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Clinical Sciences |

Rapid, Noninvasive Detection of Diabetes-Induced Retinal Metabolic Stress FREE

Matthew G. Field, BA; Victor M. Elner, MD, PhD; Donald G. Puro, MD, PhD; Jason M. Feuerman, BS; David C. Musch, PhD, MPH; Rodica Pop-Busui, MD, PhD; Richard Hackel, MA; John R. Heckenlively, MD; Howard R. Petty, PhD
[+] Author Affiliations

Author Affiliations: Departments of Ophthalmology and Visual Sciences (Mssrs Field, Feuerman, and Hackel and Drs Elner, Puro, Musch, Heckenlively, and Petty), Pathology (Dr Elner), Epidemiology (Dr Musch), and Endocrinology (Dr Pop-Busui), University of Michigan, Ann Arbor.


Arch Ophthalmol. 2008;126(7):934-938. doi:10.1001/archopht.126.7.934.
Text Size: A A A
Published online

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.

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.16 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.911 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.

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.

Place holder to copy figure label and caption
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.

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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.

Place holder to copy figure label and caption
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.

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Twenty-one of 33 consecutive subjects with DM referred for imaging met the inclusion criteria (Figure 1) and were imaged to determine the AI and the ACW for each eye. Among cases, the mean (SE) age was 44.8 (10.0) years (age range, 30-59 years), the mean (SE) documented duration of DM was 10.5 (9.8) years, and the mean (SE) HbA1c level was 8.5% (1.9%) (to convert to proportion of the total hemoglobin, multiply by 0.01). There were 6 subjects with type 1 DM and 15 subjects with type 2 DM. Diabetic retinopathy was present in 12 subjects. The mean (SE) age among controls was 44.7 (9.4) years (age range, 30-59 years).

As shown in Figure 3 and summarized in the Table, for all 3 age strata (30-39, 40-49, and 50-59 years), the mean AI in cases was significantly greater than that in controls (P ≤ .004). An overall comparison of the mean AI in all cases vs all controls, with adjustment for age, was consistent with the results found in each age category (P < .001). Similar findings are seen for mean ACW levels, which were significantly greater in cases than that in controls within each age strata (P ≤ .006) and in an overall comparison with adjustment for age (P < .001).

Place holder to copy figure label and caption
Figure 3.

Average intensity and average curve width of retinal flavoprotein autofluorescence from 21 cases with (blue squares) or without (white squares) retinopathy and from 21 age-matched controls across 3 consecutive decades of life. For each subject, values for the right and left eyes are shown paired. * Indicates the only case whose average intensity and average curve width in each eye overlapped with those of controls.

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Table Graphic Jump LocationTable. Average Intensity and Average Curve Width in Cases and in Controls by Age Categorya

The AI and the ACW in cases vs controls were compared to determine the age dependence of FA because other endogenous autofluorescent molecules (such as lipofuscin) accumulate with age and may affect FA intensity. In each age group, the AI and the ACW in cases were greater than those in controls, with the controls showing gradual steady increases of FA with age. However, the relative elevations of FA in cases vs controls seemed to be independent of patient age, suggesting that elevated FA in subjects with DM is not caused by lipofuscin or other similar fluorophores.

Differences in FA values between cases with type 1 vs type 2 DM were considered. The FA in 15 cases with type 2 DM (mean AI, 59.5 [23.6] U gray scale) and in 6 cases with type 1 DM (mean AI, 55.8 [25.9] U gray scale) did not differ (P =.65).

Elevated AI and ACW were detected in cases regardless of whether retinopathy was detected on fundus examination by an ophthalmologist specializing in diabetic retinopathy (D.G.P.). In fact, 9 of 21 cases had no visibleretinopathy (Figure 3), indicating that retinal metabolic stress due to DM is present before any visible retinopathy.

We studied the associations between FA, HbA1C level, and the presence of retinopathy (Figure 4). The mean HbA1C level among cases with retinopathy in at least 1 eye (8.9% [2.1%]) was not significantly different from those among cases without retinopathy in either eye (7.9% [1.5%]) (P =.23). However, the mean AI and ACW among cases with retinopathy in at least 1 eye (69.7 [18.3] and 63.2 [14.5] U gray scale, respectively) were significantly different from those among cases without retinopathy in either eye (43.5 [12.2] and 44.8 [10.5] U gray scale, respectively) (P =.002 and P =.005, respectively).

