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Effects of physical activity on the development and progression of microvascular complications in type 1 diabetes: retrospective analysis of the DCCT study
© Makura et al.; licensee BioMed Central Ltd. 2013
Received: 25 February 2013
Accepted: 17 September 2013
Published: 2 October 2013
To examine the effects of physical activity on the development and progression of microvascular complications in patients with type 1 diabetes.
A retrospective analysis of data from the Diabetes Control and Complications trial was undertaken. Physical activity data was collected at baseline for each of 1441 recruits, converted to metabolic equivalent of task values, and categorised according to the American College of Sports Medicine recommendations. The rates of development/progression of diabetic retinopathy, nephropathy and neuropathy were compared in those who achieved over twice recommended, up to twice recommended, and less than recommended metabolic equivalent of task levels of activity. The DCCT study had a mean duration of follow up of 6.5 years ending in 1993.
A total of 271 subjects had a sustained three-step progression in diabetic retinopathy. The rates of development or progression of retinopathy showed no significant association with physical activity level. The number of outcomes for nephropathy and neuropathy were small and there was no significant association with physical activity level.
We found no evidence that physical activity improves microvascular outcomes in type 1 diabetes. However we demonstrate no evidence of harm. We suggest that physical activity continues to play an important role in the management of type 1 diabetes.
The evidence for benefit of physical activity in type 1 diabetes is poorly delineated. Whilst it improves wellbeing, lipid profile and macrovascular disease in type 1 diabetes [1, 2], there is limited evidence for benefit to blood pressure, glucose control or microvascular diseases such as retinopathy, nephropathy and neuropathy . We set out to determine whether physical activity protects against microvascular complications, the consequences of diabetes that are often patients’ biggest fear [4, 5].
To date, cross-sectional studies have demonstrated that microvascular complications are associated with decreased physical activity in patients with type 1 diabetes . Causality however has not been demonstrated, and this association could be explained by the presence of complications impairing the ability to undertake physical activity, rather than physical activity decreasing the complications of diabetes. In one study where adult patients with type 1 diabetes were asked to estimate their physical activity during teenage years have reported an inverse relationship between activity and the subsequent development of nephropathy and neuropathy . However this inverse association was seen only in males, and was not seen for retinopathy. Although this study controlled for a number of important factors such as duration of diabetes, and baseline HbA1c, the subjective and retrospective estimation of physical activity weakens these findings.
To examine whether physical activity protects against microvascular complications in a more accurate and longitudinal fashion, we chose to examine publicly available high quality data from the Diabetes and Complications Trial (DCCT) . This is a large randomised controlled trial originally designed to examine whether good glucose control prevents microvascular complications. The study also provides detailed physical activity levels as well as accurate data on all the other predictors of microvascular diseases in Type 1 diabetes. No other prospective dataset exists, and it is therefore a powerful tool with which to examine the area of interest.
Ethical approval was obtained for each of the 29 study centres across USA and Canada for the DCCT study from the Hospital for Sick Children Research Ethics Board. All study participants provided written informed consent.
Study design, participants and intervention
Anonymised data from the Diabetes Control and Complication Trial (DCCT)  was obtained with ethical approval. Here, patients with type 1 diabetes aged between 13 to 39 years were divided into either the primary (726pts) or secondary (715pts) prevention cohort. The primary prevention cohort had no evidence of microvascular complications, and diabetes for less than 5 years. Those in the secondary prevention cohort had diabetes less than 15 years, minimal-moderate retinopathy and urinary albumin excretion rate of less than 200 mg per 24 hours. Each cohort was randomised to receive either intensive or standard glucose lowering therapy.
Exposure of interest (Leisure time physical activity)
At entry into the study, each patient was asked to specify the amount of time spent in leisure time physical activity (LTPA) of different intensities for the previous seven days. These activities were converted to Metabolic Equivalent of Task (MET) values - the median MET value for each level of activity described in the questionnaire was calculated using previously defined criteria  and used for data analysis. According to the international classification by Ainsworth used by American College of Sports Medicine (ACSM), 'light’ activity was allocated 3 METs, 'moderate’ activity (defined as 3–6 METs) was allocated of 4 METs, 'hard activity’ 6 METs and 'very hard activity’ 9 METs. For each participant, we multiplied this allocated median MET value by the time (minutes) spent in that activity to obtain the MET for that level of activity. The sum of METs from all activities was recorded as the total leisure time activity for each participant at entry into the DCCT. All participants were categorised into three groups based on the ACSM recommendation for METs.min/week (450-750METs) : those who did not achieve the recommended level of METs for a given week (<450METs), those achieving recommended to twice the recommended level (450-1500METs), and those achieving more than twice the recommended METS (>1500METs).
Progression of retinopathy was defined to have occurred if there was a sustained (6 months) change of three steps or more from baseline on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale . Nephropathy was defined as albumin excretion rate (AER) of >40 mg/24 hour [12, 13]. Each participant was examined quarterly every year and the time to progression of retinopathy and occurrence of nephropathy was recorded. Neuropathy was assessed by clinical examination and confirmed by either abnormal nerve conduction or autonomic nervous system testing or both at a fixed time point of 5 years follow up . Patients with nephropathy and neuropathy at baseline were excluded from the analysis in order to study onset of complications [13, 14].
