Physical activity and diabetic complications in patients with type 1 diabetes

Type 1 diabetes is associated with the risk for late diabetic complications which are divided into microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiovascular disease, CVD) diseases. The risk for diabetic complication can be reduced by effective treatment, most importantly the glycaemic control. Glycaemia in type 1 diabetes is influenced by the interplay between insulin injections and lifestyle factors such as physical activity and diet. The effect of physical activity in patients with type 1 diabetes is not well known, however. The aim of this thesis was to investigate the physical activity and the physical fitness of patients with type 1 diabetes with special emphasis on glycaemic control and the diabetic complications. The patients included in the study were all part of the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) Study which aims to characterise genetic, clinical, and environmental factors that predispose to diabetic complications in patients with type 1 diabetes. In addition, subjects from the IDentification of EArly mechanisms in the pathogenesis of diabetic Late complications (IDEAL) Study were studied. Physical activity was assessed in the FinnDiane Study in 1945 patients by a validated questionnaire. Physical fitness was measured in the IDEAL Study by spiroergometry (cycle test with measurement of respiratory gases) in 86 young adults with type 1 diabetes and in 27 healthy controls. All patients underwent thorough clinical characterisation of their diabetic complication status. Four substudies were cross-sectional using baseline data and one study additionally used follow-up data. Physical activity, especially the intensity of activities, was reduced in patients affected by diabetic nephropathy, retinopathy, and CVD. Low physical activity was associated with poor glycaemic control, a finding most clear in women and evident also in patients with no signs of diabetic complications. Furthermore, low physical activity was associated with a higher HbA1c variability, which in turn was associated with the progression of renal disease and CVD during follow-up. A higher level of physical activity was also associated with better insulin sensitivity. The prevalence of the metabolic syndrome in type 1 diabetes was also lower the higher the physical activity. The aerobic physical fitness level of young adults with type 1 diabetes was reduced compared with healthy peers and in men an association between higher fitness level and lower HbA1c was observed. In patients with type 1 diabetes, a higher physical activity was associated with better glycaemic control and may thus be beneficial with respect to the prevention of diabetic complications.

Study of urinary 8-hydroxydeoxyguanosine as a biomarker of oxidative DNA damage in diabetic nephropathy patients

Increased oxidative stress induced by hyperglycemia may contribute to the pathogenesis of diabetic complications. Urinary 8-hydroxydeoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. This article studied oxidative DNA damage in patients with diabetic nephropathy and in healthy control subjects by urinary 8-OHdG evaluations. Contents of 8-OHdG in urine were analyzed by capillary electrophoresis with end-column amperometric detection (CE-AD) after a single-step solid-phase extraction (SPE). Levels of urinary 8-OHdG in diabetic nephropathy patients with macroalbuminuria was significant higher than in control subjects (5.72 +/- 6.89 mumol/mol creatinine versus 2.33 +/- 2.83 mumol/mol creatinine, P = 0.018). A significant difference of 24 h urinary 8-OHdG excretions exists between the patients with macroalbuminuria and the patients with nonnoalbuminuria (19.2 +/- 16.8 mug/24 h versus 8.1 +/- 1.7 mug/24 h, P = 0.015). There was a positive correlation between urinary excretion of 8-OHdG and glycosylated hemoglobin (HbA(1)c) (r = 0.287, P = 0.022). A weak correlation exists between the levels of 8-OHdG and triglyceride (r = 0.230, P = 0.074). However, the urinary 8-OHdG contents are not correlated with blood pressure and total cholesterol. The increased excretion of urinary 8-OHdG is seen as indicating an increased systemic level of oxidative DNA damage in diabetic nephropathy patients. (C) 2004 Elsevier B.V. All rights reserved.

