19th Meeting of the European Association for the Study of Diabetes Eye Complications Study Group (EASDec)

Oxford, UK  22nd -24th May 2009



UM. Steckelings, A. Reichenbach, K. Ströder, M. Kummert, K. Schwengel, C. Thöne-Reineke, T. Unger
Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Berlin - Germany

PURPOSE. This study analysed the effect of pharmacological interference with the renin-angiotensin-system by either AT1-receptor (AT1R) blockade with Candesartan or by AT2-receptor (AT2R) stimulation with the novel non-peptide AT2R-agonist, Compound 21 (C21) on diabetic retinopathy in hypertensive rats.
METHODS. Animals rendered diabetic by streptozotocin (i.v.) were treated orally for 8 weeks according to the following protocol: 1) non-diabetic controls (CON); 2) diabetic controls (STZ); 3) STZ+ blood-pressure (BP) lowering dose of Candesartan (7,5mg/kg BW/d) (STZ+Cand7,5); 4) STZ+ non-BP-lowering dose of Candesartan (0.2mg/kg BW/d) (STZ+Cand0,2); 5) STZ+C21 (0.3mg/kg BW/d); 6) STZ+Cand7,5+C21. BP was measured every second week. Retinas were analysed for mRNA levels of neurotrophins and apoptosis markers.

RESULTS. Systolic BP was lowered in the STZ+Can7,5 (168,5±20mmHg), and the STZ+Cand7,5+C21 (145±35mmHg) groups, but not in the STZ+Cand0,2 (197,5±15mmHg) and, remarkably, not by AT2R-stimulation in the STZ+C21 (191±38mmHg) group. AT2R-stimulation and AT1R-blockade significantly increased neurotrophin (BDNF) and neurotrophin receptor (TrkB) expression. The apoptotic markers Caspase-3 and BAX/Bcl2 ratio were significantly decreased by both treatment strategies. AT1R-blockade and AT2R-stimulation acted tissue protective independent of BP reduction.
CONCLUSIONS. We conclude that pharmacological intervention with the RAS by AT1-receptor blockade or AT2-receptor stimulation ameliorates experimental diabetic retinopathy acting tissue-protective and anti-apoptotic in a BP-independent way. Our results provide a potential molecular mechanism for the reduced incidence in diabetic retinopathy in normotensive type-1 diabetic patients by Candesartan treatment observed in the recently published DIRECT study.


N. Ding3, L.A. Pérez-Jurado1, A. Antonell1, T.L. Leto2, E.M. Kohner3, R. Chibber3

1Universitat Pompeu Fabra, Barcelona – Spain
2Laboratory of Host Defenses, Rockville, MD
3Peninsula College of Medicine and Dentistry, Exeter - UK

PURPOSE. To explore NADPH oxidase signalling pathway in tumour necrosis factor-alpha (TNF-α)-induced activity of core 2 GlcNAc-T (Ben-Mahmud et al., 2006) in diabetic leukocytes.

METHODS. Human leukocytes (U937 cells) and Epstein-Barr–transformed lymphoblastoid cell lines with different gene copies of p47phox (major subunit of NADPH oxidase) were cultured in RPMI medium containing normal (5.6mM) glucose and used for the study. Cells were exposed to TNF-α (8pg/ml) for 24h in the presence and absence of (i) NADPH oxidase inhibitors (30µM apocynin and 1µM scrambled and unscrambled gp91ds-tat), (ii) LY379196 (specific PKCβ1/2 inhibitor, 50nM) and (iii) antioxidants N-acetyl cysteine (NAC, 15mM) and Tiron (5mM). NADPH oxidase activity was measured using cytochrome c reduction assay. PKCβ1/2 activity was measured using TruLight™ PKC- β1/2 assay kit.

RESULTS. Compared to control medium, exposure to TNF-α raised core 2 GlcNAc-T activity in human leukocytes [1722±255.3(n=10)vs.374±80.3(n=10), P<0.0001] that was significantly reversed with apocynin and LY379196. These findings were supported using gp91ds-tat (scrambled and unscrambled), a specific NADPH oxidase inhibitor, and lymphoblastoid cell-line deficient in p47phox, and reversal with NAC and Tiron.