Covariates included duration of diabetes, baseline HbA1c, triglycerides, cholesterol, diastolic and systolic blood pressure, BMI and smoking status. Occupational activity representing physical activity at work, school or home was also recorded by DCCT specific questionnaire as three categories namely sedentary (such as office work with occasional inter-office walking), moderate (work requiring considerable but not constant, lifting, walking, bending and pulling) and strenuous activity (requires almost constant lifting, bending, pulling, scrubbing etc.).
The DCCT study was followed by a subsequent study called Epidemiology of Diabetes Interventions and Complications (EDIC). Here the patients who had participated in the DCCT study were unblinded and asked to remain in follow-up to determine the effect of the DCCT intervention on complications in the longer term. We did not consider using the EDIC dataset because the exposure of interest was at DCCT baseline and therefore the time interval between exposure and outcome was too long to make a meaningful interpretation. Furthermore the EDIC data only recorded presence of outcome and did not have data on time to event for retinopathy or nephropathy.
Analysis was carried out separately for each of the intensive and standard glucose lowering therapy arms of the DCCT trial. We chose to analyse the data in this way because glucose lowering is now established to protect from microvascular complications and would have been an important confounder. One-way analysis of variance test was used to compare continuous variables and the chi-square test was used to compare the categorical variables in the three LTPA groups.
Kaplan Meier survival curves (with the retinopathy and nephropathy as endpoint) were generated for the three LTPA groups stratified according to the primary and secondary prevention cohort. Initially we used log-rank test in each arm stratified according to the prevention cohort to compare LTPA groups. This was supplemented by a multivariate Cox regression analysis with stratification by primary and secondary prevention cohort. In this regression model we controlled for age, gender, duration of diabetes, baseline HbA1c value and occupational activity.
Given the smaller number of outcomes and fixed time point for neuropathy, only a univariate analysis (Chi-square test) was performed. Analysis was conducted in the SPSS 18 statistical package.
Results and discussion
Baseline characteristics of the leisure time physical activity groups in intensive and standard arms of DCCT study
Category 2 (N=194)
Category 3 (N=387)
Category 1 (N=141)
Category 2 (N=207)
Category 3 (N=382)
# Age (Years)
# Duration of diabetes (Months)
# BMI (Kg/m2)
# DBP (mmHg)
# SBP (mmHg)
*Primary prevention cohort %
*Current smoker %
The numbers of subjects developing nephropathy and neuropathy were small (97 for nephropathy and 28 for neuropathy). We did however undertake an analysis of the effect of LTPA on the progression of these complications, but were not able to detect any association (see Additional files 1 and 2). Further analysis with all patients (combined primary/secondary cohort, standard/intensive treatments) provided similar results.
In this large prospective interventional study, we observed the physical activity levels were higher than the average population . Only 20% of the patients did not meet the recommended daily physical activity levels. This may be due to positive selection bias (patients volunteered are also motivated to do physical activity).
Current modifiable risk factors for microvascular complications in type 1 diabetes are recognised to be glycaemic control, blood pressure, lipids, insulin resistance and smoking [16–18]. Of these, glycaemic control is arguably the most powerful predictor of retinopathy. There is no conclusive evidence for the role of physical activity on microvascular complications. In this detailed analysis of the DCCT study, we also found no evidence that leisure time physical activity protects against either the development or progression of microvascular complications in type 1 diabetes. This lack of benefit in our analysis may be explained by the weak glycaemic benefit of exercise in type 1 diabetes [19–21]. We also speculate such lack of benefit may also be due to temporary deterioration in the glycaemic control due to reduction in insulin doses to avoid hypoglycaemia, though no such data is available in the study. However, we believe this study is better suited to examining the effect of exercise on the progression of microvascular complications, than previous cross sectional  and retrospective studies , whose results it contradicts.
The main limitation of our study is the fact that it is a post hoc analysis. The DCCT study is neither designed nor powered to test whether physical activity protects from microvascular complications. Despite the lack of validation of the physical activity types at data collection, the study is unique as the leisure time and occupational activity data in the study are detailed. Another limitation is that the levels of physical activity may have varied during the course of the study, making a baseline assessment unrepresentative. Whilst the DCCT is now a dated study and diabetes practices will likely have changed in the past 20 years, we do not believe this invalidates the use of the dataset to examine our research question.
In summary, our study does not support a benefit of physical activity on microvascular complications in patients with type 1 diabetes. However, a prospective randomised controlled study will be required to address this question adequately. In the mean time, it would be advisable to continue to support a program of physical activity in patients with type 1 diabetes for its benefits on wellbeing, macrovascular disease and mortality.
The Diabetes Control and Complications Trial (DCCT) and its follow-up the Epidemiology of Diabetes Interventions and Complications (EDIC) study were conducted by the DCCT/EDIC Research Group and supported by National Institute of Health grants and contracts and by the General Clinical Research Center Program, NCRR. The data [and samples] from the DCCT/EDIC study were supplied by the NIDDK Central Repositories. This manuscript was not prepared under the auspices of the DCCT/EDIC study and does not represent analyses or conclusions of the DCCT/EDIC study group, the NIDDK Central Repositories, or the NIH.
The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
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