Clinical StudyRetinal Vessel Diameter Changes in Relation to Dark Adaptationand Acute Hyperglycemia

Per Kappelgaard 1 Stig K Holfort1 Oliver N Klefter 12 and Michael Larsen12

1Department of Ophthalmology Rigshospitalet Copenhagen Denmark2Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Correspondence should be addressed to Per Kappelgaard perkapgmailcom

Received 31 March 2018 Accepted 16 August 2018 Published 18 September 2018

Academic Editor Laszlo Modis

Copyright copy 2018 Per Kappelgaard et al is is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

e purpose of this experimental clinical study was to assess the effects of dark adaptation and acute changes in glycemia on retinalvessel diameters in men e study included 14 patients (mean age 63 years range 48ndash74 years) with type 2 diabetes mellitus andminimal or no diabetic retinopathy Retinal vessel diameters were assessed using infrared photography before and after darkadaptation first while fasting and then at peak hyperglycemia during an oral glucose tolerance test (OGTT) Dark adaptation wasaccompanied by retinal vasodilatation both during fasting (mean glycemia 76plusmn 17mM) and postprandial hyperglycemia (157plusmn42mM) When fasting the increase in vein diameter during dark adaptation was 20 after 20min (P 0018) and 29 after40min (P 0010) When subjects were hyperglycemic the increase during dark adaptation was 28 for retinal vein diameters(P 0027) and 20 for retinal artery diameters after 20min (P 0002) and 17 for retinal artery diameters after 40min(P 0022) For identical conditions of lightdark adaptation retinal vessels were dilated when subjects were fasting compared topostprandial hyperglycemia us darkness and fasting were both associated with retinal vasodilation in this short-term ex-periment in patients with type 2 diabetes Future studies should determine whether both the stimuli of vasodilation lead to retinalhyperperfusion which would support that they may be involved in the aggravation of diabetic retinopathy

1 Introduction

Development of diabetic retinopathy and progression toproliferative diabetic retinopathy are accompanied by di-lation of the retinal veins [1ndash3] It is of interest to identifyrisk factors for retinal vasodilation especially the ones thataremodifiable because the information thus obtained can beused in the search of targets for intervention Factors ofspecific interest are the adaptation of the eye to changes inambient light and its adaptation and changes in glucoselevels notably in diabetes

Dark adaptation is accompanied by decreasing oxygentension and increasing lactate production in the retina [4ndash7]and an increase in retinal blood flow part of which might bemediated by blood vessel dilation [8ndash10]

Retinal vessel dilation occurs in response to experimentalhypoxia and flicker stimulation [11ndash13] and lower glycemiasuppresses retinal electroretinographic signaling and dark

adaptation Hence there is a reason to suspect that hypogly-cemia may dilate retinal vessels [14ndash17] While some experi-ments have found abnormal autoregulation of blood flow in theretina in diabetes the relation between light exposure glycemiaand blood flow outlined above may also exist in diabetes andthere is a reason to suspect that it may contribute to the de-velopment and progression of retinopathy in diabetes [18ndash21]

e objective of the present study was to examine theacute concomitant effects of dark adaptation and changes inglycemia levels on retinal vessel diameters in patients withtype 2 diabetes

2 Materials and Methods

is experimental clinical study included 14 patients withtype 2 diabetes mellitus 9 men and 5 women aged 48ndash74years (meanplusmn SD 626plusmn 75 years Table 1) Best-correctedvisual acuity (Snellen) was 09 or better in all eyes e

HindawiJournal of OphthalmologyVolume 2018 Article ID 7064359 6 pageshttpsdoiorg10115520187064359

patients had mild (ETDRS levellt 35) or no diabetic reti-nopathy and no study eye had macular edema Exclusioncriteria were eye diseases other than diabetic retinopathyuntreated arterial hypertension and major systemic diseasesother than diabetes All 14 patients were recruited from theinternal medicine outpatient clinic of Rigshospitalet 13 weretreated with one or more oral antidiabetic agents while onewas treated by diet alone Four patients were treated byinsulin e study was approved by the Danish NationalCommittee on Biomedical Research Ethics and conductedwith the participantsrsquo informed consent according to theHelsinki Declaration II e study was registered atClinicaltrialsgov (NCT01136902)

Infrared scanning laser fundus photography (SpectralisHRA+OCT Heidelberg Engineering Heidelberg Germany)was made over a 55-degree angle centered on the optic discwith a nominal resolution of 768 times 768 pixels A com-puterized dark adaptometer (AdapDx MacuLogix IncMiddletown PA USA) was used in three patients to verifythat full dark adaptation had been obtained at the end of theexamination [22]

Oral glucose tolerance testing (OGTT) was performed byhaving the patients ingest 75 g of glucose dissolved in 250mLof water e subsequent hyperglycemia was expected toreach its peak after 15 hours e experiments were madebetween 8 am to 12 pm after an overnight fast and the pa-tients not having taken their antidiabetic agents since theevening before

Study procedures included determination of best-corrected visual acuity (Snellen) transfoveal optical co-herence tomography (Cirrustrade HD-OCT Carl Zeiss MeditecAG Jena Germany) infrared fundus photography(Spectralisreg HRA+OCT Heidelberg Engineering Heidel-berg Germany) and venous blood analysis for HbA1csodium and potassium Pupil dilation was made withphenylephrine hydrochloride 10 and tropicamide 1 estudy eye of each patient was selected randomly except inone patient where one eye was excluded because of diabeticmacular edema

Study sessions followed a fixed time schedule (Figure 1)comprising two dark adaptation cycles beginning each withinfrared fundus photography in normal room light (ap-proximately 200 lux) after 5 minutes of adaptation andcontinuing with a second set of images after 20min of darkadaptation and finally a third set of images after 40min of

dark adaptation e first cycle was made with subjectsfasting whereas the second cycle was started 65min after theingestion of the OGTT meal and thus made during post-prandial hyperglycemia Capillary blood glucose concen-tration was measured (Precision Xceed reagent-strip andreading device Medisense Products Abbott LaboratoriesWitney Oxon United Kingdom) immediately before andafter the two dark adaptation cycles e means of the twopairs of glycemia values were used for data analysis

Vessel diameters were assessed using a semiautomatedalgorithm as previously described [23ndash25] Central retinalartery equivalent (CRAE) and central retinal vein equivalent(CRVE) diameters were estimated from the individualperipapillary vessel diameters according to the method ofKnudtson et al [26] in this case measured on the infraredfundus photographs

e same six arteriolar and six venular trunk vesselsegments were analyzed at a distance of one half to one discdiameter from the optic disc Vessel segments were mea-sured along their entire length within this interval if nocrossing or branching was present Trunk segments werepreferred to branches unless the trunk was shorter than80 microm e diameters of the central vessel equivalents werethen calculated in the following manner

arterioles 1113954W 088 times w21 + w

221113872 1113873

12 (1)

venules 1113954W 095 times w21 + w

221113872 1113873

12 (2)

where w1 is the width of the narrower branch w2 is thewidth of the wider branch W is the estimate of the width ofthe parent trunk arteriole or venule and the constant is thebranching coefficient Vessel diameters as measured orderived from equations (1) or (2) were paired and used tocalculate trunk vessel width until only one number is leftrepresenting the diameter of an idealized central retinalartery or vein and named CRAE or CRVE [26]