CONCLUSIONS. Our results demonstrate a novel signalling crosstalk between TNF-α, core 2 GlcNAc-T, NADPH oxidase and PKCβ1/2 in diabetic leukocytes.


T. Bek, P. S. Jensen, P. Jeppesen

Århus University Hospital, Århus - Denmark

PURPOSE. We therefore compared the diameter response of macular and peripheral arterioles in diabetic patients with maculopathy (D-MAC) or proliferative retinopathy (PDR) after an increase in the arterial blood pressure induced by isometric exercise.

METHODS. Twenty-four diabetic patients (mean age 49.8 years, range 31-75 years) were examined of which seventeen had D-MAC and seven had PDR. Using a Retinal Vessel Analyzer (RVA) the diameter response of a macular and a peripheral arteriole located within four disk diameters of the optic disk was recorded in each person before and after increasing the blood pressure by lifting a 2 kg hand weight.

RESULTS. There was no significant difference between the baseline diameter of the studied macular (97.3±2.4) and peripheral (93.7±3.0) arterioles (p=0.34). Lifting the hand weight increased the arterial blood pressure by 27.1±3.8 mmHg (D-MAC) and 18.7±6.1 mmHg (PDR). The increased blood pressure induced no significant change in the diameter of macular arterioles in neither D-MAC patients (-0.09%±0.76%, p=0.97), nor in PDR patients (-0.96%±2.4%, p=0.72). However, the diameter of the peripheral arterioles decreased significantly in D-MAC patients (-1.96±0.68%, p=0.01) and increased non-significantly in PDR patients (+4.00±2.33) (p=0.20).

CONCLUSIONS. Autoregulation in arterioles supplying the retinal periphery differs among diabetic patients with maculopathy and patients with proliferative retinopathy. The findings may help explain the different responses in the macular area and the retinal periphery in the two retinopathy complications.


E. Beltramo, E. Berrone, S. Tarallo, M. Porta

University of Turin, Torino – Italy

PURPOSE. Our aim was to verify if thiamine and benfotiamine are able to counter intermittent high glucose-induced damage in HRP.

METHODS. Wild-type and immortalized pericytes were kept intermittently at 48h intervals in high/normal glucose for 8 days, with or without the addition of 50 or 100 µmol/l thiamine or benfotiamine. Control cells were cultured in stable physiological or high glucose for the whole period. DNA fragmentation, Bcl-2 and Bax mRNA expression and protein concentration, as markers of glucose-induced apoptosis, were determined.

RESULTS. Intermittent, but not stable, exposure to high glucose increased apoptosis in both types of HRP. Thiamine and benfotiamine were able to counter this damaging effect, when added to intermittent high glucose samples. Bcl-2/Bax expression/concentration results were consistent with DNA fragmentation.

CONCLUSIONS. The hypothesis that daily blood glucose fluctuations play a major role in the development of diabetic retinopathy is reinforced by the confirmation that apoptosis in human pericytes is increased following intermittent high glucose exposure only. Thiamine and benfotiamine are able to prevent pericyte apoptosis, suggesting once again that this vitamin could be an inexpensive approach to the prevention and/or treatment of diabetic vascular complications.


R.J. van Geest, I. Klaassen, I.M.C. Vogels, C.J.F. van Noorden, R.O. Schlingemann

Academic Medical Center, Amsterdam - The Netherlands

PURPOSE. Our aim is to investigate TGF-beta signalling in retinal vascular cells.

METHODS. Bovine retinal endothelial cells (BRECs) and pericytes (BRPCs) were stimulated with different concentrations of TGF-beta with or without a specific TGF-beta type I receptor-inhibitor, SD-208. To determine TGF-beta-signalling activity, western blotting was used to detect phosphorylated Smad2 protein at different time points. Qualitative RT-PCR was performed to compare gene expression levels of TGF-beta receptors and determine the effect of TGF-beta on pro-fibrotic gene expression (PAI-1, fibronectin and CTGF) in endothelial cells and pericytes.

RESULTS. ALK5 was equally expressed in both cell types, whereas endoglin and TGF-beta receptor-II were preferentially expressed in BRECs. ALK1 was expressed in BRECs only. In BRECs, TGF-beta dose-dependently induced phospho-Smad2 protein, which was efficiently blocked by SD-208. In contrast, in pericytes, TGF-beta induced phospho-Smad2 protein already at low concentration which could be blocked by SD-208. TGF-beta caused up-regulation of downstream pro-fibrotic genes PAI-1 and fibronectin in both cell types, which was prevented by SD-208. However, CTGF mRNA expression was only induced by TGF-beta and inhibited by SD-208 in BRPCs.

