Early-onset type 2 diabetes: high risk for premature diabetic retinopathy

Aim

To examine the relationship between early-onset type 2 diabetes (T2D) and retinopathy in relation to the burden, severity, the extent of its premature development and associated predictive risk factors.

Methods

A cross sectional study using the hospital diabetes register and eye screening database to identify T2D subjects and to ascertain retinopathy severity. Early and later-onset cohort were defined as age of diagnosis <40 and >40 years respectively.

Results

2516 subjects were identified of which 455 were diagnosed below 40 years. After 10 years of diagnosis, the prevalence of overall retinopathy was significantly higher in the early-onset cohort (p < 0.05). For significant retinopathy (SigDR), there was a non-significant trend of higher prevalence with increasing diabetes duration in the early-onset cohort. The rate of increase for SigDR was greater in the early-onset cohort who experienced similar burden of SigDR up to 20 years earlier than the later-onset cohort. Hypertension (p < 0.05), suboptimal glycaemic control (p < 0.05) and long diabetes duration (p < 0.05) were associated with risk of retinopathy whilst lower age of diagnosis and dyslipidaemia were not significant predictive factors.

Conclusions

Early-onset T2D subjects are at risk of developing premature retinopathy driven predominantly by hypertension and prolonged exposure to suboptimal diabetes control.     

Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy

Serum pigment epithelium-derived factor (PEDF) levels were significantly higher in type 1 diabetic patients with retinopathy (n = 20, 10.38 ± 3.87 μg/ml) compared to the patients without it (n = 57, 7.68 ± 2.80 μg/ml) (p = 0.0013). Elevated PEDF levels may be related to the progression of diabetic retinopathy.     

Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients

The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy.     

The effects of fasting plasma glucose variability and time-dependent glycemic control on the long-term risk of retinopathy in type 2 diabetic patients

Long-term fasting plasma glucose (FPG) variability was a risk factor for proliferative diabetic retinopathy (PDR) independent of the mean FPG or HbA1c in people with type 2 diabetes. PDR development was also significantly associated with mean HbA1c more than 5 years earlier and with mean FPG more than 10 years earlier.     

Relationship between diabetic retinopathy and diabetic nephropathy; A longitudinal follow-up study from a tertiary care unit of Karachi,Pakistan

ObjectiveTo determine the development and progression of diabetic retinopathy in subjects with diabetic nephropathy.MethodologyThis retrospective longitudinal follow up study was conducted in outpatient department of Baqai Institute of Diabetology and Endocrinology (BIDE), a tertiary care diabetes unit of Karachi Pakistan, from January 2005 to December 2016. Type 2 diabetic subjects with newly diagnosed diabetic nephropathy (DN) and sex-age matched controls were identified from the electronic database of the institute, Health Management System (HMS). Subjects with type 1 diabetes, gestational diabetes and subjects with diabetic retinopathy (DR) at the baseline of both DN and non-DN group were excluded from the study. Statistical analyses were conducted by using SPSS version 20.ResultOut of 3056 type 2 diabetic subjects, 2389 were with DN and 667 were without DN. The incidence of retinopathy was found to be 21.7 per 1000 person years. The incidence rate ratio (IRR) of 2.57 (1.92–3.43) showed that retinopathy was significantly higher in subjects with DN as compared to subjects without DN. Kaplan-Meier survival plot confirmed that subjects with DN had a worse diabetic retinopathy-free survival than subjects without DN.ConclusionDiabetic nephropathy is an independent risk factor for the development and progression of diabetic retinopathy.     

A genetic study of retinopathy in South Indian Type 2 (non-insulin-dependent) diabetic patients

Summary Genetic marker studies in diabetic retinopathy are controversial and frequently complicated by possible independent associations of Type 1 (insulin-dependent) diabetes mellitus with the markers so far analysed. We have looked for associations of candidate genes with retinopathy in South Indian Type 2 (non-insulin-dependent) diabetic patients; patients were subdivided into those with exudative maculopathy (n=53), proliferative retinopathy (n=40) and patients free from diabetic retinopathy with a minimum disease duration of 15 years (n=45). DNA was extracted from blood samples and studied by Southern blot hybridisation techniques and the following probe enzyme combinations: HLA-DQB1; Taq 1, HLA-DQA1; Taq 1, HLA-DRA; Bgl II, insulin gene hypervariable region; Pvu II and the switch region of the immunoglobulin IgM heavy chain gene (S); Sac I. Differences in genotype distributions between the study groups were only detected with the S probe which detects polymorphism of both S and S1 (the switch region of IgA). Two alleles of S1 were detected sized 7.4 kilobase and 6.9 kilobase. The frequency of 6.9 kilobase homozygotes was lower in proliferative retinopathy (19%) compared to patients free from diabetic retinopathy (54%, p=0.005) and exudative maculopathy (46%, p=0.03). This data suggests that there is a genetic predisposition to proliferative retinopathy in Type 2 (non-insulin-dependent) diabetes of South Indian origin and that this is determined by polymorphism of the heavy chain immunoglobulin genes located on chromosome 14.     