Values for CRAE and CRVE were calculated from thethree best photographs from each time point and the meanof the three values used for statistical analysis e photo-graphs were ranked based on sharpness disc centration andevenness of illumination

e statistical analysis included two-sample paired t-tests of differences between fasting and hyperglycemic pa-rameters and between light-adapted and dark-adapted pa-rameters Measurements are expressed as meansplusmn standarddeviations (meanplusmn SD) and 95 confidence intervals (CI95)An operational level of statistical significance of Ple 005 isused in the description of the results without correction formultiple testing Additionally mixed model analysis forrepeated measurements with Tukey-adjusted comparisons(SAS 94 SAS Institute Carey NC USA) was used to modelthe relative contributions of glycemia and dark adaptation tothe variations in CRAE and CRVE

3 Results

Mean plasma glucose concentrations were 76plusmn 17mMduring the fast and rose to 157plusmn 42mM during

Table 1 Clinical characteristics of patients with type 2 diabetes

Meanplusmn SDAge (years) 626plusmn 75Sex (malefemale) 95Duration of diabetes (years) 64plusmn 50Systolic blood pressure (mmHg) 131plusmn 17Diastolic blood pressure (mmHg) 76plusmn 9HbA1c () 73plusmn 10Visual acuity (Snellen) 10plusmn 01PG fasting (mM) 76plusmn 17PG 15-hour OGTT (mM) 157plusmn 42PG plasma glucose OGTT oral glucose tolerance test

2 Journal of Ophthalmology

postprandial hyperglycemia (Plt 001) From the fastingbaseline to hyperglycemia in both cases before dark ad-aptation was begun retinal artery diameters decreasedsignicantly from 1707plusmn 148 microm to 1680plusmn 138 microm(P 0025) whereas only a numerical reduction in veindiameters was seen from 2270plusmn 210 microm to 2245plusmn 208 microm(P 0127 Table 2 Figure 1)

While fasting there was little change in retinal artery di-ameters during dark adaptation but from themore constrictedhyperglycemic baseline dark adaptation was accompanied bya 20 increase in retinal artery diameter from 1680plusmn 138micromto 1714plusmn 143microm at 20min (P 0002) and 1708plusmn 150micromor 17 more than that before dark adaptation at 40min(P 0022 Table 2)

While fasting the retinal veins had dilated by 20 after 20minutes from 2270plusmn 210 microm to 2315plusmn 210 microm (P 0018)

and by 29 after 40min to 2336plusmn 231 microm (P 0010Table 2 Figure 1) e retinal veins dilated numericallyduring hyperglycemic dark adaptation this time by 28from a hyperglycemic daylight baseline of 2245plusmn 208 microm to2307plusmn 254 microm after 20 minutes (P 0026 Table 2) and2292 microm or 21 after 40 minutes (P 0072)

In a mixed model analysis covering the entire data set ina single model we found nonsignicant interactions be-tween glycemic state and dark adaptation hence implyingindependent eects Dark adaptation had a highly signicanteect on both CRAE and CRVE (P 0001 and Plt 00001respectively) leading to increases in vessel diameters in boththe fasting condition and during hyperglycemia (Figure 1)Hyperglycemia was generally characterized by numericallylower CRAE and CRVE reected by statistical tendencies inthe mixed model analysis (P 010 and P 008)

PG

Light

ndash5

Fasting 0 Hyperglycemia 65 70 90 110

Time (min)

0

106

lowast1

lowast1

lowast1

lowast2

lowast2

lowast1lowast1

105

104

103

102

101

100

099

098

097

096

20 40 ndash5 0 20 40

Darkadaptation

Darkadaptation

Darkadaptation

DarkadaptationDaylight Light

PG PGOGTT

IR photos IR photos IR photos IR photos IR photosIR photos

PG

Figure 1 Retinal vessel diameter data indexed to baseline (triangles arteries and squares veins) in 14 patients with type 2 diabetes who werefasting (glycemia 76plusmn 17mM) and adapted to room light at baseline (0 minutes) is was followed by a cycle of dark adaptation andfundus photography during which infrared fundus photography which had also been made at baseline was repeated twice Daylight wasreintroduced after 40 minutes and then 5min later participants ingested 75 g of glucose dissolved in water After 70 more minutes whenglycemia had increased to 157plusmn 42mM infrared photographs were recorded in daylight after which a second round of dark adaptationand photography was reinitiated PG plasma glucose OGTT oral glucose tolerance test IR infrared Values greater than 1 indicate vesseldilation and values lower than 1 indicate vessel contraction One-sided error bars indicate 1 standard deviation Asterisk lowast1 indicatesPlt 005 compared to the nearest predark adaptation baseline fasting or hyperglycemic Asterisk lowast2 indicates Plt 005 for a given time pointduring the second (hyperglycemic) dark adaptation cycle compared to the rst (fasting) dark adaptation cycle

Journal of Ophthalmology 3

4 Discussion

is experimental study of retinal vessel diameter variationduring acute hyperglycemia and dark adaptation in patientswith type 2 diabetes found that both dark adaptation and lowlevels of glycemia were associated with wider retinal vesseldiameters e combined assessment of the two factors wasmade possible by infrared digital fundus photographywhich does not disturb dark adaptation

A tentative explanation is that dark adaptation leads tovessel dilation because oxygen tension in the retina is lower inthe dark-adapted state than in daylight and that hypoglycemialeads to vessel dilation because it reduces the energy substratesupply to the retina Presumably but not actually documentedby our experiments vasodilation compensates for energydeficits secondary to hypoxia and hypoglycemia by increasingblood flow and substrate supply to the retina e underlyingmechanisms may obviously be complicated if extraocularresponses are elicited by changes in glycemia us plasmainsulin which should change during the glucose tolerancetest was not measured in this study but given that the pa-tients had type 2 diabetes they will have varying levels ofresidual insulin production and insulin sensitivity Insulin isgenerally considered to have vasodilator effects [27] so ifplasma insulin influenced the study it likely acted to limit thevasoconstrictive effect of hyperglycemia by the endogenouspostprandial rise in insulin secretion [27 28]

Our assumptions are supported by the demonstration byGrunwald et al that retinal vasodilation is associated withincreased retinal blood flow [29] and that dark adaptationincreases retinal volumetric blood flow in healthy subjects by62ndash71 [8]