CONCLUSIONS. TGF-beta induces Smad2-phosphorylation in bovine retinal vascular cells through the TGF-beta type I receptor, especially in pericytes, which leads to increased expression of pro-fibrotic genes. This suggests that the pro-fibrotic gene expression observed in DR may be caused by TGF-beta, which may serve as an intervention target.


C. Lobo1,2,3, I. Pires1,2, S. Nunes2, L. Ribeiro2, I. Pereira2, R. Bernardes2,3, J. Cunha-Vaz2,3

1Coimbra University Hospital, Coimbra – Portugal
2Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra – Portugal
3Institute of Biomedical Research on Light and Image (IBILI), Faculty of
Medicine, University of Coimbra, Coimbra - Portugal.

PURPOSE. To examine the relation between microaneurysms (MA) formation rate using a new semi-automatic method based on colour fundus photographs, and DR progression.

METHODS. Ninety-five patients/eyes with type 2 diabetes and nonproliferative retinopathy were followed-up for 2 years with ophthalmological examinations every 6 months, including stereoscopic colour fundus photography and were maintained under good metabolic control. All patients were followed-up for the next 8 years by conventional general and ophthalmological care accomplishing a total follow-up of 10 years. Photocoagulation for CSME was considered the study main end-point. Using a new semi-automatic method for MA earmarking, which takes into account the exact location of each MA, the MA formation rate for the 2 first years of follow-up was computed (number of new MA appearing per year).

RESULTS. At the end of the 10-year period of follow-up, 16 of the 95 patients had developed CSME needing photocoagulation. A MA formation rate of 8.01±0.0 MA/year (Mean±SD) was found in these 16 patients' eyes, being it statistically higher than for patients' eyes that did not develop CSME (mean±SD: 1.8±2.3) (p=0.003).

CONCLUSIONS. A high MA formation rate earmarked on colour fundus photographs appears to be a good predictor of DR progression to CSME needing photocoagulation in type 2 diabetic patients with nonproliferative retinopathy.


M. Lind1, A. Green1.2, M.H. Hansen1, A.K. Sjølie1

1Odense University Hospital, Odense - Denmark
2University of Southern Denmark, Odense -Denmark

PURPOSE. To describe the prevalence and progression of retinopathy in women with diabetes examined at a photographic screening clinic during and after pregnancy.

METHODS. Pregnant women with diabetes from Southern Denmark (1,2 mill. inhabitants) were included. Fundus photographs were taken in each trimester, post partum and yearly thereafter. Retinopathy was graded according to the EURODIAB protocol.

RESULTS. 132 women were examined at least once during pregnancy from January 1997 to April 2003 and thereafter until January 2009. Median age at first examination was 29 years (range 19-42), median duration 10 years (0-36) and median HbA1c 6.8 % (4.6-10.3). At baseline 34 patients had mild nonproliferative retinopathy, 8 had severe nonproliferative retinopathy and 8 women had proliferative retinopathy. Six patients (4.5%) developed mild nonproliferative retinopathy during pregnancy and 10 (7.6%) progressed (one to proliferative retinopathy). The patients were followed for 6.2 (± 3.6) years after the pregnancy. Within 3 months post partum 10 patients (4.5%) developed or progressed in retinopathy. After 6 years of follow-up 11 patients had developed retinopathy and 36 patients had progressed in retinopathy in one or both eyes (8 to proliferative retinopathy). Risk factors for progression and PDR will be presented.

CONCLUSIONS. The incidence and progression of retinopathy during pregnancy and soon after delivery was considerable (19.7%). A few patients progress to sight threatening retinopathy. Diabetic women should be examined regularly before, under, as well as after pregnancy. Particular attention should be screening after termination of pregnancy.


D. Oladiwara, A.Sinclair, C.Collins, C.Styles

Queen Margaret Hospital, Dunfermline, Fife - Scotland

PURPOSE. To provide information that may help to refine screening criteria regarding photographic diagnosis of maculopathy and prioritise referrals.