Risk factors for development and progression of nonproliferative retinopathy in normoalbuminuric patients with type 1 diabetes

BackgroundThe aim of this study was to evaluate risk factors for development and progression of nonproliferative retinopathy (NPR) in normoalbuminuric patients with type 1 diabetes mellitus (T1DM).MethodsA total of 223 T1DM with normal renal function and normoalbuminuria were included in this study and followed for 48 months. Photodocumented retinopathy status was made according to the EURODIAB protocol. Urinary albumin excretion rate (UAE) was measured from at least two 24-h urine samples. Possible risk factors for development or progression of NPR were examined in backward stepwise Cox's multiple regression analysis.ResultsThe majority of patients (70%) had no retinopathy while 67 (30%) had NPR at baseline. Patients with NPR were older, had longer duration of diabetes, higher systolic blood pressure, BMI, resting heart rate, UAE and lower estimated glomerular filtration rate (p ≤ 0.04 for all). After 48 months 24 patients (10.7%) developed NPR or progressed to proliferative retinopathy. Systolic blood pressure (HR 1.03, CI 1.01–1.05, p = 0.02), UAE (HR 1.14, CI 1.07–1.21, p < 0.001), and resting heart rate (HR 1.05, CI 1.01–1.09, p = 0.006) were significantly associated with development or progression of NPR.ConclusionsOur results suggest that retinopathy is present and may progress in T1DM even when coexisting renal disease is excluded. Normoalbuminuric T1DM requires close monitoring for the early detection of retinopathy, especially if they have a higher UAE, systolic blood pressure and resting heart rate.     

Soluble endothelial adhesion molecules and inflammation markers in patients with β-thalassemia intermedia

The term thalassemia intermedia, indicates a clinical condition of intermediate severity between thalassaemia minor, the asymptomatic carrier, and thalassaemia major, the transfusion-dependent, severe form. Thromboembolic events frequently complicate the outcome of thalassemia intermedia patients, reflecting a hypercoagulable state to which endothelial activation is believed to play an important role. The aim of this study was to evaluate the levels of soluble endothelial adhesion molecules that reflect endothelial activation and dysfunction and levels of chronic inflammation markers in the serum of β-thalassemia intermedia patients. Thirty-five Greek patients with β-thalassemia intermedia that have received different types of treatment (Hydroxyurea, splenectomy, untreated), aged 8–63 years, were included in the study. Twenty apparently healthy individuals matched for age and sex, formed the control group. Measurements of sVCAM-1, sICAM-1, sTM, P-selectin, E-selectin and CRP levels were performed using immunoassays. We found that all endothelial adhesion molecules and CRP were significantly increased in patients (p < 0.001) and not influenced by treatment. A negative correlation was observed between levels of sICAM-1 and sTM and this finding agrees with the results of studies, which propose this correlation as a predictive marker of increased risk for vascular damage. No correlation was observed between endothelial adhesion molecules and inflammation markers. These findings support the hypothesis that a serious degree of endothelial activation and damage along with a state of chronic inflammation underlie the pathophysiology of β-thalassemia intermedia. Furthermore, these findings are of particular importance in patients who can otherwise be characterized by a subtle clinical phenotype and may have an important role in their clinical care.     

ATG5 gene expression analysis supports the involvement of autophagy in microangiopathic complications of type 2 diabetes

Background and aimsType 2 diabetes (T2D) hyperglycaemia alters basal autophagy. Since autophagy is an essential cellular process, our aim was to investigate the ATG5 (autophagy-related 5) gene expression level and genetic variants in a cohort of diabetic patients, characterized for the presence of microangiopathic complications.Methods and Resultsthe expression levels of ATG5 were evaluated in PBMCs from 48 T2D patients with an extensive evaluation for microangiopathic complications. Our analyses revealed a significant lower expression of ATG5 in T2D patients with retinopathy compared to those without retinopathy. We also highlighted a significant lower expression of ATG5 in T2D patients with early-cardiovascular autonomic neuropathy compared to those without it, after correction for sex, age, body mass index and levels of hemoglobin A1c.Conclusionour results highlight that dysregulation in the autophagy process could be involved in the development of severe microangiopathic complications.     