Place holder to copy figure label and caption
Figure 4.

Flavoprotein autofluorescence (FA) intensity (mean of right and left eyes) in 20 of 21 cases from Figure 3 with retinopathy in at least 1 eye (blue squares) or without retinopathy in either eye (white squares) compared with their concurrent hemoglobin A1c level (1 was unavailable).

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To consider the possibility that FA imaging might measure acute fluctuations in plasma glucose levels rather than metabolic effects of chronic hyperglycemia, the FA of 4 volunteers was measured in a fasting state and at 1 hour after 75-g oral glucose challenge. No significant differences were observed in FA values, indicating that acute elevations in plasma glucose levels do not affect retinal FA.

The results of FA imaging in subjects with DM differ significantly from those in age-matched controls. Only 1 case (indicated by an asterisk in Figure 3), an intensively treated subject within 1 year of diagnosis and with an HbA1C level of 7%, had AI and ACW in each eye that overlapped with those of age-matched controls. Thus, even our proof-of-concept prototype measures significant differences between groups of controls and cases regardless of disease duration or severity. In several subjects (controls and cases), there is a statistical difference in AI and ACW values between their 2 eyes, suggesting that FA measures could be detecting increased retinal stress in one eye as opposed to the other. In fact, a high degree of retinal FA asymmetry between eyes of the same individual is a strong indicator of disease.14 Improvements in FA technology, including light sources with low flash–no flash variability and feedback correction for variability, promise to greatly reduce AI and ACW standard deviations to make FA imaging a sufficiently sensitive screening tool for DM. In this scenario, because of the high prevalence of DM, individuals with abnormally high FA would undergo glucose tolerance testing that, if normal, would prompt investigation for other causes of ocular tissue dysfunction.

For cases, FA levels seem to be associated with the severity of retinal damage (Figure 3). In addition, our limited data suggest that FA may be more strongly associated with retinopathy than HbA1c levels, which are considered the most reliable measure of metabolic control.2022 The value of FA imaging is supported by 2 cases with retinopathy (Figure 4) who had elevated FA but low HbA1c levels. Future studies may show FA to be useful in monitoring disease progression and its mitigation by treatment. Unlike glucose monitoring, elevations in FA reflect ongoing diabetic tissue damage and may provide patient and caregiver motivation for intensifying disease management.

Until the recent development of a noninvasive method for clinical use,14 FA had not been used in human clinical studies of disease, to our knowledge. Ocular emission spectrophotometry has shown that mitochondrial FA23,24 constitutes a shoulder of a broad emission spectrum of other fluorescent species, especially lipofuscin.25,26 For maximal metabolic contrast, only a narrow emission band at the FA maximum is acquired, effectively excluding most of the emission of lipofuscin.2527 To account for the residual portion of the FA signal derived from age-dependent accumulation of lipofuscin,27 age-matched FA comparisons were used to correct for this variable. Our approach in obtaining metabolic contrast seems to satisfy the requirements of a disease-sensitive tool.2,25 Nevertheless, careful quantification of the effects of potentially confounding ocular fluorophores on FA measurements is warranted in future studies.

Because neuronal loss and microangiopathy occur early in human and animal DM,8,2832 tissue damage begins at the earliest stages of the disease, before it is clinically evident or detected by fasting blood glucose screening.1,31 Early diagnosis and treatment are likely to prevent this damage.32,33 Our data suggest that development of FA imaging for DM, including its evaluation in longitudinal clinical trials, is likely to result in a tool that will become increasingly important in DM detection and management.

Correspondence: Victor M. Elner, MD, PhD, Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105 (velner@umich.edu).

Submitted for Publication: November 12, 2007; final revision received January 24, 2008; accepted January 25, 2008.

Author Contributions: Messrs Field and Feuerman and Dr Musch had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: Drs Elner and Petty have a financial interest in the presented material by having founded OcuSciences, Inc, to commercialize the technology.

Funding/Support: This study was supported by grants EY09441 and EY007003 from the National Eye Institute, National Institutes of Health and by a Research to Prevent Blindness Senior Scientific Investigator Award (Dr Elner).