METHODS. Clinical data were recorded from 90 patients with M2 seen in the diabetic eye clinic over a 6 month period in 2007and repeated from clinical examinations 18-24 months later.

RESULTS. 53 patients (91%) of patients with M2HEx had follow up data available. A further 20% of patients required macula laser treatment in the follow up period. 66% required continued review. 29 patients (91%) with M2Hg had follow up data available. 1 patient required macula laser treatment in the follow up period. 77% required continued review.

CONCLUSIONS. The majority of referrals continue to require long term follow up with significant implications for diabetic eye clinics. 40% of patients with M2HEx require laser treatment within 2 years suggesting that this is a high risk group. This information is useful for prioritising referrals from diabetic retinopathy screening programmes and refining referral criteria.


A.D. Fleming1, K.A. Goatman1, P.F. Sharp1, CJ. Styles2, W.N. Wykes3, J.A. Olson1,4

1University of Aberdeen, Aberdeen - UK
2Queen Margaret Hospital, Dunfermline - UK
3Southern General Hospital, Glasgow - UK4NHS Grampian, Aberdeen - UK

PURPOSE. To evaluate the performance of combined automated image quality assessment and automated microaneurysm detection on a large multi-centre unselected data set.

METHODS. Images and grading results from 36069 anonymised patient screening episodes were obtained from two screening centres. Photography and grading had been performed according to the Scottish screening recommendations. Automated image quality and automated

RESULTS. According to the manual grades, the automated system detected: image quality failures 98.17% (1877/1912), referable maculopathy 95.79% (1183/1235), referable background retinopathy 99.13% (337/340), and proliferative retinopathy 99.04% (206/208). Automated grading provided a final grade for 36.4% of all screening episodes.

CONCLUSIONS. Automated grading reduces the manual grading working whilst achieving a high sensitivity for the detection of referable retinopathy/maculopathy in a large multi-centre unselected data set.


G. Hadley, I. Stratton, J. Sykes, V. Jones, L. Gardner, A. McDowell, P. Scanlon

Gloucestershire Hospitals NHS Foundation Trust

PURPOSE. To determine outcome and risk factor data for diabetic patients with asymptomatic emboli.

METHODS. A retrospective analysis of images and cases notes between November 2001 and November 2008.

RESULTS. 216 people were identified with asymptomatic emboli, 69% men, 31% women, of whom 82.9% are alive and 17.1% have died. The median age of 73 years was older than the general screening population (p<0.0001), minimum 52, maximum 93, interquartile range 66 to 78 (mean 72.5, standard deviation 8.7). The median follow-up was 2 years, maximum 7 years. The proportion who had died since emboli were identified was 8%, 14%, 20% and 25% at 1, 2, 3 and 4 years respectively. The embolus was in the right eye in 53.5% in the left in 46.5% (P=0.30 for equal proportions). The location was 44.5% supero-temporal, 41.6% infero-temporal, 3.3% a combination of the above, 6.7% supero-nasal, 3.3% infero-nasal and 0.5% in a naso ciliary vessel. 16.3% were calcific, 79.8% cholesterol and 3.9% fibrinoplatelet. The clinical notes review shows the following preliminary data: HbA1c median 6.9, interquartile range 6.4 to 7.5. The proportion with <50%, 50-60% and >70% ipsilateral internal carotid artery stenosis is 67%, 15%, 18%, and contralateral 76%, 21%, 3%.

CONCLUSIONS. There is a high mortality associated with asymptomatic emboli. More detailed analysis will add to the evidence base for study design to improve the outcome for these patients.


E. Berrone, E. Beltramo, S. Tarallo, M. Porta

University of Torino, Torino - Italy

PURPOSE. We aimed at evaluating human retinal pericyte (HRP) response to soluble factors released by Human Umbilical Vein EC (HUVEC) in the presence of physiological or high glucose in the medium.

METHODS. EC were cultured in physiological or high glucose for 7 days; media from the last 2 days of culture were collected and filtered (HUVEC-CM). HRP were cultured for 7 days in normal/high glucose, or in normal glucose with the addition of 25/50% HUVEC-CM. DNA fragmentation was measured by ELISA, Bax and Bcl-2 mRNA expression by RT-PCR and HRP morphology by phase-contrast microscopy.

