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Prediabetes influences the structure of the macula: thinning of the macula in the Northern Finland Birth Cohort
Abstract
Background/aim:
The aim of this study was to evaluate the effect of prediabetes and diabetes on macular thickness and retinal vascular calibres in our population-based cohort (Northern Finland Birth Cohort).
Methods:
The population of 2005 individuals was divided into diabetes (n=57), prediabetes (n=1638) and normal glucose metabolism (NGM) groups (n=310). Total thickness of the macula was measured using Cirrus HD-OCT 4000. Central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) calibres were measured from the fundus images. The diagnosis of diabetes and prediabetes was made according to WHO 2006 diagnostic standards.
Results:
Significant macular thinning was observed in subjects with prediabetes (-2.69 μm (95% CI -4.29 to -1.09), p<0.05 and -0.10 mm3 (95% CI -0.16 to -0.04), p<0.05 for macular cube average thickness and cube volume, respectively) and it was greatest in the pericentral area. Macular cube average thickness and macular cube volume decreased significantly by worsening glucose metabolism. Furthermore, CRAE was decreased by increases in 2-hour post-load glucose, glucose area under the curve and increase in Matsuda index (p<0.001, 0.019 and <0.001, respectively). In mediation analysis, macular thickness had significant average causal mediation effect (ACME) on CRVE and CRAE in subjects with prediabetes.
Conclusion:
We detected significant thinning of the macula in subjects with prediabetes. The diameters of retinal arteries were decreased by impaired glucose metabolism. This study provides a new perspective since it revealed that the early and subtle changes caused by prediabetes as macular thinning had significant ACME on retinal vessels, therefore supporting the neurodegenerative theory of diabetes-induced changes in the retina.
... Diabetic patients without these clinically detected abnormalities and DME are considered to have no retinopathy (NDR). [8] Prediabetes is a transitional stage from normal glucose metabolism (NGM) to DM. [9] It is a state of abnormal glucose tests but not up to the diagnostic criteria for diabetes, including impaired fasting glucose (IFG) (fasting plasma glucose 5.6-6.9 mmol/L), impaired glucose tolerance (IGT; 2 h glucose 7.8-11.0 ...
... The basic characteristics of the included studies are summarized in Table 1, which comprised 13,773 participants and 15,416 eyes from 23 countries worldwide. In all the studies, there were participants with T2D (n = 49), [2][3][4][5][6]9,19,21,[26][27][28][29]32, T1D (n = 27), [1,17,18,20,24,[30][31][32]36,37,46,55,56,70,71,[74][75][76][77][78][79][80][81][82][83][84][85] T1D/T2D mixed (n = 9), [22,25,33,[86][87][88][89][90][91] prediabetes (n = 5) [9,10,42,92,93] and unclear (n = 4). [16,[94][95][96] ...
... The basic characteristics of the included studies are summarized in Table 1, which comprised 13,773 participants and 15,416 eyes from 23 countries worldwide. In all the studies, there were participants with T2D (n = 49), [2][3][4][5][6]9,19,21,[26][27][28][29]32, T1D (n = 27), [1,17,18,20,24,[30][31][32]36,37,46,55,56,70,71,[74][75][76][77][78][79][80][81][82][83][84][85] T1D/T2D mixed (n = 9), [22,25,33,[86][87][88][89][90][91] prediabetes (n = 5) [9,10,42,92,93] and unclear (n = 4). [16,[94][95][96] ...
Background
Alterations in macular thickness and vascular density before clinically visible diabetic retinopathy (DR) remain inconclusive. This study aimed to determine whether retinal manifestations in abnormal glucose metabolism (AGM) patients differ from those in the healthy individuals.
Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 Statement was followed as our guideline for this meta-analysis. PubMed, Embase, and Web of Science were searched between 2000 and 2021. The eligibility criteria were AGM patients without DR. Primary and secondary outcomes measured by optical coherence tomography (OCT) and OCT angiography (OCTA) were analyzed and expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). A random-effects model was used in the data synthesis. The meta-analysis was conducted using Stata (version 13.1).
Results
A total of 86 observational studies involving 13,773 participants and 15,416 eyes were included. OCT revealed that compared to healthy controls, the total macular thickness of AGM patients was thinner, including the thickness of fovea (–0.24, 95% CI [–0.39, –0.08]; P = 0.002, I ² = 87.7%), all regions of parafovea (–0.32, 95% CI [–0.54, –0.11]; P = 0.003; I ² = 71.7%) and the four quadrants of perifovea; the thickness of peripapillary retinal nerve fiber layer (pRNFL), macular retinal nerve fiber layer (mRNFL), and ganglion cell layer (GCL) also decreased. OCTA indicated that the superficial and deep vascular density decreased, the foveal avascular zone (FAZ) area enlarged, and the acircularity index (AI) reduced in AGM individuals.
Conclusions
Retinal thinning and microvascular lesions have occurred before the advent of clinically detectable DR; OCT and OCTA may have the potential to detect these preclinical changes.
Registration
PROSPERO; http://www.crd.york.ac.uk/prospero/; No. CRD42021269885.
... The current literature on the associations of hyperglycemia with RNFL thickness has some important limitations. First, in previous population-based studies, several important confounders were not included, such as age, [13][14][15] sex, 14,15 socioeconomic status, [13][14][15][16][17][18][19][20][21][22][23] cardiovascular risk factors, 13-15, 19, 21-24 and lifestyle factors (e.g., alcohol use, 13,[16][17][18][19]21 diet, [13][14][15][16][17][18][19][20][21][22][23][24] and physical activity). [13][14][15][16][17][18][19][21][22][23][24] Second, no population-based studies have yet investigated whether advanced glycation endproducts (AGEs) or daily glucose variability are associated with RNFL thickness. ...
... The current literature on the associations of hyperglycemia with RNFL thickness has some important limitations. First, in previous population-based studies, several important confounders were not included, such as age, [13][14][15] sex, 14,15 socioeconomic status, [13][14][15][16][17][18][19][20][21][22][23] cardiovascular risk factors, 13-15, 19, 21-24 and lifestyle factors (e.g., alcohol use, 13,[16][17][18][19]21 diet, [13][14][15][16][17][18][19][20][21][22][23][24] and physical activity). [13][14][15][16][17][18][19][21][22][23][24] Second, no population-based studies have yet investigated whether advanced glycation endproducts (AGEs) or daily glucose variability are associated with RNFL thickness. ...
... The current literature on the associations of hyperglycemia with RNFL thickness has some important limitations. First, in previous population-based studies, several important confounders were not included, such as age, [13][14][15] sex, 14,15 socioeconomic status, [13][14][15][16][17][18][19][20][21][22][23] cardiovascular risk factors, 13-15, 19, 21-24 and lifestyle factors (e.g., alcohol use, 13,[16][17][18][19]21 diet, [13][14][15][16][17][18][19][20][21][22][23][24] and physical activity). [13][14][15][16][17][18][19][21][22][23][24] Second, no population-based studies have yet investigated whether advanced glycation endproducts (AGEs) or daily glucose variability are associated with RNFL thickness. ...
Objective
Diabetic retinopathy in type 2 diabetes is preceded by retinal nerve fiber layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance.
Research design and methods
We used cross-sectional data from The Maastricht Study (up to 5,455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycemia (fasting plasma glucose [FPG], 2-hour post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycemia.
Results
After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95%CI], respectively -0.16[-0.25;-0.08]; -0.05[-0.13;0.03]; Ptrend=0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP and CGM-assessed SD were also associated with lower RNFL thickness (per SD, respectively -0.05 [-0.08; -0.01]; -0.06 [-0.09; -0.02]; -0.05 [-0.08; -0.02]; -0.04 [-0.07; -0.01]; -0.06 [-0.12; -0.01]; and -0.07 [-0.21; 0.07]).
Conclusion
In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of diabetic retinopathy.
... The current literature on the associations of hyperglycaemia with RNFL thickness has some important limitations. First, in previous population-based studies, several important confounders were not included, such as age [13][14][15] , sex 14,15 , socioeconomic status [13][14][15][16][17][18][19][20][21][22][23] , cardiovascular risk factors [13][14][15]19,[21][22][23][24] , and lifestyle factors (e.g., alcohol use 13,[16][17][18][19]21 , diet [13][14][15][16][17][18][19][20][21][22][23][24] , and physical activity) [13][14][15][16][17][18][19][21][22][23][24] . Second, no population-based studies have yet investigated whether advanced glycation endproducts (AGEs) or daily glucose variability are associated with RNFL thickness. ...
... The current literature on the associations of hyperglycaemia with RNFL thickness has some important limitations. First, in previous population-based studies, several important confounders were not included, such as age [13][14][15] , sex 14,15 , socioeconomic status [13][14][15][16][17][18][19][20][21][22][23] , cardiovascular risk factors [13][14][15]19,[21][22][23][24] , and lifestyle factors (e.g., alcohol use 13,[16][17][18][19]21 , diet [13][14][15][16][17][18][19][20][21][22][23][24] , and physical activity) [13][14][15][16][17][18][19][21][22][23][24] . Second, no population-based studies have yet investigated whether advanced glycation endproducts (AGEs) or daily glucose variability are associated with RNFL thickness. ...
... The current literature on the associations of hyperglycaemia with RNFL thickness has some important limitations. First, in previous population-based studies, several important confounders were not included, such as age [13][14][15] , sex 14,15 , socioeconomic status [13][14][15][16][17][18][19][20][21][22][23] , cardiovascular risk factors [13][14][15]19,[21][22][23][24] , and lifestyle factors (e.g., alcohol use 13,[16][17][18][19]21 , diet [13][14][15][16][17][18][19][20][21][22][23][24] , and physical activity) [13][14][15][16][17][18][19][21][22][23][24] . Second, no population-based studies have yet investigated whether advanced glycation endproducts (AGEs) or daily glucose variability are associated with RNFL thickness. ...
Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively − 0.16 [− 0.25; − 0.08]; − 0.05 [− 0.13; 0.03]; Ptrend = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively − 0.05 [− 0.08; − 0.01]; − 0.06 [− 0.09; − 0.02]; − 0.05 [− 0.08; − 0.02]; − 0.04 [− 0.07; − 0.01]; − 0.06 [− 0.12; − 0.01]; and − 0.07 [− 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy.
... There are few studies confirming the existence of retinopathy in prediabetic patients [54], with venular dilation being the main finding [55,56]. A recent cohort study showed that decreased macular thickness and retinal arterial stenosis were the main findings in the prediabetic group compared to the normoglycemic group [57]. ...
... There are few studies confirming the existence of retinopathy in prediabetic patients [54], with venular dilation being the main finding [55,56]. A recent cohort study showed that decreased macular thickness and retinal arterial stenosis were the main findings in the prediabetic group compared to the normoglycemic group [57]. However, studies investigating the relationship between the diameter of the retinal vessels and the risk of developing prediabetes and DM in the future have shown conflicting results. ...
Prediabetes is a significant metabolic status since there is high potential for future progression of diabetes mellitus (DM). People with prediabetes are at increased risk of cardiovascular disease (CVD) and mortality. Endothelial and microvascular dysfunction is considered a key step towards the development and progression of CVD. Importantly, endothelial and microvascular dysfunction can be detected and monitored using non-invasive procedures in peripheral organs and tissues, including the retina, kidney, skin and skeletal muscle. Structural and functional alterations of the microvasculature have been consistently documented in the above microvascular beds in patients with diabetes mellitus. In contrast, such alterations remain understudied in prediabetes, but are currently receiving attention as markers of subclinical and future CVD. The aim of this review is to summarize available evidence regarding the presence of subclinical microvascular and endothelial dysfunction in prediabetes and their impact on cardiovascular risk.
... Furthermore, some studies have explored possible structural changes in the retina before the development of DM (i.e., preDM), although a consistent conclusion has not been reached [11][12][13]. This study aimed to investigate the differences in the inner retinal layers depicted on swept source-OCT (SS-OCT) between eyes with non-DM, preDM, and NDR in a community-dwelling elderly population. ...
... In contrast, GCIPL and GCC that include not only ganglion cells but also axons of bipolar cells and amacrine processes were not sensitive enough to reflect ganglion cell loss that is considered to occur in diabetic retina [20,21]. Furthermore, previously reported OCT findings in preDM have not been consistent, and a decrease in the thickness of choroid [13,22], GCC [11], total macular thickness [12], and central foveal thickness [13] has been reported to be associated with preDM compared to healthy controls. Our current study included larger sample size and performed regression analysis to evaluate different inner retinal thickness parameters as well as CFT and CST, and indicated that thinner mRNFL and pRNFL might be useful markers associated with preDM. ...
Purpose
To investigate retinal thickness parameters in the elderly with prediabetes mellitus (preDM) and type 2 DM without retinopathy (non-diabetic retinopathy [NDR]).
Methods
This cross-sectional study included a total of 1273 eyes without retinal pathologies of 699 volunteers aged ≥ 65 years were included. The eyes were categorized into non-DM (606 eyes), preDM (480 eyes), and NDR (187 eyes) groups according to their HbA1c levels. Fundus photography, swept-source optical coherence tomography, and comprehensive systemic examination were conducted. The thicknesses of the retinal nerve fiber layer in the macula (mRNFL) and peripapillary (pRNFL), ganglion cell complex (GCC), and ganglion cell inner plexiform layer (GCIPL), as well as central subfield thickness (CST) and central foveal thickness (CFT) were investigated for their association with DM stage using linear mixed model.
Results
A statistically significant thinning of mRNFL was observed in preDM vs. non-DM and in NDR vs. preDM in 3/6 sectors. A significant thinning of pRNFL was observed in preDM vs. non-DM and in NDR vs. preDM in 2/12 sectors. Such DM stage–dependent thinning of RNFL was observed mainly in the temporal and superior sectors. GCIPL and GCC were less sensitive to reflect DM-dependent inner retinal thinning. CST and CFT were not significantly associated with different DM stages.
Conclusion
The thinning of mRNFL in the temporal and superior sectors might be a sensitive parameter associated with early neurodegeneration in preDM and NDR.
... Macular thinning, one of the early and subtle changes associated with pre-diabetes, was found to have a considerable causal mediation effect on the retinal vasculature. Chronic hyperglycemia is thought to lead to increased glutamate release and loss of vascular Table 3 Comparison of inflammatory cytokines levels in tear between the groups protective factors due to oxidative stress and accumulation of glycolytic waste products [17]. Many studies have linked different inflammatory indicators to the presence of DR, including TNF-a, VEGF, intracellular adhesion molecules, soluble gp130, soluble tumor necrosis factor receptor 1 and so on. ...
Pre-diabetes is the preceding condition of diabetes, and in some cases, fundus changes have been seen in pre-diabetes. The inflammatory response is widely recognized as being involved in the pathophysiologic process of diabetic eye disease. Therefore, we aimed to acquire understanding of the role of early altered blood glucose levels in the development and etiology of diabetic ocular disorders from the perspective of inflammation. In this study, serum, tear, aqueous humor and vitreous fluid samples were collected from patients undergoing cataract surgery. VEGF, IL-6, TNF-a, MCP-1, APOA-1, ICAM-1, VCAM-1, PEDF, TSP-1 were measured by ELISA. The quantity of hyperreflective retinal spots (HRS) was counted by optical coherence tomography OCT images. We found that the levels of inflammatory cytokines are already altered in pre-diabetes. Levels of pro-inflammatory cytokine expression and quantity of HRS can reflect the disease process to some extent.
... However, the M-FBG considers only the FBG level and time. When the average FBG level is below the threshold, it does not lead to DR (28,29). Compared to the M-FBG, the cumulative FBG load considers the intensity, time, and emphasizes the proportion of the FBG load (17). ...
Objective
The long-term glucose monitoring is essential to the risk assessment of diabetic retinopathy (DR), the aim of this study was to investigate the predictive ability of visit-to-visit fasting blood glucose (FBG) indices on the risk of DR.
Methods
This was a community-based, cohort study conducted from 2013 to 2021. DR was diagnosed by digital fundus photography. The FPG indices included FBG, var. Associations of each FBG indices and DR were estimated using multinomial logistic regression models adjusting for confounders, and discrimination was determined by area under the curve (AUC). Predictive utility of different models was compared by changes in AUC, integrated discrimination improvement (IDI), and net reclassification index (NRI).
Results
This study analyzed 5054 participants, the mean age was 46.26 ± 11.44 years, and 2620 (51.84%) were women. After adjustment for confounders, the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for FBG, SD, CV, VIM, ARV, M-FBG, and cumulative FBG load were 1.62 (1.52—1.73), 2.74 (2.38—3.16), 1.78 (1.62—1.95), 1.11 (0.95—1.29), 1.72 (1.56—1.91), 2.15 (1.96—2.36), and 2.57 (2.31—2.85), respectively. The AUC of the model with separate cumulative FBG load and classical risk factors was 0.9135 (95%CI 0.8890—0.9380), and no substantive improvement in discrimination was achieved with the addition of other FBG indices once cumulative FBG load was in the model.
Conclusions
Cumulative FBG load is adequate for capturing the glucose-related DR risk, and the predictive utility of cumulative FBG load is not significantly improved by adding or replacing other FBG indices in the assessment of DR risk.
... The retina is an important target organ of diabetic damage, which has exceptional susceptibility to diabetes-related metabolic stresses [8][9][10] . Using state-of-the-art in vivo retinal optical coherence tomography (OCT), changes of retina were captured even before evident diabetes [11][12][13] . Retinal pigment epithelium (RPE) is the outer layer of the retina and plays an important role in maintaining retinal function by providing 60-80% of the retina's glucose supply through its highcapacity transport system 14 . ...
The retina is an important target organ of diabetes mellitus, with increasing evidence from patients and animal models suggesting that retinal pigment epithelium (RPE) may serve as an early marker for diabetes-related damages. However, their longitudinal relationship and the biological underpinnings remain less well understood. Here, we demonstrate that reduced in vivo measurements of RPE thickness (RPET) represents a significant risk factor for future type 2 diabetes mellitus (T2DM) and its microvascular phenotypes. After performing systematic analyses of circulating plasma metabolites using two complementary approaches, we identify a wide range of RPET metabolic fingerprints that are independently associated with reduced RPET. These fingerprints hold their potential to improve predictability and clinical utility for stratifying future T2DM and related microvascular phenotypes beyond traditional clinical indicators, providing insights into the promising role of retinas as a window to systemic health.
... 17 However a recent meta-analysis of OCT angiography concluded that while amblyopic eyes have significantly different vessel density compared to healthy controls, there was no difference between affected and unaffected fellow eyes. 42 By contrast, individuals with incipient metabolic syndrome and cardiovascular disease exhibit thinner mGC-IPL, 43 corroborating our findings of increased HbA1c and risk of myocardial infarction in those with amblyopia. Additionally, retinal fractal dimension was significantly lower in both eyes of individuals with unilateral amblyopia and is negatively associated with hypertension and cardiovascular disease. ...
Background
Amblyopia is a common neurodevelopmental condition and leading cause of childhood visual impairment. Given the known association between neurodevelopmental impairment and cardiometabolic dysfunction in later life, we investigated whether children with amblyopia have increased risk of cardiometabolic disorders in adult life.
Methods
This was a cross-sectional and longitudinal analysis of 126,399 United Kingdom Biobank cohort participants who underwent ocular examination. A subset of 67,321 of these received retinal imaging. Data analysis was conducted between November 1st 2021 and October 15th 2022. Our primary objective was to investigate the association between amblyopia and a number of components of metabolic syndrome and individual cardiometabolic diseases. Childhood amblyopia, dichotomised as resolved or persisting by adulthood, cardiometabolic disease and mortality were defined using ophthalmic assessment, self-reported, hospital admissions and death records. Morphological features of the optic nerve and retinal vasculature and sublayers were extracted from retinal photography and optical coherence tomography. Associations between amblyopia and cardiometabolic disorders as well as retinal markers were investigated in multivariable-adjusted regression models.