Retinal vasodilation during dark adaptation is consistentwith dark adaptation inducing an increase in metabolic

activity of the retina [7 30] Increased metabolism mayhypothetically promote the progression of diabetic reti-nopathy [31 32] because accompanying vasodilation andhyperperfusion lead to increased shear stress on the vascularendothelium Relative hypoglycemia by inducing vasodi-lation may have a comparable effect is may help explainwhy improved metabolic control in diabetes can lead toshort-term acceleration of retinopathy progression despiteits long-term benefits [33 34] Finally our findings supportthe suggestion that nocturnal vasodilation may explain whydiabetic macular edema tends to be more pronounced in themorning than later in the day [35 36]

e vasoconstricting effect of hyperglycemia may hy-pothetically be driven by the ability of the retina to balanceits metabolic needs by increasing glycolysis and lactateproduction while decreasing oxidative phosphorylation andCO2 production [12] e present study provides in-formation only about the net result however and not aboutits constituent components

Limitations of this study include the lack of inclusion ofa group of healthy subjects is might determine whetherthe characteristics in diabetes are an extension of normalphysiology induced by abnormally high postprandial rises inblood glucose in diabetes or whether the physiologicalcharacteristics or the retina has been adjusted rearranged ordisrupted by elevated and unstable glycemia or other aspectsof diabetes Additionally a larger study population mighthave enabled analysis of the relation of vessel diameterchanges to age blood pressure HbA1c and other variables ofinterest It should be noted that our results were obtained bysummarizing observations from a group of patients Wehave not shown that neither qualitative nor numerical re-sponses can be used to define any clinically relevant char-acteristics of patients with diabetes

Table 2 Fasting and hyperglycemic retinal vessel diameters in patients with type 2 diabetes

Patient

Fasting HyperglycemiaLight Dark adaptation Light Dark adaptation0min 20min 40min 0min 20min 40min

CRAE CRVE CRAE CRVE CRAE CRVE CRAE CRVE CRAE CRVE CRAE CRVE1 1910 2570 1894 2657 1897 2713 1812 2498 1898 2746 1942 26922 1750 2222 1768 2314 1709 2257 1695 2196 1716 2272 1688 22503 1817 2343 1825 2397 1917 2536 1868 2390 1903 2564 1892 25574 1603 2208 1662 2322 1624 2358 1547 2221 1631 2304 1627 22765 1765 2456 1766 2457 1774 2522 1767 2480 1766 2473 1806 24606 1697 2460 1732 2483 1749 2641 1692 2484 1733 2645 1735 26377 1507 1897 1531 2034 1537 1990 1475 1844 1542 1968 1515 19548 1785 2255 1786 2259 1735 2263 1749 2207 1806 2212 1783 22089 1428 2067 1450 2064 1443 2058 1410 1991 1407 1945 1397 196310 1902 2500 1878 2486 1842 2433 1841 2444 1827 2385 1811 234711 1537 2141 1551 2176 1543 2174 1558 2167 1549 2155 1572 217612 1858 2456 1817 2394 1806 2402 1774 2305 1825 2370 1817 235513 1679 1926 1710 1943 1700 1973 1653 1951 1686 1922 1640 192314 1666 2272 1727 2428 1686 2388 1673 2258 1700 2340 1689 2287MEAN 1707 2270 1721 2315 1712 2336 1680 2245 1714 2307 1708 2292SD 148 210 132 210 138 231 138 208 143 254 150 243AVR 075 074 073 075 074 075All values are in microm CRAE central retinal artery equivalent CRVE central retinal vein equivalent

4 Journal of Ophthalmology

In summary this study of patients with type 2 diabetesfound that dark adaptation was accompanied by retinalvasodilation both during normoglycemia and hyperglyce-mia Furthermore the retinal vessels were dilated duringnormoglycemia compared to postprandial hyperglycemiae study supports that the occasional flare-up of diabeticretinopathy after rapidly introduced and strictly maintainedrelative hypoglycemia [33 34] may be precipitated by retinalvasodilation and that rod photoreceptor activation maypromote worsening of diabetic retinopathy [32] Our in-terpretations can be tested in studies that include assessmentof perfusion rates and oxygenation preferably with enoughparticipants and a long enough period of observation todetermine if individual vessel diameter responses can predictretinopathy progression

Data Availability

All data relevant to presented results and conclusions areincluded in the manuscript

Conflicts of Interest

e authors declare no conflicts of interest in relation to thepresent paper

Acknowledgments

e study was supported by the Danish Agency for ScienceTechnology and Innovation (Grant no 10-080573) and bythe Novo Nordisk Foundation

References

[1] R Broe M L Rasmussen U Frydkjaer-Olsen et al ldquoRetinalvessel calibers predict long-term microvascular complicationsin type 1 diabetes the Danish Cohort of Pediatric Diabetes1987 (DCPD1987)rdquo Diabetes vol 63 no 11 pp 3906ndash39142014

[2] R Klein B E Klein S E Moss T Y Wong andA R Sharrett ldquoRetinal vascular caliber in persons with type 2diabetes the wisconsin epidemiological study of diabeticretinopathy XXrdquo Ophthalmology vol 113 no 9 pp 1488ndash1498 2006

[3] N P Blair J Wanek A E Felder et al ldquoRetinal oximetry andvessel diameter measurements with a commercially availablescanning laser ophthalmoscope in diabetic retinopathyrdquo In-vestigative Opthalmology and Visual Science vol 58 no 12pp 5556ndash5563 2017

[4] R A Linsenmeier ldquoEffects of light and darkness on oxygendistribution and consumption in the cat retinardquo Journal ofGeneral Physiology vol 88 no 4 pp 521ndash542 1986

[5] G Birol S Wang E Budzynski N D Wangsa-Wirawan andR A Linsenmeier ldquoOxygen distribution and consumption inthe macaque retinardquo American Journal of Physiology-Heartand Circulatory Physiology vol 293 no 3 pp H1696ndashH17042007

[6] L Wang M Kondo and A Bill ldquoGlucose metabolism in catouter retina Effects of light and hyperoxiardquo InvestigativeOphthalmology and Visual Science vol 38 no 1 pp 48ndash551997

[7] LWang P Tornquist and A Bill ldquoGlucose metabolism in pigouter retina in light and darknessrdquo Acta Physiologica Scan-dinavica vol 160 no 1 pp 75ndash81 1997

[8] C E Riva J E Grunwald and B L Petrig ldquoReactivity of thehuman retinal circulation to darkness a laser Dopplervelocimetry studyrdquo Investigative Ophthalmology and VisualScience vol 24 no 6 pp 737ndash740 1983

[9] U Havelius F Hansen B Hindfelt and T Krakau ldquoHumanocular vasodynamic changes in light and darknessrdquo In-vestigative Ophthalmology and Visual Science vol 40 no 8pp 1850ndash1855 1999

[10] G T Feke R Zuckerman G J Green and J J WeiterldquoResponse of human retinal blood flow to light and darkrdquoInvestigative Ophthalmology and Visual Science vol 24pp 136ndash141 1983

[11] S Jean-Louis J V Lovasik and H Kergoat ldquoSystemichyperoxia and retinal vasomotor responsesrdquo InvestigativeOphthalmology and Visual Science vol 46 no 5 pp 1714ndash1720 2005

