSImage, Roper Scientific). For each eye, a second EMCCD camera with interfaced software (MetaVue; MDS Analytical Technologies, Toronto, Ontario, Canada) was used to capture 3 to 5 FA 535-nm readings, each induced by a 1-ms flash of 467-nm light. Imaging required 5 minutes per patient. The depth of instrument focus results in the capture of FA from all retinal layers.

The FA images, stored as 512×512-pixel files, were analyzed to produce histograms using available software (MetaVue; Adobe Photoshop CS2; Adobe Systems, San Jose, California; and Lispix; National Institute of Standards and Technology, Gaithersburg, Maryland). Histograms of pixel intensities (Figure 2), ranging from 0 to 256 U gray scale, were plotted for each eye to yield the average intensity (AI) and the average curve width (ACW) of retinal FA. All images were independently interpreted by 2 research associates (M.G.F. and J.M.F.) trained in FA image evaluation. If disagreement was encountered, a consensus reading was performed. At the time of imaging and statistical analysis, the research associates knew if the patient had DM, but test review bias was minimized by not excluding any subject’s data and by relying on objective results of FA testing. t Test and analysis of variance were used to compare the AI and the ACW in cases vs controls. Comparisons of eye-specific AI and ACW in cases vs controls were made using mixed linear regression analysis to adjust for intereye dependency and age (where appropriate). Commercially available software (SAS 9.0; SAS Institute Inc, Cary, North Carolina) was used for all statistical analyses. P < .05 was considered significant.

Figure 2.

Retinal flavoprotein autofluorescence (FA) histograms of pixel intensities collected from 3 age-matched subjects. Each panel displays 4 histograms of the right (black line) and left (blue line) eyes of each subject. Right shift of histograms designates increased retinal FA intensity. ACW indicates average curve width; AI, average intensity; L, left; and R, right. Numerals are given as mean (SE) gray scale units.

University of Michigan researchers are trialing a new in-house device that detects retinal flavoprotein autofluorescence, a potential indicator of the presence of diabetes-induced retinal metabolic changes, such as early diabetic retinopathy.

Metabolic stress, and therefore disease, can be detected by measuring the intensity of cellular fluorescence in retinal tissue. In a previous study, Petty and Elner reported that high levels of flavoprotein autofluorescence (FA) act as a reliable indicator of eye disease.

In their new study, Elner and Petty measured the FA levels of 21 individuals who had diabetes and compared the results to age-matched healthy controls. The Kellogg scientists found that FA activity was significantly higher for those with diabetes, regardless of severity, compared to those who did not have the disease. The results were not affected by disease severity or duration and were elevated for diabetics in each age group: 30 to 39 years, 40 to 49 years, and 50 to 59 years.

Twelve individuals in the study were known to have diabetic retinopathy, a disease in which blood vessels in the eye are damaged. The individuals with diabetic retinopathy in at least one eye had significantly greater FA activity than people with diabetes who do not have any visible eye disease.

“The abnormal readings indicated that it may be possible to use this method to monitor the severity of the disease,” says Elner.

Petty, a biophysicist and imaging expert, explains that hyperglycemia — or high blood sugar — is known to induce cell death in diabetic tissue soon after the onset of disease but before symptoms can be detected clinically.

“Increased FA activity is the earliest indicator that cell death has occurred and tissue is beginning to break down,” says Petty, professor of Ophthalmology and Visual Sciences, and professor of Microbiology and Immunology at the U-M Medical School. “FA serves as a ‘spectral-biomarker’ for metabolism gone awry, and we can use the results to detect and monitor disease.”

Petty also observes that unlike glucose monitoring, elevation of FA levels reflects ongoing tissue damage. That knowledge, he says, could motivate patients to intensify their efforts to manage the disease.

The Michigan researchers also note that elevated FA does not always mean that an individual has diabetes. “Because of the prevalence of diabetes in our population, individuals with abnormally high FA would be prompted to undergo glucose tolerance testing,” says Elner. “If the findings were negative for diabetes, we would look for other causes of ocular tissue dysfunction.”

Source : http://www2.med.umich.edu/prmc/media/newsroom/details.cfm?ID=459

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