Findings
Individuals with persisting amblyopia (n = 2647) were more likely to be obese (adjusted odds ratio (95% confidence interval): 1.16 (1.05; 1.28)), hypertensive (1.25 (1.13; 1.38)) and diabetic (1.29 (1.04; 1.59)) than individuals without amblyopia (controls, (n = 18,481)). Amblyopia was also associated with an increased risk of myocardial infarction (adjusted hazard ratio: 1.38 (1.11; 1.72)) and death (1.36 (1.15; 1.60)). On retinal imaging, amblyopic eyes had significantly increased venular caliber (0.29 units (0.21; 0.36)), increased tortuosity (0.11 units (0.03; 0.19)), but lower fractal dimension (−0.23 units (−0.30; −0.16)) and thinner ganglion cell-inner plexiform layer (mGC-IPL, −2.85 microns (−3.47; −2.22)). Unaffected fellow eyes of individuals with amblyopia also had significantly lower retinal fractal dimension (−0.08 units (−0.15; −0.01)) and thinner mGC-IPL (−1.14 microns (−1.74; −0.54)). Amblyopic eyes with a persisting visual deficit had smaller optic nerve disc height (−0.17 units (−0.25; −0.08)) and width (−0.13 units (−0.21; −0.04)) compared to control eyes.
Interpretation
Although further research is needed to understand the basis of the observed associations, healthcare professionals should be cognisant of greater cardiometabolic dysfunction in adults who had childhood amblyopia. Differences in retinal features in both the amblyopic eye and the unaffected non-amblyopic suggest generalised versus local processes.
Funding
10.13039/501100000265Medical Research Council (MR/T000953/1) and the 10.13039/501100000272National Institute for Health and Care Research.
... 59 Furthermore, schizophrenia has wellestablished epidemiological and genetic codistribution with metabolic dysfunction, 3-5 and there is increasing evidence that retinal thinning may predate overt diabetes. 60,61 In our sensitivity analysis, we excluded all patients with diabetes during the study period to mitigate this; however, it is conceivable that individuals within our population had early or undiagnosed metabolic syndrome. ...
Importance:
The potential association of schizophrenia with distinct retinal changes is of clinical interest but has been challenging to investigate because of a lack of sufficiently large and detailed cohorts.
Objective:
To investigate the association between retinal biomarkers from multimodal imaging (oculomics) and schizophrenia in a large real-world population.
Design, setting, and participants:
This cross-sectional analysis used data from a retrospective cohort of 154 830 patients 40 years and older from the AlzEye study, which linked ophthalmic data with hospital admission data across England. Patients attended Moorfields Eye Hospital, a secondary care ophthalmic hospital with a principal central site, 4 district hubs, and 5 satellite clinics in and around London, United Kingdom, and had retinal imaging during the study period (January 2008 and April 2018). Data were analyzed from January 2022 to July 2022.
Main outcomes and measures:
Retinovascular and optic nerve indices were computed from color fundus photography. Macular retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (mGC-IPL) thicknesses were extracted from optical coherence tomography. Linear mixed-effects models were used to examine the association between schizophrenia and retinal biomarkers.
Results:
A total of 485 individuals (747 eyes) with schizophrenia (mean [SD] age, 64.9 years [12.2]; 258 [53.2%] female) and 100 931 individuals (165 400 eyes) without schizophrenia (mean age, 65.9 years [13.7]; 53 253 [52.8%] female) were included after images underwent quality control and potentially confounding conditions were excluded. Individuals with schizophrenia were more likely to have hypertension (407 [83.9%] vs 49 971 [48.0%]) and diabetes (364 [75.1%] vs 28 762 [27.6%]). The schizophrenia group had thinner mGC-IPL (-4.05 μm, 95% CI, -5.40 to -2.69; P = 5.4 × 10-9), which persisted when investigating only patients without diabetes (-3.99 μm; 95% CI, -6.67 to -1.30; P = .004) or just those 55 years and younger (-2.90 μm; 95% CI, -5.55 to -0.24; P = .03). On adjusted analysis, retinal fractal dimension among vascular variables was reduced in individuals with schizophrenia (-0.14 units; 95% CI, -0.22 to -0.05; P = .001), although this was not present when excluding patients with diabetes.
Conclusions and relevance:
In this study, patients with schizophrenia had measurable differences in neural and vascular integrity of the retina. Differences in retinal vasculature were mostly secondary to the higher prevalence of diabetes and hypertension in patients with schizophrenia. The role of retinal features as adjunct outcomes in patients with schizophrenia warrants further investigation.
... 35,36 The neuroretinal changes include macular thinning and reduced thickness of the circumpapillary retinal nerve fiber layer thickness. 37,38 Similar findings were also found in the animal studies with prediabetes. 39,40 We speculate that prediabetes leads to abnormal metabolic changes, which may result in retinal damage. ...
Purpose
To explore the effect of prediabetes/hyperglycemia on the incidence of retinopathy.
Methods
PubMed and EMBASE databases were retrieved to screen case-control studies or prospective cohort studies of retinopathy in prediabetic patients from January, 2004 to December, 2019. After quality evaluation by two evaluators according to inclusion and exclusion criteria, RevMan 5.3 software was used for meta-analysis.
Results
A total of 18 articles were included. Meta-analysis showed that there have been more incidents of retinal diseases in patients with prediabetes/hyperglycemia [MD (mean difference) = 2.50, 95% CI (1.74 to 3.6)] than those in normal controls (p < 0.05). The incidence of macular diseases [MD = 1.36, 95% CI (1.05 to 1.76)] was significantly higher in prediabetic patients than that of the control group (p < 0.05). No significant differences in DR-like retinopathy were found between both groups [MD = 2.02, 95% CI (0.84 to 4.85)] (p > 0.05). In neonates, hyperglycemia was associated with an increased risk of ROP [MD = 3.6, 95% CI (1.89 to 6.86)] (p < 0.001).
Conclusions
Prediabetes/hyperglycemia is associated with an increased risk of retinal diseases. Retinal diseases screening such as macular diseases among people with prediabetes should be warranted. But no significant differences in DR-like retinopathy were found. However, more further studies are needed to clarify the details between prediabetes/hyperglycemia and different kinds of retinal diseases.
... OCT studies have shown changes in the thickness profiles of selected inner retinal layers in pediatric and adult diabetes mellitus patients at an early stage or even before any manifestation of clinical signs of microangiopathy [28,29]. Overall macular thickness is reduced in prediabetes and a greater reduction occurs in type 2 DM, even before diabetic retinopathy is clinically detected [30,31]. Arterial hypertension is known as an independent risk factor for inner retinal thinning [32]. ...
Purpose
To investigate a potential association between retinal layer thinning and pregnancy-related adverse outcomes.
Methods
A prospective observational study included 32 pregnant women between the ages of 18 and 45. Seventeen had uneventful pregnancies, and 15 experienced an adverse obstetrical outcome. Macular swept-source ocular coherence tomography was performed, and selective layers of the retina were evaluated. Adverse obstetrical outcome was defined as any of the following: preterm delivery, preeclampsia, pregnancy-induced hypertension, elevated liver function tests, thrombocytopenia and need for magnesium.
Results
The inner superior ganglion cell layer (GCL) was found to be thinner in the cohort with composite adverse obstetrical outcomes than in the cohort without complications (84.5 ± 6.9 vs. 89.5 ± 6.1 μm respectively; P = 0.04). Total inner superior (295.5 ± 39.1 vs. 302.5 ± 12.7 μm; P = 0.03) and inferior retinal thickness (289.0 ± 13.9 vs. 301.0 ± 17.1 μm; P = 0.03) as well as total macular volume (7.5 ± 0.3 vs. 7.7 ± 0.3 mm³; P = 0.02) were also lower in women with adverse obstetrical outcomes.
Conclusion
Thinning of the macular ganglion cell layer was associated with adverse outcomes in pregnancy. Larger studies are necessary to assess the potential role of macular GCL analysis in pregnancy.
Diabetes mellitus (DM) is now recognized as a system-wide, autoimmune, inflammatory, microvascular disorder, which, in the retina and brain results in severe multifocal injury now recognized as a leading cause, world-wide, of progressive vision loss and dementia. To address this problem, resulting primarily from variations in glycemia in the prediabetic and overt diabetic states, it must be realized that, although some of the injury processes associated with diabetes may be system wide, there are varying responses, effector, and repair mechanisms that differ from organ to organ or within varying cell structures. Specifically, within the retina, and similarly within the brain cortex, lesions occur of the “neurovascular unit”, comprised of focal microvascular occlusions, inflammatory endothelial and pericyte injury, with small vessel leakage resulting in injury to astrocytes, Müller cells, and microglia, all of which occur with progressive neuronal apoptosis. Such lesions are now recognized to occur before the first microaneurysms are visible to imaging by fundus cameras or before they result in detectable symptoms or signs recognizable to the patient or clinician. Treatments, therefore, which currently are not initiated within the retina until edema develops or there is progression of vascular lesions that define the current staging of retinopathy, and in the brain only after severe signs of cognitive failure. Treatments, therefore are applied relatively late with some reduction in progressive cellular injury but with resultant minimal vision or cognitive improvement. This review article will summarize the multiple inflammatory and remediation processes currently understood to occur in patients with diabetes as well as pre-diabetes and summarize as well the current limitations of methods for assessing the structural and functional alterations within the retina and brain. The goal is to attempt to define future screening, monitoring, and treatment directions that hopefully will prevent progressive injury as well as enable improved repair and attendant function.
Aims:
To investigate the retinal microvasculature in the elderly persons with prediabetes mellitus (preDM) and type 2 DM.
Methods:
This cross-sectional study included a total of 452 eyes without retinal pathologies of 301 elderly volunteers aged ≥65 years, and they were categorized into nonDM (225 eyes), preDM (177 eyes), and DM (50 eyes) groups based on their HbA1c. Fundus photography, swept-source optical coherence tomography and angiography, and comprehensive systemic examinations were conducted. Vessel density (VD) and foveal avascular zone (FAZ) in superficial and deep retinal microvasculature were investigated for their association with DM stages using linear mixed model.