RESULTS. Apoptosis increased significantly in the presence of 50% HUVEC-CM produced in high glucose, but not in high glucose only, nor with HUVEC-CM produced in normal glucose. In terms of mRNA expression, there was clear over-expression of Bax and an evident reduction of Bcl-2 in the presence of 50% HUVEC-CM produced in high glucose. Cell morphology showed modifications in the presence of 50% HUVEC-CM produced in high glucose.

CONCLUSIONS. HRP apoptosis increases significantly in the presence of conditioned-medium from HUVEC cultured in high glucose, but not in other conditions, suggesting that soluble factors derived from EC are likely to play a critical role in the apoptotic response of HRP.


S. Vujosevic1, M. Casciano1, E. Bottega1, E. Benetti1, E. Midena1,2

1Department of Ophthalmology, University of Padova, Padova - Italy
2MD- Fondazione G.B. Bietti, IRCCS, Roma - Italy

PURPOSE. The aim of this study was to evaluate the role of structural and functional macular
imaging in the characterization of DME patterns.

METHODS. One hundred twenty five eyes of 78 diabetic patients with untreated DME underwent: best corrected visual acuity determination (BCVA, logMAR), slit lamp biomicroscopy, fluorescein angiography, OCT (mean central field (CF) retinal thickness, volume and DME pattern), fundus autofluorescence (FAF): absent or increased FAF (IFAF:single and multple spots;IFAF area quantification), retro-mode scanning laser ophthalmoscopy and microperimetry.

RESULTS. Thirty five eyes had normal FAF, 90 IFAF (30 single spot IFAF, 60 multiple spots IFAF). Retinal sensitivity over areas with IFAF was 10.8 dB (vs 16.2 db in normal areas,p<0.005). Retinal sensitivity of the CF vs FAF was: 14.6 dB normal FAF, 12.10 dB single spot and 10.9 dB multiple spots IFAF(p<0.05) . A significant correlation was found between IFAF, CF retinal sensitivity and positive retro-mode imaging (p=0.01). Cystoid OCT-pattern and macular volume were correlated to both presence and dimension of IFAF and retro-mode imaging (p<0.05), whereas sponge-like and subfoveal neuroretinal detachment were not correlated. BCVA did not correlate either to FAF pattern or area of IFAF.

CONCLUSIONS. The use of an integrated structural and functional retinal imaging approach allows to identify some different DME phenotypes, which may be related to treatment prognosis when prospectively evaluated.


R.O. Schlingemann1, J.M. Hughes1, A.J. Groot2, P. van der Groep2, R. Sersansie1, C.J.F. van Noorden1, I. Klaassen1

1Academic Medical Center, Amsterdam - The Netherlands
2University Medical Center, Utrecht - The Netherlands

PURPOSE. We hypothesize that HIF-1α is constitutively stabilized and active in the normal human retina.

METHODS. The cellular distribution of HIF-1α and the expression of its downstream targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1) and carbonic anhydrase IX (CAIX) were investigated by immunohistochemistry and immunoblotting in the retina of normal human donor eyes and in perfusion-fixed rat retina.

RESULTS. Both human and rat retina displayed prominent staining of HIF-1α in nuclei of most cell types in inner and outer nuclear layers and the ganglion cell layer, a cellular distribution which was confirmed in human retina by western blotting of nuclear extracts. In the human retinas, specific cell types stained for VEGF, GLUT-1 and CAIX.

CONCLUSIONS. Our observations indicate that active HIF-1 signalling occurs constitutively in the normal human and rat retina, suggesting that HIF-1 has a physiological role in the retina.


P.M. Dodson, A. Reja, W. Hailu, l. Quant, A. Woldeyes, T. Teshome, H. Wharton

Black Lions Hospital, Addis Ababa, Ethiopia (BLDC); Heartlands Hospital, Birmingham; Heart of England Diabetic Retinopathy Screening Centre (HEDRSC) - UK

PURPOSE. The aim is to establish whether digital photographic retinal screening for diabetic retinopathy (DR) is sustainable and worthwhile.

METHODS. Similar technology and protocols to the English DR screening programme have been introduced into the Black Lions Diabetes Centre ( BLDC ) (approximately 2000 diabetics, 300 outpatient attendances per month). Primary grading was performed by trained staff in the BLDC. All photographs were rechecked for quality assurance (QA) by HEDRSC graders.