[12] G T Dorner G Garhoefer C Zawinka B Kiss andL Schmetterer ldquoResponse of retinal blood flow to CO2-breathing in humansrdquo European Journal of Ophthalmologyvol 12 no 6 pp 459ndash466 2002

[13] K Polak L Schmetterer and C E Riva ldquoInfluence of flickerfrequency on flicker-induced changes of retinal vessel di-ameterrdquo Investigative Ophthalmology and Visual Sciencevol 43 no 8 pp 2721ndash2726 2002

[14] D V Arlotte R L Perrott N Drasdo D R Owens andR V North ldquoe effect of post prandial glucose changes onoscillatory potentials in subjects with type 2 diabetes mellitusrdquoDocumenta Ophthalmologica vol 109 no 1 pp 35ndash42 2004

[15] S K Holfort K Klemp P K Kofoed B Sander andM Larsen ldquoScotopic electrophysiology of the retina duringtransient hyperglycemia in type 2 diabetesrdquo InvestigativeOphthalmology and Visual Science vol 51 no 5 pp 2790ndash2794 2010

[16] S K Holfort G R Jackson and M Larsen ldquoDark adaptationduring transient hyperglycemia in type 2 diabetesrdquo Experi-mental Eye Research vol 91 no 5 pp 710ndash714 2010

[17] K Klemp M Larsen B Sander A Vaag P B Brockhoff andH Lund-Andersen ldquoEffect of short-term hyperglycemia onmultifocal electroretinogram in diabetic patients withoutretinopathyrdquo Investigative Ophthalmology and Visual Sciencevol 45 no 10 pp 3812ndash3819 2004

[18] K Fondi P A Wozniak K Howorka et al ldquoRetinal oxygenextraction in individuals with type 1 diabetes with no or milddiabetic retinopathyrdquo Diabetologia vol 60 no 8 pp 1534ndash1540 2017

[19] V Patel S Rassam R Newsom J Wiek and E KohnerldquoRetinal blood flow in diabetic retinopathyrdquo BMJ vol 305no 6855 pp 678ndash683 1992

[20] M H Cuypers J S Kasanardjo and B C Polak ldquoRetinalblood flow changes in diabetic retinopathy measured with theHeidelberg scanning laser Doppler flowmeterrdquo Graefersquos Ar-chive for Clinical and Experimental Ophthalmology vol 238no 12 pp 935ndash941 2000

[21] A Yoshida G T Feke J Morales-Stoppello G D CollasD G Goger and J W McMeel ldquoRetinal blood flow alter-ations during progression of diabetic retinopathyrdquoArchives ofOphthalmology vol 101 no 2 pp 225ndash227 1983

[22] G E Boynton M S Stem L Kwark G R Jackson S Farsiuand T W Gardner ldquoMultimodal characterization of pro-liferative diabetic retinopathy reveals alterations in outer

Journal of Ophthalmology 5

retinal function and structurerdquoOphthalmology vol 122 no 5pp 957ndash967 2015

[23] N C Taarnhoj M Larsen B Sander et al ldquoHeritability ofretinal vessel diameters and blood pressure a twin studyrdquoInvestigative Opthalmology and Visual Science vol 47 no 8pp 3539ndash3544 2006

[24] B H Jensen T Bram P Kappelgaard et al ldquoVisual functionand retinal vessel diameters during hyperthermia in manrdquoActa Ophthalmologica vol 95 no 7 pp 690ndash696 2017

[25] D Drobnjak I C Munch C Glumer et al ldquoRetinal vesseldiameters and their relationship with cardiovascular risk andall-cause mortality in the inter99 eye study a 15-year follow-uprdquo Journal of Ophthalmology vol 2016 Article ID 61386598 pages 2016

[26] M D Knudtson K E Lee L D Hubbard T Y WongR Klein and B E Klein ldquoRevised formulas for summarizingretinal vessel diametersrdquo Current Eye Research vol 27 no 3pp 143ndash149 2003

[27] L Schmetterer M Muller P Fasching et al ldquoRenal andocular hemodynamic effects of insulinrdquo Diabetes vol 46no 11 pp 1868ndash1874 1997

[28] K Polak S Dallinger E Polska et al ldquoEffects of insulin onretinal and pulsatile choroidal blood flow in humansrdquo Ar-chives of Ophthalmology vol 118 no 1 pp 55ndash59 2000

[29] J E Grunwald C E Riva J Baine and A J Brucker ldquoTotalretinal volumetric blood flow rate in diabetic patients withpoor glycemic controlrdquo Investigative Ophthalmology andVisual Science vol 33 no 2 pp 356ndash363 1992

[30] LWang P Tornquist and A Bill ldquoGlucose metabolism of theinner retina in pigs in darkness and lightrdquo Acta PhysiologicaScandinavica vol 160 no 1 pp 71ndash74 1997

[31] G B Arden ldquoe absence of diabetic retinopathy in patientswith retinitis pigmentosa implications for pathophysiologyand possible treatmentrdquo British Journal of Ophthalmologyvol 85 no 3 pp 366ndash370 2001

[32] G B Arden M K Gunduz A Kurtenbach et al ldquoA pre-liminary trial to determine whether prevention of dark ad-aptation affects the course of early diabetic retinopathyrdquo Eyevol 24 no 7 pp 1149ndash1155 2010

[33] S K Holfort K Norgaard G R Jackson et al ldquoRetinalfunction in relation to improved glycaemic control in type 1diabetesrdquo Diabetologia vol 54 no 7 pp 1853ndash1861 2011

[34] B Sander M Larsen E W Andersen and H Lund-Andersen ldquoImpact of changes in metabolic control on pro-gression to photocoagulation for clinically significant macularoedema a 20 year study of type 1 diabetesrdquo Diabetologiavol 56 no 11 pp 2359ndash2366 2013

[35] M Larsen M Wang and B Sander ldquoOvernight thicknessvariation in diabetic macular edemardquo Investigative Opthal-mology and Visual Science vol 46 no 7 pp 2313ndash2316 2005

[36] R N Frank L Schulz K Abe and R Iezzi ldquoTemporalvariation in diabetic macular edema measured by opticalcoherence tomographyrdquo Ophthalmology vol 111 no 2pp 211ndash217 2004

6 Journal of Ophthalmology

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom

4 Discussion

is experimental study of retinal vessel diameter variationduring acute hyperglycemia and dark adaptation in patientswith type 2 diabetes found that both dark adaptation and lowlevels of glycemia were associated with wider retinal vesseldiameters e combined assessment of the two factors wasmade possible by infrared digital fundus photographywhich does not disturb dark adaptation