Results:
Superficial VD (sVD) mean values in nonDM, preDM, and DM groups were 35.2, 34.9, and 34.8%, respectively. sVD in preDM was equivalent to sVD in DM, while significantly lower compared with sVD in nonDM (difference[95%CI] -0.19[-0.33 - -0.049], P=0.009). Deep VD (dVD) mean values in nonDM, preDM, and DM groups were 35.0, 35.0, 34.4%, respectively. dVD in preDM was equivalent to dVD in nonDM, while significantly higher compared with dVD in DM (difference[95%CI] 0.31[0.046-0.57], P=0.02). There was no significant association between FAZ area and DM stages.
Conclusions:
Retinal microvasculature might be affected at the prediabetic stage in the elderly.
Purpose
To study the normal relationship between retinal vessel diameter (RVD) with retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) parameters in a cohort of middle‐aged Caucasians.
Methods
We investigated 3070 individuals (6140 eyes). Central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were measured in the right eye using a semi‐automated computer‐assisted program. Retinal nerve fibre layer (RNFL) thickness and ONH parameters were assessed with Heidelberg retinal tomography (HRT).
Results
Data from 2217 persons were analysed including RNFL, CRAE, CRVE, sex, body mass index, mean arterial pressure, diabetes status, smoking status, optic disc area, rim area, spherical refraction and intraocular pressure. A larger RVD was associated with a thicker mean global RNFL thickness especially in global and inferior segments of the retina and with larger optic discs. Each 10 μm increase in the retinal arteriolar calibre was associated with a 5.58 μm increase in mean global RNFL thickness; the corresponding value for a 10 μm increase in venular calibre was 3.79 μm (p < 0.001 for both). Retinal venular calibre displayed consistent associations with RNFL thickness in both genders (p < 0.001 for all), whereas the association of arteriolar calibre and RNFL was more prominent in men (p < 0.001).
Conclusion
We found strong associations between larger RVD and thicker RNFL in all subjects. This study helps to clarify the association between RVD, RNFL thickness and ONH parameters and provides normal values for middle‐aged Caucasians that will help in future studies investigating the role of vascular aetiology in systemic and eye diseases.
Introduction:
Diabetic retina undergoes degenerative changes in retinal nerve fiber layer (RNFL) in addition to vascular changes. Loss of RNFL with changes in inner retina and their association with metabolic control have been studied with varied results in diabetic patients.
Aim:
To compare the RNFL thickness between diabetic patients and age matched healthy controls and to correlate the thickness to metabolic control.
Materials and methods:
One hundred and sixty five patients were enrolled in the study out of which 50 served as controls, 58 patients were diabetic without retinopathy and 57 patients had diabetic retinopathy. Both eyes of all patients underwent optical coherence tomography scans for RNFL and ganglion cell complex. Foveal and parafoveal thickness were also measured. All the parameters were compared to patient's metabolic control.
Results:
RNFL thinning was observed in superotemporal (p-value = 0.001) and upper nasal sectors (p-value = 0.031) around the optic disc in eyes with diabetic retinopathy. Ganglion cell complex also showed statistically significant thinning in diabetic patients. Creatinine levels showed a weak negative correlation to the RNFL.
Conclusion:
This study positively concluded that neurodegeneration in an early component of diabetic retinopathy.
Background:
Diabetic retinopathy is a microvascular neurodegenerative disorder in diabetic patients. Peripapillary retinal nerve fiber layer changes have been described in patients with preclinical diabetic retinopathy, but study results have been inconsistent.
Objective:
To assess changes in peripapillary retinal nerve fiber layer thickness in diabetic patients with preclinical diabetic retinopathy.
Methods:
A literature search was conducted through PubMed, EMBASE, Web of Science and Cochrane Library. Case-control studies on RNFL thickness in preclinical diabetic retinopathy patients and healthy controls were retrieved. A meta-analysis of weighted mean difference and a sensitivity analysis were performed using RevMan 5.2 software.
Results:
Thirteen case-control studies containing 668 diabetic patients and 556 healthy controls were selected. Peripapillary RNFL thickness was significantly reduced in patients with preclinical diabetic retinopathy compared to healthy controls in studies applying Optical Coherence Tomography (-2.88 μm, 95%CI: -4.44 to -1.32, P = 0.0003) and in studies applying Scanning Laser Polarimeter (-4.21 μm, 95%CI: -6.45 to -1.97, P = 0.0002). Reduction of RNFL thickness was significant in the superior quadrant (-3.79 μm, 95%CI: -7.08 to -0.50, P = 0.02), the inferior quadrant (-2.99 μm, 95%CI: -5.44 to -0.54, P = 0.02) and the nasal quadrant (-2.88 μm, 95%CI: -4.93 to -0.82, P = 0.006), but was not significant in the temporal quadrant (-1.22 μm, 95%CI: -3.21 to 0.76, P = 0.23), in diabetic patients.
Conclusion:
Peripapillary RNFL thickness was significantly decreased in preclinical diabetic retinopathy patients compared to healthy control. Neurodegenerative changes due to preclinical diabetic retinopathy need more attention.
Background
Luminance contrast sensitivity and colour vision are considered to have great predictive value in the evaluation of type 2 diabetic retinopathy. However, these two visual characteristics have seldom been investigated in the same group of patients. In the present study we measured contrast sensitivity and colour vision in a group of patients with type 2 diabetes and correlated the results with estimates of common metabolic markers for the disease. A subgroup of the patients had no clinical signs of retinopathy.
Methods
The vision of 27 patients (n = 50 eyes) with type 2 diabetes, with retinopathy (n = 20 eyes), or without retinopathy (n = 30 eyes) were evaluated using two psychophysical tests, the Farnsworth–Munsell 100 hue test (FM 100), and measurements of the luminance contrast sensitivity at 11 spatial frequencies. The results were compared with measurements obtained from an age-matched control group (n = 32), and were correlated with the level of glycated haemoglobin, glycaemic level, and time of disease onset. Signs of retinopathy were identified during the ophthalmological examinations.
Results
Contrast sensitivity and colour vision impairments were present at different levels in diabetes patients. Eyes with retinopathy showed more severe vision loss than eyes without retinopathy. The FM 100 test was more sensitive for separation of patients from controls. Colour vision loss had no colour axes preference. The contrast sensitivity test appeared to have some advantage in differentiating patients with retinopathy from patients without retinopathy.
Conclusions
Both methods can be useful to follow the visual function of diabetic patients and should be used together to discriminate patients from controls, as well as to identify early signs of retinal damage.
Pericyte loss is an early characteristic change in diabetic retinopathy. Despite accumulating evidences that hyperglycemia induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study was to investigate the role of Ang2 in pericyte loss in diabetic retinopathy. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mice retina, and the source of Ang2 could be endothelial cell. Ang2 induced pericyte apoptosis via p53 pathway under high glucose while Ang2 alone did not induce apoptosis. Integrin, not Tie-2 receptor, was involved for Ang2 induced pericyte apoptosis under high glucose as an Ang2 receptor. High glucose changed integrin expression pattern which increased integrin α3 and β1 in pericyte. Furthermore, in vitro, Ang2 induced pericyte apoptosis was effectively attenuated via p53 suppression by blocking integrin α3 and β1. In vivo, while intravitreal injection of Ang2 induced pericyte loss in C57/BL6 mice retina, intravitreal injection of anti-integrin α3 and β1 antibodies attenuated Ang2 induced pericyte loss. Taken together, Ang2 induced pericyte apoptosis under high glucose via α3β1 integrin. Glycemic control or blocking Ang2/integrin signaling could be a potential therapeutic target to prevent pericyte loss in early diabetic retinopathy.
To describe the rationale and design of the Northern Finland Birth Cohort (NFBC) Eye Study.
The NFBC Eye Study is a randomised prospective cohort study. The original NFBC study population consists of 12058 subjects born in the region of Lapland and the Province of Oulu. A postal questionnaire covering extensively the medical and socioeconomical background was sent to the 10300 subjects of the NFBC alive and residing in Finland. For the NFBC eye study the subjects were randomised to the screening group (50%) and the control group (50%). The screening protocol includes the following tests: automated and manifest refraction, best corrected visual acuity, central corneal thickness, intraocular pressure, Humphrey 24--2 perimetry, stereoscopic optic nerve head (ONH) and retinal nerve fibre layer (RNFL) photography and imaging with Scanning Laser Ophthalmoscopy (HRT), Scanning Laser Polarimetry (GDx) and Optical Coherence Tomography (OCT).Two ophthalmologists evaluate the ONH and RNFL photographs and the visual fields independently. All suspected glaucoma cases are re-evaluated by two independent glaucoma experts. HRT, GDx and OCT findings are assessed separately. In the future, both groups (100%) will be examined. The effectiveness and the cost-effectiveness of glaucoma screening will be calculated. The response rate of the questionnaire was 67% (n = 6855) and 871 randomised subjects had undergone the eye screening protocol by the end of April 2013.
The trial is designed to address the following questions: what is the best combination of diagnostic tests for detecting glaucoma in an unscreened population, what are the benefits and disadvantages of the screening to the individual and the society and is glaucoma screening both effective and cost-effective. The prevalence, incidence and risk factors of glaucoma and other eye diseases will be evaluated, as well as their impact on quality of life.
Purpose:
To evaluate the changes in thickness of individual inner and outer macular and peripapillary retinal layers in diabetes.
Methods:
124 subjects (124 eyes) were enrolled: 74 diabetics and 50 controls. Macular edema, proliferative diabetic retinopathy (DR), any intraocular treatment and refractive error >6 diopters were the main exclusion criteria. Full ophthalmic examination, stereoscopic fundus photography, and spectral domain-OCT were performed. After automatic retinal segmentation (layering) in 5 layers, the thickness of each layer was calculated, and values compared among groups.