Association of diabetic retinopathy, ischemic heart disease, and albuminuria with diabetic treatment in type 2 diabetic patients

The management of type 2 diabetes has been a controversial issue. The objective of the present study was to estimate patients' characteristics, particularly diabetes treatment, associated with retinopathy, coronary heart disease, and microalbuminuria in an unselected population of 532 type 2 diabetic individuals from three communities. Questionnaires, clinic record review, and physical examination were used for the assessment of the three conditions. Fasting C-peptide was measured in all insulin-treated participants to establish type 2 diabetes. Patients with and without each of the studied complications were matched for age at diagnosis of diabetes and duration of diabetes. Univariate matched and multivariate conditional logistic regression analyses were used to estimate the independent association between each of the various factors studied and the three complications. Insulin treatment was the only factor independently associated with all three complications (odds ratios 3.3, 3.4, and 5.3 for diabetic retinopathy, coronary heart disease, and albuminuria, respectively). Glycosylated hemoglobin, uric acid, systolic blood pressure levels, and body mass index were also independently associated with at least one of the complications but not with all of them. Although no cause-effect relationship can be established from this cross-sectional design, insulin therapy seems to be a marker of severer diabetes from the time of diagnosis. Received: 14 March 1997 / Accepted in revised form: 4 September 1997     

Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn Study

Aims/hypothesis The exact pathogenesis of retinopathy in diabetic and non-diabetic individuals is incompletely understood, but may involve chronic low-grade inflammation and dysfunction of the vascular endothelium. The aim of this study was to investigate the association of inflammation and endothelial dysfunction with prevalent retinopathy in individuals with and without type 2 diabetes.Methods As part of a population-based cohort study, 625 individuals aged 50–74 years, stratified according to age, sex and glucose tolerance status, underwent an extensive physical examination. Retinopathy was assessed by an ophthalmological examination, including funduscopy and two-field 45° fundus photography with mydriasis in both eyes. Levels of C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), von Willebrand factor, and soluble vascular adhesion molecule-1 (sVCAM-1) were assessed, together with the urinary albumin : creatinine ratio, and the results were combined to obtain summarising z scores for inflammation and endothelial dysfunction.Results The prevalence of retinopathy was positively associated with tertiles of CRP and sICAM-1. When compared with the lowest tertile, the highest tertile of the inflammatory z score was associated with retinopathy in all subjects (odds ratio [OR]=2.2, 95% CI 1.2–4.1, adjusted for age, sex and glucose tolerance status). The highest tertile of the endothelial dysfunction z score was associated with retinopathy among diabetic individuals (OR=4.4, 95% CI 1.2–15.9, adjusted for age and sex) but not in non-diabetic individuals. Additional adjustment for other risk factors, such as systolic and diastolic blood pressure, BMI, total cholesterol and triglycerides, or mutual adjustment of the inflammatory and endothelial dysfunction z scores did not change the results.Conclusions/interpretation In this study, inflammatory activity and endothelial dysfunction were associated with retinopathy, which suggests their involvement in the pathogenesis of retinopathy.     

The relationship between angiotensin-converting enzyme insertion/deletion polymorphism and proliferative retinopathy in type 2 diabetes

A total of 136 type 2 diabetic patients with nonproliferative and 94 patients with proliferative diabetic retinopathy (PDR) without nephropathy were studied. The DD genotype of the angiotensin-converting enzyme polymorphism was more common in the PDR group (P < 0.001). In multivariate regression, the association remained significant (OR = 3.516).     

2型糖尿病患者尿白蛋白/肌酐比值与糖尿病视网膜病变关系的研究

目的 探讨2型糖尿病患者尿白蛋白/肌酐比值(UACR)与糖尿病视网膜病变(DR)的关系.方法 595例2型糖尿病患者进行UACR和眼底摄片检查,并根据UACR将患者分为3组:正常白蛋白尿组(n =519)、微量白蛋白尿组(n=28)和大量白蛋白尿组(n=48).比较3组患者的年龄、糖尿病病程等基本情况及DR发生率;同时以正常白蛋白尿组为参照,分析另外两组患者DR的相对危险度;最后,运用多元逐步线性回归和二元Logistic回归验证UACR与DR发生率的关系.结果 (1)3组患者的年龄、糖尿病病程、腰臀比、收缩压、舒张压、UACR差异有统计学意义(P＜0.05).(2)3组患者DR发生率依次升高,分别为30.4％、53.6％、54.2％,且差异有统计学意义(P＜0.001).(3)微量白蛋白尿组患DR的相对危险度为2.638 (95％ CI:1.225 ～ 5.682),大量白蛋白尿组患DR的相对危险度为2.702(95％ CI:1.486 ～4.902),且差异均存在统计学意义(P＜0.05).(4)多元逐步线性回归和二元Logistic回归显示,UACR与DR发生率有着显著的联系(P＜0.05).结论 2型糖尿病患者UACR与DR的发生密切相关.     