A tentative explanation is that dark adaptation leads tovessel dilation because oxygen tension in the retina is lower inthe dark-adapted state than in daylight and that hypoglycemialeads to vessel dilation because it reduces the energy substratesupply to the retina Presumably but not actually documentedby our experiments vasodilation compensates for energydeficits secondary to hypoxia and hypoglycemia by increasingblood flow and substrate supply to the retina e underlyingmechanisms may obviously be complicated if extraocularresponses are elicited by changes in glycemia us plasmainsulin which should change during the glucose tolerancetest was not measured in this study but given that the pa-tients had type 2 diabetes they will have varying levels ofresidual insulin production and insulin sensitivity Insulin isgenerally considered to have vasodilator effects [27] so ifplasma insulin influenced the study it likely acted to limit thevasoconstrictive effect of hyperglycemia by the endogenouspostprandial rise in insulin secretion [27 28]

Our assumptions are supported by the demonstration byGrunwald et al that retinal vasodilation is associated withincreased retinal blood flow [29] and that dark adaptationincreases retinal volumetric blood flow in healthy subjects by62ndash71 [8]

Retinal vasodilation during dark adaptation is consistentwith dark adaptation inducing an increase in metabolic

activity of the retina [7 30] Increased metabolism mayhypothetically promote the progression of diabetic reti-nopathy [31 32] because accompanying vasodilation andhyperperfusion lead to increased shear stress on the vascularendothelium Relative hypoglycemia by inducing vasodi-lation may have a comparable effect is may help explainwhy improved metabolic control in diabetes can lead toshort-term acceleration of retinopathy progression despiteits long-term benefits [33 34] Finally our findings supportthe suggestion that nocturnal vasodilation may explain whydiabetic macular edema tends to be more pronounced in themorning than later in the day [35 36]

e vasoconstricting effect of hyperglycemia may hy-pothetically be driven by the ability of the retina to balanceits metabolic needs by increasing glycolysis and lactateproduction while decreasing oxidative phosphorylation andCO2 production [12] e present study provides in-formation only about the net result however and not aboutits constituent components

Limitations of this study include the lack of inclusion ofa group of healthy subjects is might determine whetherthe characteristics in diabetes are an extension of normalphysiology induced by abnormally high postprandial rises inblood glucose in diabetes or whether the physiologicalcharacteristics or the retina has been adjusted rearranged ordisrupted by elevated and unstable glycemia or other aspectsof diabetes Additionally a larger study population mighthave enabled analysis of the relation of vessel diameterchanges to age blood pressure HbA1c and other variables ofinterest It should be noted that our results were obtained bysummarizing observations from a group of patients Wehave not shown that neither qualitative nor numerical re-sponses can be used to define any clinically relevant char-acteristics of patients with diabetes

Table 2 Fasting and hyperglycemic retinal vessel diameters in patients with type 2 diabetes

Patient

Fasting HyperglycemiaLight Dark adaptation Light Dark adaptation0min 20min 40min 0min 20min 40min

CRAE CRVE CRAE CRVE CRAE CRVE CRAE CRVE CRAE CRVE CRAE CRVE1 1910 2570 1894 2657 1897 2713 1812 2498 1898 2746 1942 26922 1750 2222 1768 2314 1709 2257 1695 2196 1716 2272 1688 22503 1817 2343 1825 2397 1917 2536 1868 2390 1903 2564 1892 25574 1603 2208 1662 2322 1624 2358 1547 2221 1631 2304 1627 22765 1765 2456 1766 2457 1774 2522 1767 2480 1766 2473 1806 24606 1697 2460 1732 2483 1749 2641 1692 2484 1733 2645 1735 26377 1507 1897 1531 2034 1537 1990 1475 1844 1542 1968 1515 19548 1785 2255 1786 2259 1735 2263 1749 2207 1806 2212 1783 22089 1428 2067 1450 2064 1443 2058 1410 1991 1407 1945 1397 196310 1902 2500 1878 2486 1842 2433 1841 2444 1827 2385 1811 234711 1537 2141 1551 2176 1543 2174 1558 2167 1549 2155 1572 217612 1858 2456 1817 2394 1806 2402 1774 2305 1825 2370 1817 235513 1679 1926 1710 1943 1700 1973 1653 1951 1686 1922 1640 192314 1666 2272 1727 2428 1686 2388 1673 2258 1700 2340 1689 2287MEAN 1707 2270 1721 2315 1712 2336 1680 2245 1714 2307 1708 2292SD 148 210 132 210 138 231 138 208 143 254 150 243AVR 075 074 073 075 074 075All values are in microm CRAE central retinal artery equivalent CRVE central retinal vein equivalent

4 Journal of Ophthalmology

In summary this study of patients with type 2 diabetesfound that dark adaptation was accompanied by retinalvasodilation both during normoglycemia and hyperglyce-mia Furthermore the retinal vessels were dilated duringnormoglycemia compared to postprandial hyperglycemiae study supports that the occasional flare-up of diabeticretinopathy after rapidly introduced and strictly maintainedrelative hypoglycemia [33 34] may be precipitated by retinalvasodilation and that rod photoreceptor activation maypromote worsening of diabetic retinopathy [32] Our in-terpretations can be tested in studies that include assessmentof perfusion rates and oxygenation preferably with enoughparticipants and a long enough period of observation todetermine if individual vessel diameter responses can predictretinopathy progression

Data Availability

All data relevant to presented results and conclusions areincluded in the manuscript

Conflicts of Interest

e authors declare no conflicts of interest in relation to thepresent paper

Acknowledgments

e study was supported by the Danish Agency for ScienceTechnology and Innovation (Grant no 10-080573) and bythe Novo Nordisk Foundation

References

[1] R Broe M L Rasmussen U Frydkjaer-Olsen et al ldquoRetinalvessel calibers predict long-term microvascular complicationsin type 1 diabetes the Danish Cohort of Pediatric Diabetes1987 (DCPD1987)rdquo Diabetes vol 63 no 11 pp 3906ndash39142014

[2] R Klein B E Klein S E Moss T Y Wong andA R Sharrett ldquoRetinal vascular caliber in persons with type 2diabetes the wisconsin epidemiological study of diabeticretinopathy XXrdquo Ophthalmology vol 113 no 9 pp 1488ndash1498 2006

[3] N P Blair J Wanek A E Felder et al ldquoRetinal oximetry andvessel diameter measurements with a commercially availablescanning laser ophthalmoscope in diabetic retinopathyrdquo In-vestigative Opthalmology and Visual Science vol 58 no 12pp 5556ndash5563 2017

[4] R A Linsenmeier ldquoEffects of light and darkness on oxygendistribution and consumption in the cat retinardquo Journal ofGeneral Physiology vol 88 no 4 pp 521ndash542 1986

[5] G Birol S Wang E Budzynski N D Wangsa-Wirawan andR A Linsenmeier ldquoOxygen distribution and consumption inthe macaque retinardquo American Journal of Physiology-Heartand Circulatory Physiology vol 293 no 3 pp H1696ndashH17042007

[6] L Wang M Kondo and A Bill ldquoGlucose metabolism in catouter retina Effects of light and hyperoxiardquo InvestigativeOphthalmology and Visual Science vol 38 no 1 pp 48ndash551997