Results:
Thirty patients had no DR, 44 patients had non proliferative DR. A significant increase of inner plexiform and nuclear layers was found in DR eyes versus controls (P < 0.001). A significant decrease (P < 0.01) of retinal nerve fiber layer (RNFL) and at specific sites of retinal ganglion cell layer (P = 0.02) was documented in the macula. In the peripapillary area there were no differences between diabetics and controls.
Conclusions:
Decreased RNFL thickness and increased INL/OPL thickness in diabetics without DR or with initial DR suggest early alterations in the inner retina. On the contrary, the outer retina seems not to be affected at early stages of DM. Automatic intraretinal layering by SD-OCT may be a useful tool to diagnose and monitor early intraretinal changes in DR.
To test the hypothesis that autoantibodies against retinal pericytes could develop in diabetic retinopathy, and that these autoantibodies could induce retinal pericyte dysfunction/death via complement.
Human primary retinal pericytes cultured in media containing normal (5 mM) or high (30 mM) glucose concentrations were incubated with normal human sera in the presence of a retinal pericyte-reactive antibody, then their viability was assessed by a BCECF-based cytotoxicity assay, and their function was assessed by a T-cell proliferation assay. The pericytes were also analyzed by RT-PCR and flow cytometry to detect CD38, an established diabetes-associated cell surface autoantigen. The potential of the anti-CD38 antibodies in inducing pericyte cellular injury was evaluated using the same cytotoxicity assays. In addition, autoantibody-mediated cytotoxicity in mouse retinal pericytes sensitized by sera from mice with developing diabetic retinopathy or control normal mice were also studied.
Retinal pericyte-reactive antibodies induced cellular damage by activating complement in the serum. The antibody-injured pericytes had reduced efficacy in inhibiting T cells. Hyperglycemic culture conditions rendered pericytes more susceptible to antibody-mediated attack. CD38 was expressed in retinal pericytes, and upregulated by TNF-α and IFN-γ, and anti-CD38 antibodies induced pericyte cytotoxicity. Retinal pericytes sensitized with sera from chronic diabetic mice suffered significantly augmented cytotoxicity compared with those sensitized with sera from the control mice.
The autoantibody-initiated complement activation could be a mechanism underlying the loss of function, and eventually, death of retinal pericytes in diabetic patients, suggesting that inhibiting complement activation could be a novel therapeutic approach.
Diabetic Retinopathy (DR) is a severe and widely spread eye disease. Thus, an objective test for the early diagnosis and evaluation of treatment in DR is certainly needed. In this study, the ability of intraretinal layer segmentation to locally detect early retinal changes in diabetic patients is assessed using optical coherence tomography (OCT).
Fifty diabetic patients with no or minimal DR underwent ophthalmic examination, OCT and fundus photography. Automated segmentation of intraretinal layers of the OCT images was performed using a custom-built algorithm. Mean thickness of the macula and intraretinal layers of patients with no DR (DM) was calculated in the fovea, pericentral and peripheral regions and compared with those in patients with mild DR (MDR).
We found reduced retinal nerve fiber layer (RNFL) thickness in the pericentral and peripheral regions (27 + or - 2 versus 18 + or - 5 microm and 42 + or - 3 versus 33 + or - 9 microm, respectively, p<0.001) and reduced thickness of ganglion cell/inner plexiform layer (GCL+IPL) complex in the pericentral region of the macula (92 + or - 7 microm versus 80 + or - 10 microm, p<0.001) in the MDR group. Accordingly, macular thickness was reduced in the pericentral and peripheral region of the macula in the MDR group.
Our results support the view of neurodegeneration in diabetes in the early stage of retinopathy which seems to involve the ganglion cells and cells of the inner plexiform layers (RNFL+GCL+IPL) mostly. Local retinal thickness measures can be obtained from OCT scans using an intraretinal layer segmentation procedure, and these measures could be helpful in finding a surrogate for following development of retinopathy that could affect vision.
To elucidate changes in the neurosensory retina in the macular area, using spectral domain OCT and correlate with functional loss on fundus-related microperimetry, in patients with diabetes and no diabetic retinopathy compared with age-matched healthy volunteers.
This was a prospective study enrolling 39 patients in each group. All patients underwent comprehensive dilated eye examination. The foveal thickness and the photoreceptor layer thickness at the foveal centre were measured using spectral domain OCT, and the mean retinal sensitivity of central 20 degrees was measured using microperimetry.
The mean age of the patients with diabetes was 50.92+/-4.75 years, and of controls, 49.87+/-5.50 years. SD-OCT measured photoreceptor layer thickness (PLT) to be 61.62+/-4.48 microm in cases, and 68.79+/-7.84 microm in controls (P<0.0001); foveal thickness (FT) was 168.64+/-16.46 microm in cases and 177.74+/-14.58 microm in controls (P=0.012). The mean retinal sensitivity (MRS) of the central 20 degrees, measured on microperimetry was 15.74+/-3.74 db in cases and 17.70+/-1.5 db in controls (P<0.003). In cases compared with controls (aged under 50 years) statistically significant differences were noted in all the three outcome variables: FT, P=0.030; PLT, P=0.015; and MRS, P=0.020. The duration of diabetes influenced only the PLT (P=0.017). Statistical analysis was performed with Student's t-test and chi2 test.
Neuronal damage was observed in those eyes that did not have clinical evidence of diabetic retinopathy.
The aim of this study was to examine the relationship of retinal vascular caliber with diabetes and impaired fasting glucose (IFG) in a multiethnic Asian population.
This work was a population-based cross-sectional study comprising 3,404 Singaporean Chinese, Indian, and Malay participants. Retinal arteriolar and venular diameters, CRAE and CRVE, respectively were measured from digital retinal photographs. Diabetes was defined as physician-diagnosis of diabetes, self-reported use of diabetic medication, or fasting plasma glucose (FPG) > or = 7 mmol/L; IFG as FPG 6.1-6.9 mmol/L.
After adjusting for age, gender, ethnicity, systolic blood pressure, body mass index, total cholesterol, triglycerides, smoking, and vascular caliber (Model 3), participants with diabetes had both larger CRAE and CRVE, compared to those with normal fasting glucose (NFG) or IFG. In a multivariate analysis, including clinical risk factors and CRVE, mean CRAE increased from 143.6 microm in NFG to 145.3 microm with diabetes (P for trend = 0.01). On the other hand, each mmol/L increase in FPG was associated with a 0.51-microm increase in CRVE (P=0.006). In a subgroup analysis stratified by ethnicity, the association between FPG and larger CRVE was predominantly present among ethnic Indians (0.9-microm increase in CRVE per mmol/L increase in FPG).
Diabetes was associated with larger retinal arteriolar diameters and glucose level was associated with larger retinal venular diameters in this multiethnic Asian population. The magnitude of association between glucose level and venular widening was stronger among ethnic Indians.
The purpose of the present study was to investigate the contribution of basal nitric oxide (NO) on retinal vascular tone in humans. In addition, we set out to elucidate the role of NO in flicker-induced retinal vasodilation in humans. Twelve healthy young subjects were studied in a three-way crossover design. Subjects received an intravenous infusion of either placebo or NG-monomethyl-L-arginine (L-NMMA; 3 or 6 mg/kg over 5 min), an inhibitor of NO synthase. Thereafter, diffuse luminance flicker was consecutively performed for 16, 32, and 64 s at a frequency of 8 Hz. The effect of L-NMMA on retinal arterial and venous diameter was assessed under resting conditions and during the hyperemic flicker response. Retinal vessel diameter was measured with a Zeiss retinal vessel analyzer. L-NMMA significantly reduced arterial diameter (3 mg/kg: -2%; 6 mg/kg: -4%, P < 0.001) and venous diameter (3 mg/kg: -5%; 6 mg/kg: -8%, P < 0.001). After placebo infusion, flicker induced a significant increase in retinal vessel diameter (P < 0.001). At a flicker duration of 64 s, arterial diameter increased by 4% and venous diameter increased by 3%. L-NMMA did not abolish these hyperemic responses but blunted venous vasodilation (P = 0.017) and arterial vasodilation (P = 0.02) in response to flicker stimulation. Our data indicate that NO contributes to basal retinal vascular tone in humans. In addition, NO appears to play a role in flicker-induced vasodilation of the human retinal vasculature.
To investigate the expression of the apoptotic mediators in the retinas from human subjects with diabetes mellitus.
Ten donor eyes from five subjects with diabetes mellitus, and eight eyes from four nondiabetic subjects without known ocular disease serving as control subjects were examined. Immunohistochemical techniques were used with antibodies directed against glial fibrillary acidic protein (GFAP), caspase-3, Fas, Fas ligand (FasL), Bax, Bcl-2, survivin, p53, extracellular signal-regulated kinases (ERK1/2), and p38.
In retinas from all subjects without diabetes, weak Bcl-2 immunoreactivity was confined to GFAP-positive glial cells in the nerve fiber layer. Weak immunoreactivity for ERK1/2 was noted in a few nuclei in the inner nuclear layer and in a few Müller cell processes. Cytoplasmic immunostaining for survivin was noted in the retinal pigment epithelial cells. There was no immunoreactivity for the other antibodies tested. All diabetic retinas showed cytoplasmic immunoreactivity for caspase-3, Fas, and Bax in ganglion cells. FasL immunoreactivity was detected in GFAP-positive cells. Upregulation of Bcl-2 immunoreactivity was noted in GFAP-positive cells in nerve fiber and ganglion cell layers, and Bcl-2 induction was noted in Müller cell processes. Strong immunoreactivity for ERK1/2 was observed in many nuclei in the inner nuclear layer in GFAP-positive cells in the nerve fiber and ganglion cell layers and numerous Müller cell processes. Survivin immunoreactivity was not altered in the diabetic retinas. There was no immunoreactivity for p53 and p38.
Ganglion cells in diabetic retinas express several proapoptosis molecules, suggesting that these cells are the most vulnerable population. Glial cells in diabetic retinas are activated and express several antiapoptosis molecules in addition to the cytotoxic effector molecule FasL, suggesting a possible role of glial cells in induction of apoptosis in ganglion cells.