Investigation of DNA polymorphisms in SMAD genes for genetic predisposition to diabetic nephropathy in patients with type 1 diabetes mellitus

Aims/hypothesis: SMAD proteins are involved in multiple signalling pathways and are key modulators of gene expression. We hypothesised that genetic variation in selected SMAD genes contributes to susceptibility to diabetic nephropathy. Methods: We selected 13 haplotype tag (ht) single nucleotide polymorphisms (SNPs) from 67 variants identified by resequencing the SMAD2 and SMAD3 genes. For SMAD1, SMAD4 and SMAD5 genes, genotype data were downloaded for 217 SNPs from Phase II of the International HapMap project. Of these, 85 SNPs met our inclusion criteria, resulting in the selection of 13 tag SNPs for further investigation. A case-control approach was employed, using 267 nephropathic patients and 442 controls with type 1 diabetes from Ireland. Two further populations (totalling 1,407 patients, 2,238 controls) were genotyped to validate initial findings. Genotyping was conducted using iPLEX, TaqMan and gel electrophoresis.
Results: The distribution of genotypes was in Hardy-Weinberg equilibrium. Analysis by the ? 2 test of genotype and allele frequencies in patients versus controls in the Irish population (n?=?709) revealed evidence for the association of one allele at 5% level of significance (rs10515478, p uncorrected?=?0.006; p corrected?=?0.04). This finding represents a relatively small difference in allele frequency of 6.4% in the patient group compared with 10.7% in the control group; this difference was not supported in subsequent investigations using DNA from European individuals with similar phenotypic characteristics.
Conclusions/interpretation: We selected an appropriate subset of variants for the investigation of common genetic risk factors and assessed SMAD1 to SMAD5 genes for association with diabetic nephropathy. We conclude that common polymorphisms in these genes do not strongly influence genetic susceptibility to diabetic nephropathy in white individuals with type 1 diabetes mellitus.

Angiogenic potential of vitreous from proliferative diabetic retinopathy and eales' disease patients

Proliferative Diabetic Retinopathy (PDR) and Eales' Disease (ED) have different aetiologies although they share certain common clinical symptoms including pre-retinal neovascularization. Since there is a need to understand if the shared end-stage angiogenic pathology of PDR and ED is driven by common stimulating factors, we have studied the cytokines contained in vitreous from both patient groups and analyzed the angiogenic potential of these samples in vitro.

Vitreous samples from patients with PDR (n = 13) and ED (n = 5) were quantified for various cytokines using a cytokine biochip array and sandwich ELISA. An additional group of patients (n = 5) with macular hole (MH) was also studied for comparison. To determine the angiogenic potential of these vitreous samples, they were analyzed for their ability to induce tubulogenesis in human microvascular endothelial cells. Further, the effect of anti-VEGF (Ranibizumab) and anti-IL-6 antibodies were studied on vitreous-mediated vascular tube formation.

Elevated levels of IL-6, IL-8, MCP-1 and VEGF were observed in vitreous of both PDR and ED when compared to MH. PDR and ED vitreous induced greater levels of endothelial cell tube formation compared to controls without vitreous (P<0.05). When VEGF in vitreous was neutralized by clinically-relevant concentrations of Ranibizumab, tube length was reduced significantly in 5 of 6 PDR and 3 of 5 ED samples. Moreover, when treated with IL-6 neutralizing antibody, apparent reduction (71.4%) was observed in PDR vitreous samples.

We have demonstrated that vitreous specimens from PDR and ED patients share common elevations of pro-inflammatory and pro-angiogenic cytokines. This suggests that common cytokine profiles link these two conditions.

SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes

Aims/hypothesis

Optical coherence tomography (OCT) for detection of macular oedema in patients with diabetic retinopathy

Background

Diabetic macular oedema (DMO) is a thickening of the central retina, or the macula, and is associated with long-term visual loss in people with diabetic retinopathy (DR). Clinically significant macular oedema (CSMO) is the most severe form of DMO. Almost 30 years ago, the Early Treatment Diabetic Retinopathy Study (ETDRS) found that CSMO, diagnosed by means of stereoscopic fundus photography, leads to moderate visual loss in one of four people within three years. It also showed that grid or focal laser photocoagulation to the macula halves this risk. Recently, intravitreal injection of antiangiogenic drugs has also been used to try to improve vision in people with macular oedema due to DR.Optical coherence tomography (OCT) is based on optical reflectivity and is able to image retinal thickness and structure producing cross-sectional and three-dimensional images of the central retina. It is widely used because it provides objective and quantitative assessment of macular oedema, unlike the subjectivity of fundus biomicroscopic assessment which is routinely used by ophthalmologists instead of photography. Optical coherence tomography is also used for quantitative follow-up of the effects of treatment of CSMO.