Du  YMiller  CMKern  TS Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med 2003;35 (11) 1491- 1499
PubMed Link to Article
Kowluru  RATang  JKern  TS Abnormalities of retinal metabolism in diabetes and experimental galactosemia, VII: effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 2001;50 (8) 1938- 1942
PubMed Link to Article
Mizutani  MKern  TSLorenzi  M Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 1996;97 (12) 2883- 2890
PubMed Link to Article
Kowluru  RA Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. Antioxid Redox Signal 2005;7 (11-12) 1581- 1587
PubMed Link to Article
Kanwar  MChan  PSKern  TSKowluru  RA Oxidative damage in the retinal mitochondria of diabetic mice: possible protection by superoxide dismutase. Invest Ophthalmol Vis Sci 2007;48 (8) 3805- 3811
PubMed Link to Article
Cai  JNelson  KCWu  MSternberg  P  JrJones  DP Oxidative damage and protection of the RPE. Prog Retin Eye Res 2000;19 (2) 205- 221
PubMed Link to Article
Thompson  CB Apoptosis in the pathogenesis and treatment of disease. Science 1995;267 (5203) 1456- 1462
PubMed Link to Article
Ning  XBaoyu  QYuzhen  LShuli  SReed  ELi  QQ Neuro-optic cell apoptosis and microangiopathy in KKAY mouse retina. Int J Mol Med 2004;13 (1) 87- 92
PubMed
Benson  RCMeyer  RAZaruba  ME McKhann  GM Cellular autofluorescence: is it due to flavins? J Histochem Cytochem 1979;27 (1) 44- 48
PubMed Link to Article
Kindzelskii  APetty  HR Fluorescence spectroscopic detection of mitochondrial flavoprotein redox oscillations and transient reduction of the NADPH oxidase-associated flavoprotein in leukocytes. Eur Biophys J 2004;33 (4) 291- 299
PubMed Link to Article
Reinert  KCDunbar  RLGao  WChen  GEbner  TJ Flavoprotein autofluorescence imaging of neuronal activation in the cerebellar cortex in vivo. J Neurophysiol 2004;92 (1) 199- 211
PubMed Link to Article
Maynard  JDRohrscheib  MWay  JFNguyen  CMEdiger  MN Noninvasive type 2 diabetes screening: superior sensitivity to fasting plasma glucose and A1C. Diabetes Care 2007;30 (5) 1120- 1124
PubMed Link to Article
Centers for Disease Control and Prevention,  National Diabetes Fact Sheet.   Atlanta, GA US Dept of Health and Human Services2005;
Elner  VMPark  SCornblath  WHackel  RPetty  HR Flavoprotein autofluorescence detection of early ocular dysfunction. Arch Ophthalmol 2008;126 (2) 259- 260
PubMed Link to Article
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20 (7) 1183- 1197
PubMed
Chobanian  AVBakris  GLBlack  HR  et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290(2):197]. JAMA 2003;289 (19) 2560- 2572
PubMed Link to Article
Grundy  SMCleeman  JIDaniels  SR  et al. American Heart Association, National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [published corrections appear in Circulation. 2005;112(17):e297 and e298]. Circulation 2005;112 (17) 2735- 2752
PubMed Link to Article