To investigate the expression of the antiapoptotic and proapoptotic markers in diabetic retinas.
In total, 12 donor eyes from six subjects with diabetes mellitus, and 10 eyes from five nondiabetic subjects without known ocular disease serving as control subjects were examined. Immunohistochemical techniques were used with antibodies directed against cyclooxygenase-2 (Cox-2), Akt (protein kinase B), Mcl-1, Bad, cytochrome c, apoptosis-inducing factor (AIF), tumour necrosis factor receptor-1-associated death domain protein (TRADD), and Fas-associated death domain protein (FADD).
In retinas from all subjects without diabetes, cytoplasmic immunoreactivity for the antiapoptotic molecules Cox-2, Akt, and Mcl-1 was noted in ganglion cells. Cytoplasmic immunostaining for Cox-2 was also noted in the retinal pigment epithelial cells. Weak immunoreactivity for the mitochondrial apoptogenic proteins cytochrome c, and AIF was noted in the inner segments of photoreceptors, in the inner one-third of the outer plexiform layer, in cells in the inner nuclear layer, in the inner plexiform layer, and in ganglion cells. There was no immunoreactivity for the other antibodies tested. All diabetic retinas showed de novocytoplasmic immunoreactivity for Bad in ganglion cells, and in occasional cells in the inner nuclear layer. Upregulation of cytochrome cand AIF immunoreactivity was noted. Cox-2, Akt, and Mcl-1 immunoreactivity was not altered in the diabetic retinas. There was no immunoreactivity for TRADD, and FADD.
Ganglion cells in diabetic and nondiabetic retinas express the antiapoptotic molecules Cox-2, Akt, and Mcl-1. Retinal ganglion cells express the proapoptotic molecule Bad in response to diabetes-induced neuronal injury. Diabetic retinas show upregulation of the mitochondrial proteins cytochrome c, and AIF.
To examine the relationship of retinal vascular caliber with diabetes, glycemia, and diabetic retinopathy.
Population-based study using data from the Multi-Ethnic Study of Atherosclerosis (MESA), comprising 5,976 individuals (whites, blacks, Hispanics, and Chinese) residing in six U.S. communities who were free of clinical cardiovascular disease at baseline. Retinal vascular caliber was measured from digital retinal photographs.
There were 4,585 individuals with normal fasting glucose (NFG), 499 with impaired fasting glucose (IFG), 165 with diabetes with retinopathy signs, and 727 with diabetes without retinopathy signs. After multivariate analysis, retinal arteriolar caliber increased from 143.8 microm in subjects with NFG to 144.5 microm in IFG and 146.1 microm in diabetes (P < 0.001 for trend). Retinal venular caliber increased from 214.4 microm in NFG to 216.7 microm in IFG and 218.0 microm in diabetes (P < 0.001 for trend). Retinal venular caliber was significantly larger with increasing levels of fasting glucose and A1C. In a subgroup analysis by ethnicity, the association between wider arteriolar caliber and diabetes was evident in whites only, whereas wider venular caliber and diabetes was evident in Hispanics and Chinese only. In people with diabetes, eyes with retinopathy had larger retinal venular but not arteriolar caliber.
Retinal arteriolar and venular calibers are larger in individuals with diabetes, but the pattern of associations appears to vary by ethnicity. Retinal venular caliber is additionally associated with retinopathy signs. These findings add further to the concept that variations in retinal vascular caliber may reflect early diabetic microvascular damage.
To examine the relationship of retinal vascular caliber to incident diabetes in a population-based cohort.
The Australian Diabetes, Obesity and Lifestyle (AusDiab) Study recruited adults aged 25+ years across Australia in 1999-2000, with a follow-up 5 years later in 2004-2005. Participants' glycemic status was classified using fasting plasma glucose (FPG) and 2-h oral glucose tolerance (2-h plasma glucose [2hPG]) tests. Diabetes was diagnosed if FPG was >or=7.0 mmol/l or 2hPG was >or=11.1 mmol/l. Retinal vascular caliber was measured from baseline retinal photographs using a computer-assisted program.
Of the 803 participants without diabetes at baseline, 108 (13.4%) developed diabetes at follow-up: 7 (2.8%) of 246 participants with normal glucose tolerance, 9 (13.6%) of 66 participants with impaired fasting glucose, and 92 (18.7%) of 491 participants with impaired glucose tolerance. After multivariate analysis, participants with narrower retinal arteriolar caliber had a higher risk of diabetes (odds ratio 2.21 [95% CI 1.02-4.80], comparing smallest versus highest arteriolar caliber tertiles, P = 0.04 for trend). There was no association between retinal venular caliber and incident diabetes.
Narrower retinal arteriolar caliber predicted risk of diabetes. These data provide further evidence that microvascular changes may contribute to the pathogenesis of diabetes.
Aims: To investigate the loss of retinal nerve fiber layer (RNFL) in type-2 diabetic patients with early-stage diabetic retinopathy (DR) and to identify potential risk factors accounting for these alterations.
Methods: In this cross-sectional study, 158 type-2 diabetic patients were divided into three groups based on their DR status. RNFL thickness and other optic disc parameters were obtained by optical coherence tomography (OCT) and then compared among different groups. We investigated the potential association between RNFL loss and systemic risk factors for DR, including diabetes duration, body mass index (BMI), serum lipids, hemoglobin A1c (HbA1c) and albumin-creatinine ratio (ACR). One-way ANOVA was carried out to compare RNFL thickness among different groups, Pearson correlation and multivariate linear regression analysis were performed to determine potential risk factors related to RNFL thickness in these patients.
Results: There were significant differences in the average (F = 8.872, P = 0.003), superior (F = 8.769, P = 0.004), and inferior (F = 8.857, P = 0.003) RNFL thickness of both eyes among the groups, but no obvious difference in optic disc parameters was found. Diabetic duration, BMI, TG, High density lipoprotein cholesterol (HDL), HbA1c, and ACR were found negatively related to the RNFL thickness in both or single eye according to Pearson correlation analysis. After controlling for age, gender, and axis length (AL) in multivariate linear regression analysis, the diabetic duration was associated significantly with RNFL thickness of superior in both eye (right eye: p = 0.016, left eye: p = 0.024), BMI was related to the nasal quadrant of the right eye (p = 0.034), and TG was related to the inferior of the right eye (p = 0.037), HbA1c (p = 0.026) was associated significantly with the average RNFL thickness of the right eye. In addition, ACR was found negatively related to average (p = 0.042) and inferior quadrant (p = 0.014) of the left eye, respectively.
Conclusions: RNFL loss might be the earliest structural change of retina in diabetic patients, and associated with diabetic duration, BMI, TG, HbA1c, and ACR. The conclusions of this study need to be proved by other well-matched and large-scale prospective clinical trials in the future, because the correlations discovered in our study were weak.
Purpose:
To assess macular thinning in individuals with prediabetes or type 2 diabetes without diabetic retinopathy (DM2 w/o DR) compared with individuals with normal glucose metabolism (NGM).
Methods:
Using spectral domain optical coherence tomography (SD-OCT), we measured macular thickness in six subfields as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) in 1838 participants from The Maastricht Study, a population-based cohort study (mean age 59 ± 8 years, 49% men, 1087 NGM, 279 prediabetes, 472 DM2 w/o DR). Multivariable linear regression was used to assess the association between macular thickness and glucose metabolism status.
Results:
After adjustment for age, sex and spherical equivalent, individuals with prediabetes showed a significant decrease in pericentral superior macular thickness [β = -2.14 μm (95% confidence interval (CI): -4.24 to -0.03), p < 0.05] compared with individuals with NGM. In individuals with DM2 w/o DR, the fovea [β = -4.05 μm (95% CI: -6.30 to -1.79), p < 0.001] and the four pericentral quadrants (range: β = -4.64 to -5.29 μm, p < 0.001) were significantly thinner compared with individuals with NGM. There was a significant linear trend of macular thinning with severity of glucose metabolism status in five subfields (p < 0.001).
Conclusion:
Macular thickness is reduced in prediabetes and a greater reduction occurs in DM2, even before DR is clinically present. About half of the thinning observed in DM2 w/o DR was already found in prediabetes. Generalized thinning of the macula could be related to thinning of the temporal side of the optic nerve head through the connecting papillo-macular bundle.
Purpose: To compare the retina ganglion cell complex (GCC) layer and peripapillary nerve fibre layer thickness (pRNFL) in patients with prediabetes and healthy subjects analysed by spectral domain optical coherence tomography (SD-OCT).
Methods: This cross-sectional and comparative study included prediabetic patients and healthy subjects. All participants underwent SD-OCT measurement of pRNFL thickness, and GCC thickness.
Results: A total of 30 eyes of the 30 patients with prediabetes and 30 eyes of 30 controls were included. The overall calculated pRNFL thicknesses were similar between the prediabetic and control subjects. The GCC thickness was significantly lower in all quadrants of the inner macula, and outer nasal quadrant in the prediabetes group when compared to the control group.
Conclusion: Our study demonstrated that inner macular GCC thickness was significantly thinner in prediabetic subjects. As a result neurodegeneration may play role in the thinning of GCC.
Purpose:
Diabetes mellitus (DM) is one of the most important risk factors for nonarteritic anterior ischemic optic neuropathy (AION). In this study, we investigated for the first time the impact of experimental AION in a DM model.
Methods:
We induced a photochemical thrombosis model of AION after streptozotocin-induced DM and performed serial optical coherence tomography (OCT), morphometric analyses, and VEGF levels in the retina and sera.