Objectives

To determine the diagnostic accuracy of OCT for detecting DMO and CSMO, defined according to ETDRS in 1985, in patients referred to ophthalmologists after DR is detected. In the update of this review we also aimed to assess whether OCT might be considered the new reference standard for detecting DMO.

Search methods

We searched the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA) and the NHS Economic Evaluation Database (NHSEED) (The Cochrane Library 2013, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2013), EMBASE (January 1950 to June 2013), Web of Science Conference Proceedings Citation Index - Science (CPCI-S) (January 1990 to June 2013), BIOSIS Previews (January 1969 to June 2013), MEDION and the Aggressive Research Intelligence Facility database (ARIF). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 25 June 2013. We checked bibliographies of relevant studies for additional references.

Selection Criteria

We selected studies that assessed the diagnostic accuracy of any OCT model for detecting DMO or CSMO in patients with DR who were referred to eye clinics. Diabetic macular oedema and CSMO were diagnosed by means of fundus biomicroscopy by ophthalmologists or stereophotography by ophthalmologists or other trained personnel.

Data collection and analysis

Three authors independently extracted data on study characteristics and measures of accuracy. We assessed data using random-effects hierarchical sROC meta-analysis models.

Main results

We included 10 studies (830 participants, 1387 eyes), published between 1998 and 2012. Prevalence of CSMO was 19% to 65% (median 50%) in nine studies with CSMO as the target condition. Study quality was often unclear or at high risk of bias for QUADAS 2 items, specifically regarding study population selection and the exclusion of participants with poor quality images. Applicablity was unclear in all studies since professionals referring patients and results of prior testing were not reported. There was a specific 'unit of analysis' issue because both eyes of the majority of participants were included in the analyses as if they were independent.In nine studies providing data on CSMO (759 participants, 1303 eyes), pooled sensitivity was 0.78 (95% confidence interval (CI) 0.72 to 0.83) and specificity was 0.86 (95% CI 0.76 to 0.93). The median central retinal thickness cut-off we selected for data extraction was 250 µm (range 230 µm to 300 µm). Central CSMO was the target condition in all but two studies and thus our results cannot be applied to non-central CSMO.Data from three studies reporting accuracy for detection of DMO (180 participants, 343 eyes) were not pooled. Sensitivities and specificities were about 0.80 in two studies and were both 1.00 in the third study.Since this review was conceived, the role of OCT has changed and has become a key ingredient of decision-making at all levels of ophthalmic care in this field. Moreover, disagreements between OCT and fundus examination are informative, especially false positives which are referred to as subclinical DMO and are at higher risk of developing clinical CSMO.

Authors' conclusions

Using retinal thickness thresholds lower than 300 µm and ophthalmologist's fundus assessment as reference standard, central retinal thickness measured with OCT was not sufficiently accurate to diagnose the central type of CSMO in patients with DR referred to retina clinics. However, at least OCT false positives are generally cases of subclinical DMO that cannot be detected clinically but still suffer from increased risk of disease progression. Therefore, the increasing availability of OCT devices, together with their precision and the ability to inform on retinal layer structure, now make OCT widely recognised as the new reference standard for assessment of DMO, even in some screening settings. Thus, this review will not be updated further.

Attitudes of physicians, patients, and village health workers toward glaucoma and diabetic retinopathy in rural China:A focus group study