RESULTS. During the first year, a total of 493 diabetic patients completed the screening protocol (47% male, 51% female, mean age 47 years, range 8 to 78). 33/493 (7%) patients had best binocular visual acuity (VA) of 6/60 or worse. Final grading showed that 190/493 (39%) patients had no DR and 58/493 (12 % ) had ungradable image sets. Retinopathy status in the remainder ( 49 % of total ) was background 17 %, pre-proliferative 7%, proliferative 4 % and 28% (n=138) had referrable maculopathy. Inter-grader agreement between BLDC and HEDRSC was 92% for those returned to annual screening, 69% for those requiring urgent referral, and 98 % for specifically identifying sight threatening DR for referral.

CONCLUSIONS. After 18 months screening, the digital camera technology employed is sustainable, and the BLDC trained staff have achieved accurate identification and referral for sight threatening DR.


H. Zavrelova, M. Alssema, G. Nijpels, JM. Dekker, BCP. Polak

VU University Medical Center, Amsterdam - The Netherlands

PURPOSE. To explore the association of glycation with retinopathy and nephropathy.

METHODS. Ten year follow-up data of a glucose status stratified sample (n = 631, age 50-75) of the Hoorn Study, a population-based cohort, were used. Odds ratios from logistic regression analysis were computed for three categories of HbA1c with three levels of fasting glucose (FG) and with the category of low HbA1c and low FG as a reference. Within each subgroup of FG (≤ 6 mmol/l, 6-7 mmol/l and >7 mmol/l) subjects with HbA1c >6% were considered high glycators. Furthermore, a measure of glycation, the glycation gap, observed HbA1c minus HbA1c corrected for fructosamine, was analysed in tertiles. Retinopathy incidence was assessed by fundus photography in n=233, nephropathy was estimated by the Cockcroft-Gault formulas in n=221.

RESULTS. The crude odds ratios for retinopathy were 37.0 (95% CI: 2.3-602.7), 44.4 (4.4-49.0) and 9.3 (1.1-81.7) for high glycators with low, intermediate and high FG levels, respectively. Gender, age and hypertension did only slightly attenuate these associations. The highest glycation gap tertile showed a crude odds ratio of 2.1 (95% CI: 0.7-6.5) for retinopathy compared to the lowest tertile. Results on nephropathy were statistically non significant.

CONCLUSIONS. Elevated HbA1c predicts retinopathy, but not nephropathy, also in subjects with low fasting glucose levels.


J. Grauslund1, A. Green1,2, AK. Sjølie1

1Odense University Hospital, Odense – Denmark
2University of Southern Denmark, Odense - Denmark

PURPOSE. To evaluate the prevalence of retinopathy among long-time surviving type 1 diabetic patients as well as the 25-year incidence of proliferative retinopathy and associated risk factors in a Danish population-based cohort.

METHODS. A population-based cohort of 727 type 1 diabetic patients from Fyn County, Denmark, was identified in 1973. In 1981-82, baseline retinopathy was graded and other risk factors were assessed in 573 patients. Twenty five years later, 308 patients were still alive. Of these, 201 (65.3%) were re-examined at follow-up in 2007-08.

RESULTS. Median age and duration of diabetes at follow-up were 58.8 and 43 years, respectively. At follow-up, the prevalence of any retinopathy was 96.9%. Non-proliferative retinopathy was found in 47.9%, and 49.0% had proliferative retinopathy. The 25-year incidence of proliferative retinopathy was 41.1% among patients at risk. In multivariate analyses, baseline HbA1 (OR 2.26 per 1% increase, 95% CI 1.08-4.72) and non-proliferative retinopathy (OR 4.96, 95% CI 2.00-12.3) were the only risk factors for incident proliferative retinopathy. The long-term incidence of proliferative retinopathy was not associated with baseline duration of diabetes, proteinuria, smoking, BMI, maculopathy, systolic or diastolic blood pressure.

CONCLUSIONS. Retinopathy among long-term surviving type 1 diabetic patients is almost universal. Proliferative retinopathy was found in half of these patients. Additionally, the 25-year incidence of proliferative retinopathy was high. Baseline glycaemic regulation and non-proliferative retinopathy were identified as risk factors for incident proliferative retinopathy.



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