Jorge Freitas Esteves

The UCP1 −3826A/G Polymorphism Is Associated with Diabetic Retinopathy and Increased UCP1 and MnSOD2 Gene Expression in Human Retina

PURPOSE Uncoupling protein 1 (UCP1) reduces mitochondrial production of reactive oxygen species (ROS). ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Therefore, deleterious polymorphisms in the UCP1 gene are candidate risk factors for DR. We investigated the relationships between the UCP1 -3826A/G polymorphism and risk of DR and UCP1 gene expression in human retina. Considering that superoxide dismutase-2 (MnSOD2) enzyme is the first line of defense against oxidative stress in mitochondria, we also analyzed MnSOD2 gene expression in retinal samples according to different UCP1 -3826A/G genotypes. METHODS In a case-control study, frequencies of -3826A/G polymorphisms were analyzed in 257 type 1 DM patients (154 cases with DR and 103 controls without DR). In a cross-sectional study comprising cadaveric cornea donors, UCP1 and MnSOD2 gene expressions were evaluated in 107 retinal samples differentiated according to different -3826A/G genotypes. RESULTS In the type 1 DM group, multivariate analysis confirmed that the G/G genotype was an independent risk factor for DR (OR = 3.503; P = 0.043). In cornea donors, G allele carriers had higher UCP1 cDNA and protein concentrations than A/A carriers (P = 0.034 and P = 0.039, respectively). Interestingly, G allele carriers exhibited increased MnSOD2 expression (P = 0.001). CONCLUSIONS This study suggests that the -3826A/G polymorphism is associated with DR in type 1 DM patients. This is the first report demonstrating UCP1 gene expression in human retinas and indicates that the -3826A/G polymorphism influences its expression. In addition, the -3826G allele was associated with increased MnSOD2 expression; thus, suggesting that this allele could be a marker of oxidative stress.

Prevalence of diabetic retinopathy in patients with type 1 diabetes mellitus

OBJECTIVES Diabetic retinopathy (DR) is the leading cause of legal blindness in young adults. Scarce data from Brazilian subjects with type 1 diabetes mellitus (DM) are available. AIMS The objectives of this study were to determine the prevalence of DR and its risk factors in type 1 diabetes mellitus (DM) outpatients from a general hospital. METHODS A cross-sectional study of 437 type 1 DM (50.3% males, 82.4% whites) was conducted. DR was graded as absent, mild and moderate non-proliferative DR (mild/moderate NPDR) or severe non-proliferative and proliferative DR (advanced DR). Presence of clinically significant macular edema (CSME) was also recorded. RESULTS Any DR was present in 44.4% of subjects. In multivariate analysis, DM duration, systolic blood pressure (SBP) and A1C test were associated with mild/moderate NPDR (P<0.005). Advanced DR, was associated with DM duration, SBP, smoking [odds ratio (OR) 2.75, 95%CI 1.15-6.60] and micro-or macroalbuminuria (OR 8.53, 95%CI 3.81-18.05). CSME was present in 21 (9.4%) patients and was associated with smoking (OR 3.19, 95%CI 1.24-8.2). Its frequency increased with the severity of DR (16.4% in advanced DR, 9.6% in mild/moderate NPDR, and 4.7% in the group without DR; P = 0.020). CONCLUSION Patients with type 1 DM attending an endocrine out-patient clinic at a general hospital had a high prevalence of DR associated with traditional risk-factors and smoking.

Caracterização de pacientes com diabetes mellitus tipo 1 do sul do Brasil: complicações crônicas e fatores associados

OBJETIVO: Avaliar a prevalencia de complicacoes cronicas vasculares e fatores associados em pacientes com diabetes mellitus (DM) tipo 1. METODOS: Estudo transversal com pacientes DM tipo 1 atendidos no Servico de Endocrinologia do Hospital de Clinicas de Porto Alegre. Os pacientes foram avaliados quanto a presenca de complicacoes cronicas vasculares. RESULTADOS: Avaliamos 573 pacientes, idade media de 33 anos. A presenca de retinopatia diabetica (RD) foi observada em 43,3%, o tempo de DM [RC: 1,07; IC95% 1,03-1,11; P 100 mg/dl. CONCLUSAO: Observamos elevadas prevalencias de complicacoes microvasculares e de HAS. A duracao do DM, HAS e presenca de ND foram associados a RD. HAS e dislipidemia foram associados a ND. A maioria dos pacientes encontrava-se fora dos alvos desejados de controle glicemico, pressorico e lipidico. Maiores esforcos sao necessarios para intensificar o controle metabolico e pressorico de pacientes com DM tipo 1.

Masked hypertension, nocturnal blood pressure and retinopathy in normotensive patients with type 1 diabetes.