Bossuyt  PMReitsma  JBBruns  DE  et al. Standards for Reporting of Diagnostic Accuracy, Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Clin Chem 2003;49 (1) 1- 6
PubMed Link to Article
Bossuyt  PMReitsma  JBBruns  DE  et al. Standards for Reporting of Diagnostic Accuracy, The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem 2003;49 (1) 7- 18
PubMed Link to Article
Nathan  DMSinger  DEHurxthal  KGoodson  JD The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 1984;310 (6) 341- 346
PubMed Link to Article
Singer  DEColey  CMSamet  JHNathan  DM Tests of glycemia in diabetes mellitus: their use in establishing a diagnosis and treatment. Ann Intern Med 1989;110 (2) 125- 137
PubMed Link to Article
Delamater  AM Clinical use of hemoglobin A1C to improve diabetes management. Clin Diabetes 2006;246- 8
Link to Article
Kunz  DWinkler  KElger  CEKunz  WS Functional imaging of mitochondrial redox state. Methods Enzymol 2002;352135- 151
PubMed
Kunz  WSKunzetsov  AVWinkler  KGellerich  FNNeuhof  SNeumann  HW Measurement of fluorescence changes of NAD(P)H and of fluorescent flavoproteins in saponin-skinned human skeletal muscle fibers. Anal Biochem 1994;216 (2) 322- 327
PubMed Link to Article
Schweitzer  DHammer  MAnders  RDoebbecke  TSchenke  S Alterations in autofluorescence decay time in the fundus after oxygen provocation [in German]. Ophthalmologe 2004;101 (1) 66- 72
PubMed Link to Article
Schweitzer  DKolb  AHammer  MAnders  R Time-correlated measurement of autofluorescence: a method to detect metabolic changes in the fundus [in German]. Ophthalmologe 2002;99 (10) 774- 779
PubMed Link to Article
Sharifzadeh  MBernsetin  PSGellermann  W Nonmydriatic fluorescence-based quantitative imaging of human macular pigment distribution. J Opt Soc Am A Opt Image Sci Vis 2006;23 (10) 2373- 2387
PubMed Link to Article
Barber  AJLieth  EKhin  SAAntonetti  DABuchanan  AGGardner  TW Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin. J Clin Invest 1998;102 (4) 783- 791
PubMed Link to Article
Abu-El-Asrar  AMDralands  LMissotten  LAl-Jadaan  IAGeboes  K Expression of apoptosis markers in the retinas of human subjects with diabetes. Invest Ophthalmol Vis Sci 2004;45 (8) 2760- 2766
PubMed Link to Article
Podestà  FRomeo  GLiu  WH  et al.  Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro. Am J Pathol 2000;156 (3) 1025- 1032
PubMed Link to Article
Martin  PMRoon  PVan Ells  TKGanapathy  VSmith  SB Death of retinal neurons in streptozotocin-induced diabetic mice. Invest Ophthalmol Vis Sci 2004;45 (9) 3330- 3336
PubMed Link to Article
Barber  AJ A new view of diabetic retinopathy: a neurodegenerative disease of the eye. Prog Neuropsychopharmacol Biol Psychiatry 2003;27 (2) 283- 290
PubMed Link to Article
Lieth  EGardner  TWBarber  AJAntonetti  DAPenn State Retina Research Group, Retinal neurodegeneration: early pathology in diabetes. Clin Experiment Ophthalmol 2000;28 (1) 3- 8
PubMed Link to Article