Intercellular adhesion molecule, plasma adiponectin and albuminuria in type 2 diabetic patients

Aims

Our study addressed the influence of early inflammatory stages of diabetic kidney disease: leukocyte adhesion and monocyte activation (as assessed by intercellular leukocyte adhesion molecule-ICAM-1 and monocyte chemoatractant protein-MCP-1) on the degree of albuminuria. Plasma levels of adiponectin, a possible anti-inflammatory counteracting mechanism, were also studied in correlation to the above-mentioned cytokines.

Methods

79 consecutive type 2 diabetic outpatients and 46 controls were included. Routine laboratory analysis, urinary albumin to creatinine ratio (uACR), plasma adiponectin, plasma ICAM-1 and urinary MPC-1 were assessed.

Results

In multiple regression ICAM-1 (p = 0.004) and adiponectin (p = 0.04) were the main determinants of uACR. Plasma adiponectin positively correlated to ICAM-1 (p = 0.03, r = 0.24).In albuminuric patients (uACR ≥30 mg/g) plasma adiponectin was significantly higher compared to normoalbuminuric ones (uACR <30 mg/g). In albuminuric patients the main determinants of uACR were plasma ICAM-1 and adiponectin. In multiple regression ICAM-1 is the only one that retains statistical significance (p = 0.02). Urinary MCP-1 did not correlate to uACR.

Conclusions

In our type 2 diabetic patients, plasma levels of ICAM-1 and adiponectin are predictive for albuminuria. Urinary MCP-1 does not correlated to uACR. Plasma adiponectin positively correlates to adhesion molecule ICAM-1 in our cohort.     

The effect of cigarette smoking on soluble adhesion molecules in middle-aged patients with Type 2 diabetes mellitus.

AIMS: To investigate the effect of smoking on soluble adhesion molecules in middle-aged diabetic patients. METHODS: One hundred out-patients with Type 2 diabetes and 100 age- and sex-matched non-diabetic subjects without clinical macrovascular disease were selected. Soluble serum levels of adhesion molecules were analysed using enzyme immunoassay. Carotid atherosclerosis was assessed using an ultrasound system. RESULTS: When compared with non-diabetic subjects, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and sE-selectin were found at significantly high levels in diabetic patients and significantly higher levels of sICAM-1, sE-selectin, and sP-selectin were observed in current smokers than never-smokers among diabetic or non-diabetic subjects, respectively. The combined, but not enhanced, effects of diabetes mellitus and smoking were observed in sICAM-1 and sE-selectin levels. Additionally, levels of sICAM-1 (P < 0.05) and sE-selectin (P < 0.01), but not sP-selectin, were high in ex-smokers when compared with never-smokers among diabetic patients. Diabetic smokers were also found to have marked carotid atherosclerosis, which was related to increased levels of sICAM-1. CONCLUSIONS: Our present study shows that levels of adhesion molecules were higher in diabetic smokers than diabetic non-smokers or non-diabetic smokers, and that cessation after chronic smoking did not restore the levels of sICAM-1 and sE-selectin, though sP-selectin levels were restored. These data suggest a possible mechanism for accelerated atherosclerosis induced by smoking in patients with diabetes.     

粘附分子与实验性糖尿病视网膜病变的初步研究

目的　探讨粘附分子在糖尿病视网膜病变（ Ｄ Ｒ） 发病中的作用。方法　应用链脲佐菌素（ Ｓ Ｔ Ｚ） 建立糖尿病大鼠模型,分别于成模后３ 个月和６ 个月时经光镜和透射电镜观察视网膜的形态学改变。应用免疫组化方法及微机图像处理系统,对视网膜组织细胞间粘附分子１（ Ｉ Ｃ Ａ Ｍ１） 及整合素族 Ｃ Ｄ６１ 的分布与含量进行动态观察与分析;应用流式细胞术测定循环血中粒细胞表面β２ 整合素族 Ｃ Ｄ１１ａ 、 Ｃ Ｄ１１ｂ 的表达。结果　病变３ 月组已有 Ｉ Ｃ Ａ Ｍ１ 及 Ｃ Ｄ６１ 的表达明显增加,并随病程延长表达进一步增多,而在正常对照组未见明显表达（ Ｐ＜ ０ ．０１） 。糖尿病大鼠粒细胞表面抗原 Ｃ Ｄ１１ａ 、 Ｃ Ｄ１１ｂ 阳性细胞群体所占的比例较对照组显著升高（ Ｐ＜ ０ ．００１） 。视网膜毛细血管基底膜厚度与 Ｉ Ｃ Ａ Ｍ１ 、 Ｃ Ｄ６１ 表达灰度值呈显著正相关（ ｒ ＝ ０ ．７７２ ,０ ．６９４ , Ｐ＜ ０ ．０５） 。结论　粘附分子与其配基过度表达,加重内皮细胞损伤及微血管栓塞,很可能是导致 Ｄ Ｒ 发生中进展性微血管病变的重要因素之一。     