AIM To analyze the prevalence of masked hypertension and its possible association with microvascular complications in patients with type 1 diabetes (T1D). METHODS A cross-sectional study was conducted in 188 consecutive normotensive patients at the office with T1D without renal replacement therapy or previous renal transplant. All patients were assessed regarding the presence of diabetic retinopathy (DR) (direct and indirect fundoscopy), urinary albumin excretion rate (immunoturbidimetry), and ambulatory blood pressure monitoring (ABPM) (Spacelabs 90207). RESULTS Masked hypertension was observed in 14 (13.6%) out of 103 clinical normotensive patients and in 7.4% of the entire cohort. Twenty-three percent of patients with clinical normotension had masked nocturnal hypertension. DR was associated with night systolic and diastolic BP [OR of each 5mmHg change 1.41 (95%CI: 1.09-1.83, P=0.009) and 1.40 (95%CI: 1.02-1.93, P=0.04), respectively] and with masked nocturnal hypertension [OR: 3.23 (95%CI: 1.29-8.11, P=0.01)]. CONCLUSIONS In T1D patients with clinic BP<130/80mmHg, masked hypertension and especially masked nocturnal hypertension are present. Normotensive patients with nocturnal BP>120/70mmHg have higher presence of DR, and only will be identified through ABPM.

Cataract and type 1 diabetes mellitus

AIMS To evaluate the prevalence of cataract and the possible factors associated with cataract in young type 1 diabetes mellitus (DM). METHODS 293 patients were evaluated. The association of cataract with diabetic retinopathy (DR), retinal laser treatment, hypertension, body mass index, peripheral neuropathy, lipid profile, glycemic control, serum creatinine and albuminuria was evaluated. RESULTS Cataract was present in 19.8% (n=58) of the sample. Patients with cataracts were older, had a higher frequency of history of retina photocoagulation treatment, higher serum creatinine values and higher prevalence of arterial hypertension. There was a progressive increase in cataract frequency according to the number of risk factors, starting to rise with two or more. In logistic regression model cataract was associated with mild/moderate DR (odd ratio (OR) 4.28 95% CI 1.63-11.29), severe DR (OR 4.07 95% CI 1.63-10.23) and macroalbuminuria (OR 2.34 95% CI 1.06-5.16). CONCLUSION These data indicate a high prevalence of cataract in subjects with type 1 DM attending a general hospital in Southern Brazil and suggest that the more severe the disease process the greater is the risk of having this diabetic complication. Cataract should be suspected in young patients with two or more risk factors.

Fatores de risco para retinopatia diabética

Diabetic retinopathy (DR) occurs in about 95% of patients with type 1 diabetes mellitus (DM) and in 60% of type 2 DM patients and it is the main cause of legal blindness in adult people. The aim of this manuscript was to review the main risk factors for DR. The major environmental risk factors are hyperglycemia, high blood pressure levels, and long-term duration of DM. However, not all patients will not develop DR, suggesting the presence of a genetic predisposition to DR, especially for severe forms of DR. Special strategies has been used to evaluate the genetic role in DR. Family studies shown that there is a familial aggregation of DR. Candidates genes have been studied (RAGE; VEGF; PPAR-delta; ICAM-1; ECA; ENPP 1; eNOS) and positive or negative associations with DR were demonstrated. Some chromosomes were also associated to DR in selected populations. Finally, genetic expression studies reinforce the association of candidate genes, or participation of others genes, with the presence of DR. DR is a common complication of DM and, along with non-genetic or environmental risk factors, the identification of genes related to DR could result in more specific and efficient DR treatment.

ACE and PC-1 gene polymorphisms in normoalbuminuric Type 1 diabetic patients: A 10-year prospective study

The aim of this study was to analyze the role of ACE gene insertion/deletion (I/D) and PC-1 gene K121Q polymorphisms in the changes of glomerular filtration rate (GFR), urinary albumin excretion rate (UAER), and blood pressure (BP) levels in a cohort of normoalbuminuric Type 1 diabetic patients. This is a 10.2+/-2.0-year prospective study of 30 normotensive normoalbuminuric Type 1 diabetic patients. UAER (immunoturbidimetry), GFR ((51)Cr-EDTA single injection technique), GHb (ion exchange chromatography), and BP levels were measured at baseline and at 1.7+/-0.6-year intervals. The presence of ACE gene I/D and PC-1 gene K121Q polymorphisms was determined by polymerase chain reaction (PCR) and restriction enzyme techniques. Three patients developed diabetic nephropathy (DN), all carriers of allele D. The presence of allele D was the only predictor (R(2)=.15, F=4.92, P=.035) of the observed GFR decline (-0.29+/-0.34 ml/min/month, P<.05). UAER increased during the study (log UAER=0.0275+/-0.042 microg/min/month, P=.002) and was associated with baseline UAER levels only (R(2)=.17, F=5.72, P=.024). A significant increase (P<.05) in cases of hypertension and retinopathy were observed in ID/DD (n=19) and not in II patients (n=11). Patients with the KQ/QQ genotype (n=8) presented a significant increase (P=.045) in new cases of retinopathy. In conclusion, the presence of the ACE gene D allele in this sample of normoalbuminuric normotensive Type 1 diabetic patients was associated with a higher proportion of microvascular complications and hypertension.