[7] LWang P Tornquist and A Bill ldquoGlucose metabolism in pigouter retina in light and darknessrdquo Acta Physiologica Scan-dinavica vol 160 no 1 pp 75ndash81 1997

[8] C E Riva J E Grunwald and B L Petrig ldquoReactivity of thehuman retinal circulation to darkness a laser Dopplervelocimetry studyrdquo Investigative Ophthalmology and VisualScience vol 24 no 6 pp 737ndash740 1983

[9] U Havelius F Hansen B Hindfelt and T Krakau ldquoHumanocular vasodynamic changes in light and darknessrdquo In-vestigative Ophthalmology and Visual Science vol 40 no 8pp 1850ndash1855 1999

[10] G T Feke R Zuckerman G J Green and J J WeiterldquoResponse of human retinal blood flow to light and darkrdquoInvestigative Ophthalmology and Visual Science vol 24pp 136ndash141 1983

[11] S Jean-Louis J V Lovasik and H Kergoat ldquoSystemichyperoxia and retinal vasomotor responsesrdquo InvestigativeOphthalmology and Visual Science vol 46 no 5 pp 1714ndash1720 2005

[12] G T Dorner G Garhoefer C Zawinka B Kiss andL Schmetterer ldquoResponse of retinal blood flow to CO2-breathing in humansrdquo European Journal of Ophthalmologyvol 12 no 6 pp 459ndash466 2002

[13] K Polak L Schmetterer and C E Riva ldquoInfluence of flickerfrequency on flicker-induced changes of retinal vessel di-ameterrdquo Investigative Ophthalmology and Visual Sciencevol 43 no 8 pp 2721ndash2726 2002

[14] D V Arlotte R L Perrott N Drasdo D R Owens andR V North ldquoe effect of post prandial glucose changes onoscillatory potentials in subjects with type 2 diabetes mellitusrdquoDocumenta Ophthalmologica vol 109 no 1 pp 35ndash42 2004

[15] S K Holfort K Klemp P K Kofoed B Sander andM Larsen ldquoScotopic electrophysiology of the retina duringtransient hyperglycemia in type 2 diabetesrdquo InvestigativeOphthalmology and Visual Science vol 51 no 5 pp 2790ndash2794 2010

[16] S K Holfort G R Jackson and M Larsen ldquoDark adaptationduring transient hyperglycemia in type 2 diabetesrdquo Experi-mental Eye Research vol 91 no 5 pp 710ndash714 2010

[17] K Klemp M Larsen B Sander A Vaag P B Brockhoff andH Lund-Andersen ldquoEffect of short-term hyperglycemia onmultifocal electroretinogram in diabetic patients withoutretinopathyrdquo Investigative Ophthalmology and Visual Sciencevol 45 no 10 pp 3812ndash3819 2004

[18] K Fondi P A Wozniak K Howorka et al ldquoRetinal oxygenextraction in individuals with type 1 diabetes with no or milddiabetic retinopathyrdquo Diabetologia vol 60 no 8 pp 1534ndash1540 2017

[19] V Patel S Rassam R Newsom J Wiek and E KohnerldquoRetinal blood flow in diabetic retinopathyrdquo BMJ vol 305no 6855 pp 678ndash683 1992

[20] M H Cuypers J S Kasanardjo and B C Polak ldquoRetinalblood flow changes in diabetic retinopathy measured with theHeidelberg scanning laser Doppler flowmeterrdquo Graefersquos Ar-chive for Clinical and Experimental Ophthalmology vol 238no 12 pp 935ndash941 2000

[21] A Yoshida G T Feke J Morales-Stoppello G D CollasD G Goger and J W McMeel ldquoRetinal blood flow alter-ations during progression of diabetic retinopathyrdquoArchives ofOphthalmology vol 101 no 2 pp 225ndash227 1983

[22] G E Boynton M S Stem L Kwark G R Jackson S Farsiuand T W Gardner ldquoMultimodal characterization of pro-liferative diabetic retinopathy reveals alterations in outer

Journal of Ophthalmology 5

retinal function and structurerdquoOphthalmology vol 122 no 5pp 957ndash967 2015

[23] N C Taarnhoj M Larsen B Sander et al ldquoHeritability ofretinal vessel diameters and blood pressure a twin studyrdquoInvestigative Opthalmology and Visual Science vol 47 no 8pp 3539ndash3544 2006

[24] B H Jensen T Bram P Kappelgaard et al ldquoVisual functionand retinal vessel diameters during hyperthermia in manrdquoActa Ophthalmologica vol 95 no 7 pp 690ndash696 2017

[25] D Drobnjak I C Munch C Glumer et al ldquoRetinal vesseldiameters and their relationship with cardiovascular risk andall-cause mortality in the inter99 eye study a 15-year follow-uprdquo Journal of Ophthalmology vol 2016 Article ID 61386598 pages 2016

[26] M D Knudtson K E Lee L D Hubbard T Y WongR Klein and B E Klein ldquoRevised formulas for summarizingretinal vessel diametersrdquo Current Eye Research vol 27 no 3pp 143ndash149 2003

[27] L Schmetterer M Muller P Fasching et al ldquoRenal andocular hemodynamic effects of insulinrdquo Diabetes vol 46no 11 pp 1868ndash1874 1997

[28] K Polak S Dallinger E Polska et al ldquoEffects of insulin onretinal and pulsatile choroidal blood flow in humansrdquo Ar-chives of Ophthalmology vol 118 no 1 pp 55ndash59 2000

[29] J E Grunwald C E Riva J Baine and A J Brucker ldquoTotalretinal volumetric blood flow rate in diabetic patients withpoor glycemic controlrdquo Investigative Ophthalmology andVisual Science vol 33 no 2 pp 356ndash363 1992

[30] LWang P Tornquist and A Bill ldquoGlucose metabolism of theinner retina in pigs in darkness and lightrdquo Acta PhysiologicaScandinavica vol 160 no 1 pp 71ndash74 1997

[31] G B Arden ldquoe absence of diabetic retinopathy in patientswith retinitis pigmentosa implications for pathophysiologyand possible treatmentrdquo British Journal of Ophthalmologyvol 85 no 3 pp 366ndash370 2001

[32] G B Arden M K Gunduz A Kurtenbach et al ldquoA pre-liminary trial to determine whether prevention of dark ad-aptation affects the course of early diabetic retinopathyrdquo Eyevol 24 no 7 pp 1149ndash1155 2010

[33] S K Holfort K Norgaard G R Jackson et al ldquoRetinalfunction in relation to improved glycaemic control in type 1diabetesrdquo Diabetologia vol 54 no 7 pp 1853ndash1861 2011

[34] B Sander M Larsen E W Andersen and H Lund-Andersen ldquoImpact of changes in metabolic control on pro-gression to photocoagulation for clinically significant macularoedema a 20 year study of type 1 diabetesrdquo Diabetologiavol 56 no 11 pp 2359ndash2366 2013