甲状腺疾病患者可溶性粘附分子的变化

利用酶联免疫法对168例Graves′病患者、36例桥本氏甲状腺炎患者、32例亚急性甲状腺炎患者和35例单纯性甲状腺肿患者和26例正常人测定血清中可溶性细胞间粘附分子（sICAM-1）和可溶性血管粘附分子（sVCAM-1）含量。结果以上五组sICAM-1依次为1105.1±106.7ng／ml、950.23±310.5ng／ml、786.23±462.4ng／ml、296.2±148.15ng／ml、342.5±250.2ng／ml。sVCAM-1依次为1760.6±403.7ng／ml、1231.7±110.6ng／ml;113.2±143.59ng／ml;941.3±95.4ng／ml;661.19±320.78ng／ml。说明不同的甲状腺疾病患者,其血清中粘附分子含量变化不同,并具有临床价值。     

Familial clustering of diabetic retinopathy in South Indian Type 2 diabetic patients.

AIM: The aim of the study was to determine whether there is familial clustering of diabetic retinopathy among South Indian Type 2 diabetic subjects. METHODS: During the period September 1991 to September 1997, 322 families with at least two diabetic siblings who were registered at our centre and had undergone a retinal examination were selected for the study.The sibling with the longest duration of diabetes was defined as the proband. The prevalence of retinopathy was compared between the siblings of probands with and without retinopathy. RESULTS: Diabetic retinopathy was diagnosed in 11.2% of the siblings of the probands without diabetic retinopathy and in 35.3% of the siblings of the probands with diabetic retinopathy (P < 0.0001). The increased prevalence of retinopathy among siblings of probands with retinopathy represented all grades of retinopathy, namely non-proliferative diabetic retinopathy with and without maculopathy and proliferative diabetic retinopathy, although the latter did not reach statistical significance due to the small numbers. Hypertension, metabolic control and the duration of diabetes among the probands did not affect the clustering of retinopathy. The odds ratio for retinopathy in the siblings of probands with retinopathy after adjusting for age, glycosylated haemoglobin, duration of diabetes, proteinuria and other confounding variables was 3.37(95% confidence interval 1.56-7.29, P = 0.002). CONCLUSIONS: Familial clustering of diabetic retinopathy was three times higher in siblings of Type 2 diabetic subjects with diabetic retinopathy.     

The association of early atherosclerosis and retinopathy in adolescents with type 1 diabetes: preliminary report

Recent studies have shown a close correlation between advanced diabetic retinopathy and the late stages of atherosclerosis. The purpose of this study was to analyse the association between diabetic retinopathy and early atherosclerotic changes in adolescents with type 1 diabetes. We studied 28 adolescents with type 1 diabetes. Eight patients with nonproliferative retinopathy were compared with the remaining 20 patients, and with 11 healthy controls. The function of endothelium was assessed by measuring flow-mediated dilatation (FMD), the intima-media thickness (IMT) of the common carotid arteries and adhesion molecules (sICAM-1, sVCAM-1, sE-selectin). In the group with retinopathy FMD equalled 7.8±4.1% vs. 12.1±5.1% in the control group (p=0.04), and in the group without retinopathy, 7.6±5.5% (p=0.04 compared to controls). Higher IMT was found in all patients with diabetes in comparison with healthy controls: 0.49±0.06 mm vs. 0.42±0.03 mm (p=0.001). Patients with retinopathy had a significantly higher value of IMT in comparison not only with controls but also with patients without complications: 0.56±0.06 mm vs. 0.47±0.03 mm (p=0.0001). Adhesion molecule levels were not changed in patients with retinopathy. Higher IMT was found in adolescents with diabetic retinopathy in comparison with patients without complications, which may suggest that macrovascular changes are more advanced in these patients than in their diabetic peers without retinopathy.