Objective: To understand the knowledge and attitudes of rural Chinese physicians, patients, and village health workers (VHWs) toward diabetic eye disease and glaucoma. Methods: Focus groups for each of the 3 stakeholders were conducted in 3 counties (9 groups). The focus groups were recorded, transcribed, and coded using specialized software. Responses to questions about barriers to compliance and interventions to remove these barriers were also ranked and scored. Results: Among 22 physicians, 23 patients, and 25 VHWs, knowledge about diabetic eye disease was generally good, but physicians and patients understood glaucoma only as an acutely symptomatic disease of relatively low prevalence. Physicians did not favor routine pupillary dilation to detect asymptomatic disease, expressing concerns about workflow and danger and inconvenience to patients. Providers believed that cost was the main barrier to patient compliance, whereas patients ranked poorly trained physicians as more important. All 3 stakeholder groups ranked financial interventions to improve compliance (eg, direct payment, lotteries, and contracts) low and preferred patient education and telephone contact by nurses. All the groups somewhat doubted the ability of VHWs to screen for eye disease accurately, but patients were generally willing to pay for VHW screening. The VHWs were uncertain about the value of eye care training but might accept it if accompanied by equipment. They did not rank payment for screening services as important. Conclusions: Misconceptions about glaucoma's asymptomatic nature and an unwillingness to routinely examine asymptomatic patients must be addressed in training programs. Home contact by nurses and patient education may be the most appropriate interventions to improve compliance.

DETECTION of MOGIBACTERIUM TIMIDUM IN SUBGINGIVAL BIOFILM of AGGRESSIVE and NONDIABETIC and DIABETIC CHRONIC PERIODONTITIS PATIENTS

The aim of the present study was to evaluate the frequency of detection of Mogibacterium timidum in subgingival samples of subjects with generalized aggressive periodontitis (GAgP) and uncontrolled diabetic and non-diabetic subjects with generalized chronic periodontitis (GChP). 48 patients with GAgP, 50 nondiabetic and 39 uncontrolled (glycated hemoglobin >7%) type 2 diabetic subjects with GChP were enrolled in this study. Subgingival biofilm were collected from deep pockets (probing depth > 7 mm). After DNA extraction, M. timidum was detected by Nested Polymerase Chain Reaction and chi-square test was used to data analysis (p>0.05). There were no differences in the frequency of detection of M. timidum between subjects with GAgP (35%) and non-diabetic subjects with GChP (40%) (p>0.05). The frequency of detection of M. timidum was significantly higher in deep pockets of diabetic subjects with GChP (56%) when compared to GAgP (p<0.05), but similar to non-diabetic subjects with GChP (p>0.05). The frequency of detection of M. timidum was higher in subjects GChP presenting uncontrolled type 2 diabetes mellitus, when compared to GAgP subjects.

INTRAVITREAL INJECTION OF RANIBIZUMAB DURING CATARACT SURGERY IN PATIENTS WITH DIABETIC MACULAR EDEMA

Purpose: To investigate macular thickness and visual acuity changes after 1 intravitreal injection of 0.5-mg ranibizumab during phacoemulsification cataract surgery in eyes with diabetic macular edema refractory to laser treatment. Methods: Eleven eyes of 11 patients with diabetic macular edema refractory to modified Early Treatment Diabetic Retinopathy Study laser therapy received intravitreal during phacoemulsification cataract surgery. Comprehensive ophthalmic evaluation was performed preoperatively and at 1, 4, 8 +/- 1, and 12 +/- 2 weeks postoperatively. Main outcome measures included central subfield thickness and best-corrected Early Treatment Diabetic Retinopathy Study visual acuity. Results: Eleven patients completed the 12-week study visit. Mean central subfield thickness (+/- SEM) was 399.82 +/- 29.50 mu m at baseline and did not change significantly at any postoperative study visit (P > 0.05). Mean (+/- SEM) best-corrected Early Treatment Diabetic Retinopathy Study visual acuity was 0.95 +/- 0.13 logarithm of the minimum angle of resolution (20/200) at baseline and was significantly improved at Weeks 1 (0.38 +/- 0.13), 4 (0.38 +/- 0.11), 8 (0.35 +/- 0.08), and 12 (0.46 +/- 0.12) after treatment (P < 0.05). Conclusion: In this case series of patients with diabetic macular edema refractory to laser therapy, intravitreal ranibizumab administered during cataract surgery was associated with no significant change in central subfield thickness postoperatively. Significant improvement in best-corrected Early Treatment Diabetic Retinopathy Study visual acuity was observed after treatment, likely because of cataract removal. RETINA 32:1799-1803, 2012