Results:
Compared with non-DM animals, experimental AION in DM mice led to significantly greater retinal swelling on day 1 and worse thinning at week 3 on OCT measurements. Greater retinal swelling on OCT in DM-AION eyes was associated with significantly increased loss of brain-specific homeobox/POU domain protein 3A (Brn3A+) retinal ganglion cells at week 3. In acute AION, there was greater inflammation as seen by an increase in ionized calcium-binding adapter molecule 1 (Iba1+)-activated microglia. On day 1, there was increase in vascular endothelial growth factor (VEGF) level in nondiabetic AION retinae and sera, but the VEGF level was the highest in the diabetic AION group, which decreased to nondiabetic levels after insulin treatment. The decrease in retinal and serum VEGF levels after insulin treatment correlated with a reduction in retinal swelling.
Conclusions:
In the setting of hyperglycemia, AION led to greater acute, postischemic microglial activation and elevation of VEGF levels, which likely contributed to greater retinal swelling acutely and worse retinal thinning and loss of retinal ganglion cells chronically. Treatment of hyperglycemia with insulin reduced VEGF levels and retinal swelling, consistent with the idea that VEGF is an important factor in postischemic swelling and that good glycemic control following AION may lead to better visual outcome.
Purpose: To evaluate the macular and peripapillary choroidal thickness and retinal volume in prediabetes.
Material and Methods: This prospective comparative study included 53 patients with prediabetes and 53 age- and sex-matched healthy subjects. Only right eyes were selected. Choroidal thicknesses (CT) and retinal volume were measured by optical coherence tomography. Macular CT was measured at the seven points including macular center, 1, 2, and 3 mm distances along the temporal and nasal scans. Peripapillary CT was measured at the eight points of the optic disk area. Systemic and laboratory findings of the subjects were also recorded.
Results: There were no significant differences in blood pressures, ocular findings including intraocular pressure, visual acuity, and refractive powers, and macular volumes between the two groups (p > 0.005). Macular and peripapillary CT at all measuring points, body mass index (BMI), fasting blood glucose (FBG), hemoglobinA1C, and lipid profile were significantly higher in prediabetic patients (p < 0.05). There was a significant positive correlation between all points of macular choroidal thicknesses with BMI, FBG, and hemoglobin A1C (p < 0.05).
Conclusion: Prediabetic factors including impaired FBG, increased hemoglobinA1C, and BMI are independent risk factors for increase in choroidal thickness. Increased macular choroidal thickness may be the earliest determiner to detect the onset of diabetic retinopathy in prediabetes.
Background:
-Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease (CVD). This can be partly explained by large artery dysfunction, which already occurs in prediabetes ('ticking clock hypothesis'). Whether a similar phenomenon also applies to microvascular dysfunction is not known. We therefore tested the hypothesis that microvascular dysfunction is already present in prediabetes and is more severe in T2DM. To do so, we investigated the associations of prediabetes, T2DM, and measures of hyperglycemia with microvascular function measured as flicker light-induced retinal arteriolar dilation and heat-induced skin hyperemia.
Methods:
-In The Maastricht Study, a T2DM-enriched population-based cohort study (N=2213, 51% men, aged ((mean±standard deviation (SD)) 59.7±8.2 years), we determined flicker light-induced retinal arteriolar %-dilation (Dynamic Vessel Analyzer), heat-induced skin %-hyperemia (laser-Doppler flowmetry) and glucose metabolism status (OGTT; normal glucose metabolism (NGM), (N=1269), prediabetes (N=335) or T2DM (N=609)). Differences were assessed with multivariable regression analyses adjusted for age, sex, body mass index, smoking, physical activity, systolic blood pressure, lipid profile, retinopathy, estimated glomerular filtration rate, (micro)albuminuria, the use of lipid-modifying and/or blood pressure-lowering medication, and prior CVD.
Results:
-Retinal arteriolar %-dilation was (mean±SD) 3.4±2.8 in NGM, 3.0±2.7 in prediabetes, and 2.3±2.6 in T2DM. Adjusted analyses showed a lower arteriolar %-dilation in prediabetes (B=-0.20,95%CI [-0.56;0.15]), with further deterioration in T2DM (B=-0.61, [-0.97;-0.25]) vs NGM, p for trend=0.001. Skin %-hyperemia was (mean±SD) 1235±810 in NGM, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed a lower %-hyperemia in prediabetes (B=-46, [-163;72]), with further deterioration in T2DM (B=-184, [-297;-71]) vs NGM, p for trend=0.001. In addition, higher HbA1c and fasting plasma glucose (FPG) were associated with lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for HbA1c, standardized B (stB)=-0.10, [-0.15;-0.05], p<0.001 and stB=-0.13, [-0.19;-0.07], p<0.001, respectively; for FPG, stB=-0.09, [-0.15;-0.04], p<0.001 and stB=-0.10, [-0.15;-0.04], p=0.002, respectively).
Conclusions:
-Prediabetes, T2DM and measures of hyperglycemia are independently associated with impaired microvascular function in the retina and skin. These findings support the concept that microvascular dysfunction precedes and thus may contribute to T2DM-associated CVD and other complications which may in part have a microvascular origin, such as impaired cognition and heart failure.
Purpose:
To investigate the characteristics of retinal nerve fiber layer (RNFL) defects associated with type II diabetes.
Methods:
Forty nonglaucomatous eyes with type II diabetes and 54 eyes with early open angle glaucoma that exhibited a localized RNFL defect and 42 eyes from age- and sex-matched nondiabetic, nonglaucomatous controls were imaged with red-free fundus photography and optical coherence tomography (Cirrus HD-OCT, Carl Zeiss Meditec). The area under the receiver operating characteristic curves of eyes with diabetes was compared with that of eyes with glaucoma. When an RNFL defect on fundus photographs was identified in the quadrant, clock-hour, temporal-superior-nasal-inferior-temporal (TSNIT), deviation, and thickness maps, it was considered a true detection.
Results:
In eyes with diabetes, the RNFL defects were located more frequently in the superior hemisphere than they were in those with glaucoma (P < 0.001). The angular locations of RNFL defects in eyes with diabetes (56.1 ± 12.7°) were significantly farther from the fovea compared with those in glaucoma (44.3 ± 17.3°; P < 0.001); in addition, the width of RNFL defects in diabetes (5.1 ± 2.3°) was significantly narrower than those in glaucoma (20.8 ± 12.3°; P < 0.001). The best parameter discriminating RNFL defects in diabetes from those in glaucoma was width of RNFL defect (0.955), followed by rim area (0.844), and average RNFL (0.791). The thickness map showed a sensitivity (70%) and specificity (69.1%), superior to those of all other maps in eyes with diabetes.
Conclusions:
The narrow width and identification of RNFL defect in thickness map obtained with Cirrus HD-OCT seems to be an effective tool for detecting RNFL defects in diabetes.
Purpose:
The purpose of this study was to assess changes in the neural retina in eyes with different stages of diabetic retinopathy (DR) in comparison to age-matched healthy subjects.
Methods:
Retrospective analysis of spectral-domain optical coherence tomography (SD-OCT) scans of 76 naïve eyes of 62 subjects with diabetes was performed. Key exclusion criteria included presence of diabetic macular edema, any other retinal disease, history of any treatment for DR, or incorrect segmentation of the retinal layers on SD-OCT scans. Eyes from diabetic patients were divided into three groups, including no DR, nonproliferative DR (NPDR), and proliferative DR (PDR). A control group of 67 eyes of 66 age-matched healthy volunteers was included for comparison. Average, minimum, and sectoral thicknesses for the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) were collected from both groups and compared using an ANOVA test.
Results:
Among the 76 included eyes, 43 had NPDR, 13 had PDR, and 20 had no signs of DR. Average and minimum GCIPL showed significant thinning in diabetic subjects compared with controls in all stages of DR (P < 0.05), especially involving the papillo-macula bundle. However, GCIPL thickness was similar between diabetic groups. There was no significant difference in average or sectoral RNFL thicknesses among groups; however, the minimum RNFL thickness was lower in diabetics compared with controls (P < 0.05). No relationship between GCIPL and RNFL thicknesses and duration of diabetes was present.
Conclusions:
Early thinning on the inner retina happens in type 2 diabetes, even before visible vascular signs of DR. This supports the presence of a neurodegenerative process in eyes of patients with diabetes and warrants neuroprotective intervention to prevent chronic neurodegeneration. The SD-OCT may represent an indispensable tool for identifying early signs of neurodegeneration in diabetic patients.
The purpose of this study was to determine whether diabetes type 2 causes thinning of retinal layers as a sign of neurodegeneration and to investigate the possible relationship between this thinning and duration of diabetes mellitus, diabetic retinopathy (DR) status, age, sex, and glycemic control (HbA1c).
Mean layer thickness was calculated for retinal layers following automated segmentation of spectral domain optical coherence tomography images of diabetic patients with no or minimal DR and compared with controls. To determine the relationship between layer thickness and diabetes duration, DR status, age, sex, and HbA1c, a multiple linear regression analysis was used.
In the pericentral area of the macula, the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) were thinner in patients with minimal DR compared to controls (respective difference 1.9 μm, 95% confidence interval [CI] 0.3-3.5 μm; 5.2 μm, 95% CI 1.0-9.3 μm; 4.5 μm, 95% CI 2.2-6.7 μm). In the peripheral area of the macula, the RNFL and IPL were thinner in patients with minimal DR compared to controls (respective difference 3.2 μm, 95% CI 0.1-6.4 μm; 3.3 μm, 95% CI 1.2-5.4 μm). Multiple linear regression analysis showed DR status to be the only significant explanatory variable (R = 0.31, P = 0.03) for this retinal thinning.
This study demonstrated thinner inner retinal layers in the macula of type 2 diabetic patients with minimal DR than in controls. These results support the concept that early DR includes a neurodegenerative component.
Mitochondrial dysfunction is known to play a role in retinal vascular cell loss, a prominent lesion of diabetic retinopathy. High glucose (HG) has been reported to induce mitochondrial fragmentation and dysfunction in retinal endothelial cells, contributing to apoptosis. In this study, the effects of HG on mitochondrial morphology, membrane potential, and metabolic changes and whether they could contribute to HG-induced apoptosis in retinal pericytes were investigated.