Figures

Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Average intensity and average curve width of retinal flavoprotein autofluorescence from 21 cases with (blue squares) or without (white squares) retinopathy and from 21 age-matched controls across 3 consecutive decades of life. For each subject, values for the right and left eyes are shown paired. * Indicates the only case whose average intensity and average curve width in each eye overlapped with those of controls.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Flavoprotein autofluorescence (FA) intensity (mean of right and left eyes) in 20 of 21 cases from Figure 3 with retinopathy in at least 1 eye (blue squares) or without retinopathy in either eye (white squares) compared with their concurrent hemoglobin A1c level (1 was unavailable).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Average Intensity and Average Curve Width in Cases and in Controls by Age Categorya

References

Du  YMiller  CMKern  TS Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med 2003;35 (11) 1491- 1499
PubMed Link to Article
Kowluru  RATang  JKern  TS Abnormalities of retinal metabolism in diabetes and experimental galactosemia, VII: effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 2001;50 (8) 1938- 1942
PubMed Link to Article
Mizutani  MKern  TSLorenzi  M Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 1996;97 (12) 2883- 2890
PubMed Link to Article
Kowluru  RA Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. Antioxid Redox Signal 2005;7 (11-12) 1581- 1587
PubMed Link to Article
Kanwar  MChan  PSKern  TSKowluru  RA Oxidative damage in the retinal mitochondria of diabetic mice: possible protection by superoxide dismutase. Invest Ophthalmol Vis Sci 2007;48 (8) 3805- 3811
PubMed Link to Article
Cai  JNelson  KCWu  MSternberg  P  JrJones  DP Oxidative damage and protection of the RPE. Prog Retin Eye Res 2000;19 (2) 205- 221
PubMed Link to Article
Thompson  CB Apoptosis in the pathogenesis and treatment of disease. Science 1995;267 (5203) 1456- 1462
PubMed Link to Article
Ning  XBaoyu  QYuzhen  LShuli  SReed  ELi  QQ Neuro-optic cell apoptosis and microangiopathy in KKAY mouse retina. Int J Mol Med 2004;13 (1) 87- 92
PubMed
Benson  RCMeyer  RAZaruba  ME McKhann  GM Cellular autofluorescence: is it due to flavins? J Histochem Cytochem 1979;27 (1) 44- 48
PubMed Link to Article
Kindzelskii  APetty  HR Fluorescence spectroscopic detection of mitochondrial flavoprotein redox oscillations and transient reduction of the NADPH oxidase-associated flavoprotein in leukocytes. Eur Biophys J 2004;33 (4) 291- 299
PubMed Link to Article
Reinert  KCDunbar  RLGao  WChen  GEbner  TJ Flavoprotein autofluorescence imaging of neuronal activation in the cerebellar cortex in vivo. J Neurophysiol 2004;92 (1) 199- 211
PubMed Link to Article
Maynard  JDRohrscheib  MWay  JFNguyen  CMEdiger  MN Noninvasive type 2 diabetes screening: superior sensitivity to fasting plasma glucose and A1C. Diabetes Care 2007;30 (5) 1120- 1124
PubMed Link to Article
Centers for Disease Control and Prevention,  National Diabetes Fact Sheet.   Atlanta, GA US Dept of Health and Human Services2005;
Elner  VMPark  SCornblath  WHackel  RPetty  HR Flavoprotein autofluorescence detection of early ocular dysfunction. Arch Ophthalmol 2008;126 (2) 259- 260
PubMed Link to Article
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20 (7) 1183- 1197
PubMed
Chobanian  AVBakris  GLBlack  HR  et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290(2):197]. JAMA 2003;289 (19) 2560- 2572
PubMed Link to Article
Grundy  SMCleeman  JIDaniels  SR  et al. American Heart Association, National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [published corrections appear in Circulation. 2005;112(17):e297 and e298]. Circulation 2005;112 (17) 2735- 2752
PubMed Link to Article
Bossuyt  PMReitsma  JBBruns  DE  et al. Standards for Reporting of Diagnostic Accuracy, Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Clin Chem 2003;49 (1) 1- 6
PubMed Link to Article
Bossuyt  PMReitsma  JBBruns  DE  et al. Standards for Reporting of Diagnostic Accuracy, The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem 2003;49 (1) 7- 18
PubMed Link to Article
Nathan  DMSinger  DEHurxthal  KGoodson  JD The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 1984;310 (6) 341- 346
PubMed Link to Article
Singer  DEColey  CMSamet  JHNathan  DM Tests of glycemia in diabetes mellitus: their use in establishing a diagnosis and treatment. Ann Intern Med 1989;110 (2) 125- 137
PubMed Link to Article
Delamater  AM Clinical use of hemoglobin A1C to improve diabetes management. Clin Diabetes 2006;246- 8
Link to Article
Kunz  DWinkler  KElger  CEKunz  WS Functional imaging of mitochondrial redox state. Methods Enzymol 2002;352135- 151
PubMed
Kunz  WSKunzetsov  AVWinkler  KGellerich  FNNeuhof  SNeumann  HW Measurement of fluorescence changes of NAD(P)H and of fluorescent flavoproteins in saponin-skinned human skeletal muscle fibers. Anal Biochem 1994;216 (2) 322- 327
PubMed Link to Article
Schweitzer  DHammer  MAnders  RDoebbecke  TSchenke  S Alterations in autofluorescence decay time in the fundus after oxygen provocation [in German]. Ophthalmologe 2004;101 (1) 66- 72
PubMed Link to Article
Schweitzer  DKolb  AHammer  MAnders  R Time-correlated measurement of autofluorescence: a method to detect metabolic changes in the fundus [in German]. Ophthalmologe 2002;99 (10) 774- 779
PubMed Link to Article
Sharifzadeh  MBernsetin  PSGellermann  W Nonmydriatic fluorescence-based quantitative imaging of human macular pigment distribution. J Opt Soc Am A Opt Image Sci Vis 2006;23 (10) 2373- 2387
PubMed Link to Article
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