Absence of diabetic retinopathy in a patient who has had diabetes mellitus for 69 years, and inadequate glycemic control: case presentation

The main risk factors for the development and progression of diabetic retinopathy (DR) are chronic hyperglycemia, disease duration and systemic blood pressure. So far chronic hyperglycemia is the strongest evidence concerning the risk of developing DR. However there are some patients with poor metabolic control who never develop this diabetic complication. We present a case of a 73-year-old woman with type 1 diabetes mellitus, diagnosed 69 years ago. The patient is 73 years old, with no evidence of DR, despite poor glycemic control and several risk factors for DR. This case suggests the presence of a possible protection factor, which could be genetic.

Accuracy of continuous glucose monitoring system during exercise in type 2 diabetes

The concordance of continuous glucose monitoring system (CGMS) and finger-stick blood glucose (FSBG) was assessed in patients with type 2 diabetes during daily activities and two different exercise sessions. Agreement between FSBG and CGMS becomes weaker during exercise, but more than 90% of the CGMS readings are within acceptable range.

Smoking habit is associated with diabetic macular edema in Type 1 diabetes mellitus patients.

Diabetic macular edema (DME) affects up to 29% of patients with diabetic retinopathy (DR) and is the most frequent cause of visual impairment in these patients (Klein, Klein, Moss, Davis, & DeMets, 1984). However, risk factors for DME have not been fully established. Recently, Romero et al. (2007) prospectively studied 112 type 1 diabetes mellitus (DM) patients (age 39.9±10.5 years; DM duration 23.4±7.5 years; 48.2% males) to evaluate risk factors for DME. After 15 years, the incidence of DME was 20.5%. In logistic multivariate regression models, adjusted for gender and age, A1c test and low-density lipoprotein (LDL) cholesterol levels, arterial hypertension, macroangiopathy, severity of retinopathy, and macroalbuminuria were the recognized risk factors for DME. In a cross-sectional study, we evaluated 224 Type 1 DM patients aged 33.3±13.9 years, with 16.5±9.6 years of DM duration (105 males) regularly attending the DM outpatient clinic at Hospital de Clinicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil. A complete clinical evaluation was performed as previously described (Leitao et al., 2007). DME was defined as one or more of the following: any retinal thickening within 500 μm of the center of the macula, with or without loss of retinal transparency; hard exudates associated with retinal thickening within 500 μm of the center of the macula; or one disc area of thickening within one disc diameter of the center of the macula (ETDRS, 1985). Twenty-four percent of the patients had nonproliferative DR (mild, n=38; moderate, n=9; severe, n=7), and 20.7 % (n=46) proliferative DR. The prevalence of DME was 9.4% (n=21). In univariate analysis, patients with DME had higher levels of urinary albumin excretion (UAE) [26.2 mg/dl (0.1–1105) vs. 8.7 (0.1– 71110), P=.049] than those without it. DM duration, body mass index, blood pressure levels, glycemic (A1c test) and lipid profile (total, LDL, and high-density lipoprotein cholesterol and triglycerides) did not differ between groups. Current or former smoking habit (50% vs. 25%; P=.034) and diabetic nephropathy (micro- and macroalbuminuria) (58.8% vs. 29.5%; P=.026) were more frequent in patients with than those without DME. The severity of DR was also associated with DME (P for trend .027). In logistic multivariate regression analysis, with the presence of DME as the dependent variable and DM duration, smoking habit, systolic blood pressure, A1c test, and UAE as independent ones, only the smoking habit was associated with DME (OR 2.02, 95%CI 1.01–4.00; P=.04). Differences between our results and those of Romero et al., besides study design, could be explained by the younger age and shorter DM duration of our patients: a difference of about 6 years of age [6.6 years (95% CI 3.6–9.5; Pb.0001)] and of 7 years of DM duration [6.9 years (95% CI 4.7-8.9; Pb.0001)]. The present data demonstrated that, besides glycemic, lipid, and blood pressure control, the smoking habit, a nontraditional DME risk factor, should also be taken into account in order to prevent it. To our knowledge, this is the first report of this association.