Bovine retinal pericytes (BRPs) were grown in normal or HG medium for 7 days. Both sets of cells were double stained with mitochondrial membrane potential-independent dye and tetramethylrhodamine-ethyl-ester-perchlorate (TMRE) and imaged by confocal microscopy. The images were analyzed for average mitochondria shape, by using form factor and aspect ratio values, and membrane potential changes, by using the ratio between the red and green dye. BRPs grown in normal or HG medium were analyzed for transient changes in oxygen consumption and extracellular acidification with a flux analyzer and apoptosis by TUNEL assay.
BRPs grown in HG media exhibited significant fragmentation of mitochondria and increased membrane potential heterogeneity compared with the BRPs grown in normal medium. Concomitantly, BRPs grown in HG showed reduced steady state and maximum oxygen consumption and reduced extracellular acidification. Number of TUNEL-positive pericytes was increased in HG condition as well.
In HG condition, mitochondria of retinal pericytes display significant fragmentation, metabolic dysfunction, and reduced extracellular acidification. The detrimental effects of HG on mitochondrial function and cellular metabolism could play a role in the accelerated apoptosis associated with the retinal pericytes in diabetic retinopathy.
To describe the relationship of retinal arteriolar and venular caliber with diabetes, retinopathy and hyperglycemia, in an Asian Indian population.
This was a population-based cross-sectional study of 3400 (75.6% response rate) Singapore ethnic Indians aged 40-80 years. Central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were obtained using a validated computer-assisted program. Diabetes mellitus was identified using standardized criteria. Diabetic retinopathy was graded based on the modified Airlie House Classification System.
There were 980 (32.2%) participants with diabetes. Of these, 327 (33.4%) had diabetic retinopathy. After multivariate adjustment, diabetic persons had a wider CRAE (145.23μm vs 142.38μm, P<0.001). This relationship was stronger in persons without hyperlipidemia (P-interaction<0.1). Among diabetic participants, wider CRVE was related to increasing severity of retinopathy (P for trend<0.05) and this association may be altered by hypertensive status. Retinal arteriolar caliber widened with increasing glucose (P<0.001) and HbA1C (P<0.001) levels.
In Indian adults, wider retinal arteriolar caliber is associated with diabetes and hyperglycemia, while wider retinal venular caliber is associated with diabetic retinopathy. This is consistent with white populations and confirms the differential systemic association of retinal vascular caliber in Asian Indians.
Diabetic retinopathy (DR) classically presents with micro-aneurysms, small haemorrhages and/or lipoprotein exudates. Several studies have indicated that neural loss occurs in DR even before vascular damage can be observed. This study evaluated the possible relationship between structure (spectral domain-optical coherence tomography) and function (Rarebit visual field test) in patients with type 1 diabetes mellitus and no or minimal diabetic retinopathy (DR). Results demonstrated loss of macular visual function and corresponding thinning of the ganglion cell layer (GCL) in the pericentral area of the macula of diabetic patients (Rs = 0.65, p < 0.001). In multivariable logistic regression analysis, GCL thickness remained an independent predictor of decreased visual function (OR 1.5, 95% CI 1.1-2.1). Early DR seems to include a neurodegenerative component.
To assess the relationship of foveal microcirculation to contrast sensitivity function in early diabetes mellitus.
Twenty patients with diabetes with visual acuity of 20/25 or better without clinically significant macular edema were evaluated. Measurements of contrast sensitivity at four spatial frequencies (3, 6, 12, and 18 cycles/degree [c/deg]), macular capillary blood velocity (CBV), capillary density (PIA: perifoveal intercapillary area), foveal avascular zone (FAZ), and microaneurysm count were performed. Contrast sensitivity data collected from age-matched normal subjects and previously published normal angiographic data were used for comparison with our cohort with diabetes.
The CBV was significantly reduced (P < 0.0001) and PIA and FAZ were significantly enlarged (P < 0.0001) when compared with healthy subjects. Contrast sensitivity was significantly lower in the group with diabetes at 6 (P = 0.01) and 12 (P = 0.002) c/deg as compared with healthy control values. FAZ and PIA correlated significantly (FAZ; r = -0.60, P = 0.005; PIA; r = -0.54, P = 0.02) with contrast sensitivity at 12 c/deg.
The alterations of the perifoveal network are related to selective disturbances of central visual function as measured by contrast sensitivity. In patients with diabetes measurement of contrast sensitivity may provide a clinical adjunct in further identifying early ischemic diabetic maculopathy.
Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique.
In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis.
The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp.
Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.
Background/Purpose. Recent findings suggest that an objective assessment of retinal vessel caliber from fundus photographs provide information about the association of microvascular characteristics with macrovascular disease. Current methods used to quantify retinal vessel caliber, introduced by Parr(1,2) and Hubbard,(3) are not independent of scale and are affected by the number of vessels. To improve upon these methods we introduce revised formulas for quantifying vessel caliber. Methods. Revised formulas were estimated using retinal vessel measurements from 44 young adults free of hypertension and diabetes. Comparisons between the two methods were done using digitized photographs from 4926 participants at the baseline examination of the Beaver Dam Eye Study (BDES), an ongoing population-based cohort study initiated in 1987. Individual arterioles and venules were measured using semi-automated computer software from which summary measures were calculated. Results. Correlation coefficients between the Parr-Hubbard and revised formulas were high (Pearson correlation coefficients ranging from 0.94 to 0.98). Both arteriolar and venular caliber significantly increased with an increasing number of vessels measured using the Parr-Hubbard formulas (p < 0.001), which in turn affected the relationship to mean arterial blood pressure. To the contrary, the revised formulas were not affected by the number of measured vessels (p > 0.50). Conclusions. We describe revised formulas for summarizing retinal vessel diameters measured from fundus photographs to be used in future studies and analyses. The revised formulas correlate highly with the previously used Parr-Hubbard formulas, but offer the advantages of being more robust against variability in the number of vessels observed, being independent of image scale, and being easier to implement.
Microvascular disease and hypertension have been linked with risk of diabetes mellitus. We examined the association of retinal arteriolar narrowing, a marker of chronic hypertension, with incident diabetes.
Prospective cohort study of 3251 nondiabetic persons aged 43 to 86 years living in Wisconsin. The diameters of retinal vessels were measured from baseline retinal photographs of participants. Retinal measurements were summarized as the retinal arteriole-to-venule ratio, with smaller ratios indicating narrower arteriolar diameters. Incident diabetes cases were ascertained at the 5-year and 10-year follow-up examinations.
There were 249 incident diabetes cases. Participants with narrower retinal arteriolar diameters had a higher incidence of diabetes (cumulative incidences of 5.1%, 7.0%, 9.2%, and 11.7%, comparing decreasing quartiles of arteriole-to-venule ratio). After controlling for baseline casual blood glucose level, glycosylated hemoglobin level, body mass index, and other risk factors, retinal arteriolar narrowing was significantly associated with risk of incident diabetes (multivariable-adjusted relative risk, 1.53; 95% confidence interval, 1.03-2.27; comparing smallest to largest arteriole-to-venule ratio quartiles). Participants with both hypertension and retinal arteriolar narrowing had a 3-fold higher risk of incident diabetes (multivariable-adjusted relative risk, 3.41; 95% confidence interval, 1.66-6.98) than normotensive participants without arteriolar narrowing.
Retinal arteriolar narrowing is related to risk of incident diabetes. These data suggest a possible link between systemic arteriolar narrowing associated with hypertension and diabetes development.
To examine the relationship of systemic markers of inflammation, endothelial dysfunction, and serum folate level to retinal vessel diameter.
Cross-sectional analyses were completed for data from a random sample of 396 persons aged 50 to 86 years who underwent a baseline examination from 1988 to 1990. Standardized protocols for blood collection and measurement of markers were used. Diameters of arterioles and venules were measured from digitized photographs. Standard univariate and multivariate analyses were performed.
While controlling for age, smoking status, diabetes status, serum high-density lipoprotein cholesterol, and hematocrit, wider retinal venular diameters were associated with higher serum high-sensitivity C-reactive protein, interleukin 6, and amyloid A levels. While controlling for age, systolic and diastolic blood pressure, smoking, serum high-density lipoprotein cholesterol level, and gout, smaller arteriolar diameters were associated with higher serum amyloid A and lower serum albumin and folate levels but not high-sensitivity C-reactive protein or interleukin 6 levels. Levels of serum soluble intercellular adhesion molecule-1 and serum soluble E-selectin, markers of endothelial dysfunction, were not associated with retinal arteriolar or venular diameters.
These data show an association of inflammatory markers with larger retinal venular diameter, suggesting that retinal venular caliber may be a marker of systemic inflammation.
The association between a smaller retinal arteriolar-to-venular ratio (AVR) and incident diabetes may be due to arteriolar narrowing, venular dilatation, or both. We investigated associations between baseline vessel diameters and incident impaired fasting glucose or diabetes in a population-based cohort (aged > or =55 years). Baseline retinal vessel diameters (1990-1993) were measured on digitized images of 2,309 subjects with a normal glucose tolerance test (postload glucose <7.8 mmol/l). At follow-up (1997-1999), impaired fasting glucose was defined as 6.1-7.0 mmol/l and diabetes as > or =7.0 mmol/l and/or antidiabetic medication use. Odds ratios (ORs) per SD increase in venular diameters were 1.13 (95% CI 1.00-1.29) for impaired fasting glucose and 1.09 (0.90-1.33) for diabetes. ORs per SD decrease in arteriolar diameters were 1.12 (0.98-1.27) and 1.08 (0.89-1.31) and per SD decrease in AVR were 1.29 (1.13-1.46) and 1.19 (0.98-1.45). After adjustment for cardiovascular risk factors, the associations were unaltered for venules and disappeared for arterioles. After stratification on age, associations between venular dilatation and impaired fasting glucose (1.23 [1.02-1.47]) or diabetes (1.18 [0.89-1.56]) were mainly present in participants aged <70 years. In conclusion, in our study, the risk of impaired fasting glucose and diabetes with AVR was explained by venular dilatation rather than arteriolar narrowing, warranting more focus on the causes of this dilatation.