[35] M Larsen M Wang and B Sander ldquoOvernight thicknessvariation in diabetic macular edemardquo Investigative Opthal-mology and Visual Science vol 46 no 7 pp 2313ndash2316 2005

[36] R N Frank L Schulz K Abe and R Iezzi ldquoTemporalvariation in diabetic macular edema measured by opticalcoherence tomographyrdquo Ophthalmology vol 111 no 2pp 211ndash217 2004

6 Journal of Ophthalmology

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom

In summary this study of patients with type 2 diabetesfound that dark adaptation was accompanied by retinalvasodilation both during normoglycemia and hyperglyce-mia Furthermore the retinal vessels were dilated duringnormoglycemia compared to postprandial hyperglycemiae study supports that the occasional flare-up of diabeticretinopathy after rapidly introduced and strictly maintainedrelative hypoglycemia [33 34] may be precipitated by retinalvasodilation and that rod photoreceptor activation maypromote worsening of diabetic retinopathy [32] Our in-terpretations can be tested in studies that include assessmentof perfusion rates and oxygenation preferably with enoughparticipants and a long enough period of observation todetermine if individual vessel diameter responses can predictretinopathy progression

Data Availability

All data relevant to presented results and conclusions areincluded in the manuscript

Conflicts of Interest

e authors declare no conflicts of interest in relation to thepresent paper

Acknowledgments

e study was supported by the Danish Agency for ScienceTechnology and Innovation (Grant no 10-080573) and bythe Novo Nordisk Foundation

References

[1] R Broe M L Rasmussen U Frydkjaer-Olsen et al ldquoRetinalvessel calibers predict long-term microvascular complicationsin type 1 diabetes the Danish Cohort of Pediatric Diabetes1987 (DCPD1987)rdquo Diabetes vol 63 no 11 pp 3906ndash39142014

[2] R Klein B E Klein S E Moss T Y Wong andA R Sharrett ldquoRetinal vascular caliber in persons with type 2diabetes the wisconsin epidemiological study of diabeticretinopathy XXrdquo Ophthalmology vol 113 no 9 pp 1488ndash1498 2006

[3] N P Blair J Wanek A E Felder et al ldquoRetinal oximetry andvessel diameter measurements with a commercially availablescanning laser ophthalmoscope in diabetic retinopathyrdquo In-vestigative Opthalmology and Visual Science vol 58 no 12pp 5556ndash5563 2017

[4] R A Linsenmeier ldquoEffects of light and darkness on oxygendistribution and consumption in the cat retinardquo Journal ofGeneral Physiology vol 88 no 4 pp 521ndash542 1986

[5] G Birol S Wang E Budzynski N D Wangsa-Wirawan andR A Linsenmeier ldquoOxygen distribution and consumption inthe macaque retinardquo American Journal of Physiology-Heartand Circulatory Physiology vol 293 no 3 pp H1696ndashH17042007

[6] L Wang M Kondo and A Bill ldquoGlucose metabolism in catouter retina Effects of light and hyperoxiardquo InvestigativeOphthalmology and Visual Science vol 38 no 1 pp 48ndash551997

[7] LWang P Tornquist and A Bill ldquoGlucose metabolism in pigouter retina in light and darknessrdquo Acta Physiologica Scan-dinavica vol 160 no 1 pp 75ndash81 1997

[8] C E Riva J E Grunwald and B L Petrig ldquoReactivity of thehuman retinal circulation to darkness a laser Dopplervelocimetry studyrdquo Investigative Ophthalmology and VisualScience vol 24 no 6 pp 737ndash740 1983

[9] U Havelius F Hansen B Hindfelt and T Krakau ldquoHumanocular vasodynamic changes in light and darknessrdquo In-vestigative Ophthalmology and Visual Science vol 40 no 8pp 1850ndash1855 1999

[10] G T Feke R Zuckerman G J Green and J J WeiterldquoResponse of human retinal blood flow to light and darkrdquoInvestigative Ophthalmology and Visual Science vol 24pp 136ndash141 1983

[11] S Jean-Louis J V Lovasik and H Kergoat ldquoSystemichyperoxia and retinal vasomotor responsesrdquo InvestigativeOphthalmology and Visual Science vol 46 no 5 pp 1714ndash1720 2005

[12] G T Dorner G Garhoefer C Zawinka B Kiss andL Schmetterer ldquoResponse of retinal blood flow to CO2-breathing in humansrdquo European Journal of Ophthalmologyvol 12 no 6 pp 459ndash466 2002

[13] K Polak L Schmetterer and C E Riva ldquoInfluence of flickerfrequency on flicker-induced changes of retinal vessel di-ameterrdquo Investigative Ophthalmology and Visual Sciencevol 43 no 8 pp 2721ndash2726 2002

[14] D V Arlotte R L Perrott N Drasdo D R Owens andR V North ldquoe effect of post prandial glucose changes onoscillatory potentials in subjects with type 2 diabetes mellitusrdquoDocumenta Ophthalmologica vol 109 no 1 pp 35ndash42 2004

[15] S K Holfort K Klemp P K Kofoed B Sander andM Larsen ldquoScotopic electrophysiology of the retina duringtransient hyperglycemia in type 2 diabetesrdquo InvestigativeOphthalmology and Visual Science vol 51 no 5 pp 2790ndash2794 2010

[16] S K Holfort G R Jackson and M Larsen ldquoDark adaptationduring transient hyperglycemia in type 2 diabetesrdquo Experi-mental Eye Research vol 91 no 5 pp 710ndash714 2010

[17] K Klemp M Larsen B Sander A Vaag P B Brockhoff andH Lund-Andersen ldquoEffect of short-term hyperglycemia onmultifocal electroretinogram in diabetic patients withoutretinopathyrdquo Investigative Ophthalmology and Visual Sciencevol 45 no 10 pp 3812ndash3819 2004

[18] K Fondi P A Wozniak K Howorka et al ldquoRetinal oxygenextraction in individuals with type 1 diabetes with no or milddiabetic retinopathyrdquo Diabetologia vol 60 no 8 pp 1534ndash1540 2017

[19] V Patel S Rassam R Newsom J Wiek and E KohnerldquoRetinal blood flow in diabetic retinopathyrdquo BMJ vol 305no 6855 pp 678ndash683 1992

[20] M H Cuypers J S Kasanardjo and B C Polak ldquoRetinalblood flow changes in diabetic retinopathy measured with theHeidelberg scanning laser Doppler flowmeterrdquo Graefersquos Ar-chive for Clinical and Experimental Ophthalmology vol 238no 12 pp 935ndash941 2000

[21] A Yoshida G T Feke J Morales-Stoppello G D CollasD G Goger and J W McMeel ldquoRetinal blood flow alter-ations during progression of diabetic retinopathyrdquoArchives ofOphthalmology vol 101 no 2 pp 225ndash227 1983

[22] G E Boynton M S Stem L Kwark G R Jackson S Farsiuand T W Gardner ldquoMultimodal characterization of pro-liferative diabetic retinopathy reveals alterations in outer

Journal of Ophthalmology 5

retinal function and structurerdquoOphthalmology vol 122 no 5pp 957ndash967 2015

[23] N C Taarnhoj M Larsen B Sander et al ldquoHeritability ofretinal vessel diameters and blood pressure a twin studyrdquoInvestigative Opthalmology and Visual Science vol 47 no 8pp 3539ndash3544 2006

[24] B H Jensen T Bram P Kappelgaard et al ldquoVisual functionand retinal vessel diameters during hyperthermia in manrdquoActa Ophthalmologica vol 95 no 7 pp 690ndash696 2017

[25] D Drobnjak I C Munch C Glumer et al ldquoRetinal vesseldiameters and their relationship with cardiovascular risk andall-cause mortality in the inter99 eye study a 15-year follow-uprdquo Journal of Ophthalmology vol 2016 Article ID 61386598 pages 2016

[26] M D Knudtson K E Lee L D Hubbard T Y WongR Klein and B E Klein ldquoRevised formulas for summarizingretinal vessel diametersrdquo Current Eye Research vol 27 no 3pp 143ndash149 2003

[27] L Schmetterer M Muller P Fasching et al ldquoRenal andocular hemodynamic effects of insulinrdquo Diabetes vol 46no 11 pp 1868ndash1874 1997

[28] K Polak S Dallinger E Polska et al ldquoEffects of insulin onretinal and pulsatile choroidal blood flow in humansrdquo Ar-chives of Ophthalmology vol 118 no 1 pp 55ndash59 2000

[29] J E Grunwald C E Riva J Baine and A J Brucker ldquoTotalretinal volumetric blood flow rate in diabetic patients withpoor glycemic controlrdquo Investigative Ophthalmology andVisual Science vol 33 no 2 pp 356ndash363 1992

[30] LWang P Tornquist and A Bill ldquoGlucose metabolism of theinner retina in pigs in darkness and lightrdquo Acta PhysiologicaScandinavica vol 160 no 1 pp 71ndash74 1997

[31] G B Arden ldquoe absence of diabetic retinopathy in patientswith retinitis pigmentosa implications for pathophysiologyand possible treatmentrdquo British Journal of Ophthalmologyvol 85 no 3 pp 366ndash370 2001

[32] G B Arden M K Gunduz A Kurtenbach et al ldquoA pre-liminary trial to determine whether prevention of dark ad-aptation affects the course of early diabetic retinopathyrdquo Eyevol 24 no 7 pp 1149ndash1155 2010

[33] S K Holfort K Norgaard G R Jackson et al ldquoRetinalfunction in relation to improved glycaemic control in type 1diabetesrdquo Diabetologia vol 54 no 7 pp 1853ndash1861 2011

[34] B Sander M Larsen E W Andersen and H Lund-Andersen ldquoImpact of changes in metabolic control on pro-gression to photocoagulation for clinically significant macularoedema a 20 year study of type 1 diabetesrdquo Diabetologiavol 56 no 11 pp 2359ndash2366 2013

[35] M Larsen M Wang and B Sander ldquoOvernight thicknessvariation in diabetic macular edemardquo Investigative Opthal-mology and Visual Science vol 46 no 7 pp 2313ndash2316 2005

[36] R N Frank L Schulz K Abe and R Iezzi ldquoTemporalvariation in diabetic macular edema measured by opticalcoherence tomographyrdquo Ophthalmology vol 111 no 2pp 211ndash217 2004

6 Journal of Ophthalmology

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom

retinal function and structurerdquoOphthalmology vol 122 no 5pp 957ndash967 2015

[23] N C Taarnhoj M Larsen B Sander et al ldquoHeritability ofretinal vessel diameters and blood pressure a twin studyrdquoInvestigative Opthalmology and Visual Science vol 47 no 8pp 3539ndash3544 2006

[24] B H Jensen T Bram P Kappelgaard et al ldquoVisual functionand retinal vessel diameters during hyperthermia in manrdquoActa Ophthalmologica vol 95 no 7 pp 690ndash696 2017

[25] D Drobnjak I C Munch C Glumer et al ldquoRetinal vesseldiameters and their relationship with cardiovascular risk andall-cause mortality in the inter99 eye study a 15-year follow-uprdquo Journal of Ophthalmology vol 2016 Article ID 61386598 pages 2016

[26] M D Knudtson K E Lee L D Hubbard T Y WongR Klein and B E Klein ldquoRevised formulas for summarizingretinal vessel diametersrdquo Current Eye Research vol 27 no 3pp 143ndash149 2003

[27] L Schmetterer M Muller P Fasching et al ldquoRenal andocular hemodynamic effects of insulinrdquo Diabetes vol 46no 11 pp 1868ndash1874 1997

[28] K Polak S Dallinger E Polska et al ldquoEffects of insulin onretinal and pulsatile choroidal blood flow in humansrdquo Ar-chives of Ophthalmology vol 118 no 1 pp 55ndash59 2000

[29] J E Grunwald C E Riva J Baine and A J Brucker ldquoTotalretinal volumetric blood flow rate in diabetic patients withpoor glycemic controlrdquo Investigative Ophthalmology andVisual Science vol 33 no 2 pp 356ndash363 1992

[30] LWang P Tornquist and A Bill ldquoGlucose metabolism of theinner retina in pigs in darkness and lightrdquo Acta PhysiologicaScandinavica vol 160 no 1 pp 71ndash74 1997

[31] G B Arden ldquoe absence of diabetic retinopathy in patientswith retinitis pigmentosa implications for pathophysiologyand possible treatmentrdquo British Journal of Ophthalmologyvol 85 no 3 pp 366ndash370 2001

[32] G B Arden M K Gunduz A Kurtenbach et al ldquoA pre-liminary trial to determine whether prevention of dark ad-aptation affects the course of early diabetic retinopathyrdquo Eyevol 24 no 7 pp 1149ndash1155 2010

[33] S K Holfort K Norgaard G R Jackson et al ldquoRetinalfunction in relation to improved glycaemic control in type 1diabetesrdquo Diabetologia vol 54 no 7 pp 1853ndash1861 2011

[34] B Sander M Larsen E W Andersen and H Lund-Andersen ldquoImpact of changes in metabolic control on pro-gression to photocoagulation for clinically significant macularoedema a 20 year study of type 1 diabetesrdquo Diabetologiavol 56 no 11 pp 2359ndash2366 2013

[35] M Larsen M Wang and B Sander ldquoOvernight thicknessvariation in diabetic macular edemardquo Investigative Opthal-mology and Visual Science vol 46 no 7 pp 2313ndash2316 2005

[36] R N Frank L Schulz K Abe and R Iezzi ldquoTemporalvariation in diabetic macular edema measured by opticalcoherence tomographyrdquo Ophthalmology vol 111 no 2pp 211ndash217 2004

6 Journal of Ophthalmology

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom