Timing of exercise impacts glycaemic control
The timing of moderate-to-vigorous exercise has an impact on HbA1c, with the afternoon hours being more favourable. This aspect of lifestyle intervention comes from the Look AHEAD trial in type 2 diabetes and was reported in Diabetes Care. Dr Susan Aldridge reports.
Regular physical activity is key to blood glucose management in diabetes. Elevated HbA1c is a predictor of cardiac events and microvascular complications in type 2 diabetes and we know that moderate-to-vigorous physical activity (MVPA) reduces HbA1c in a dose-dependent manner. It enhances muscle glucose uptake and improves long-term glycaemic control by increasing skeletal muscle oxidative capacity and insulin signalling. Many studies have looked at the type and dose of MVPA for optimising its health benefits, but little is known about how the timing of this exercise influences long-term glycaemic control.
Animal studies have suggested that metabolic responses to a bout of MVPA do vary by time of day. Small studies in humans have found better improvements in glycaemic control with afternoon or evening exercise compared with morning exercise in people with type 2 diabetes or obesity/overweight. Other studies have shown that afternoon or evening MVPA is negatively associated with insulin resistance and HbA1c.
However, it’s not known whether the timing of unsupervised bouts of MVPA – everyday activity, in other words – has an impact on longer term improvements in glycaemic control. Accordingly, Jingyi Qian from Brigham and Women’s Hospital, Boston, US, and colleagues elsewhere, have drawn upon the Look AHEAD (Action for Health in Diabetes) study to explore the relationship between the timing of bouts of MVPA with changes in HbA1c over a four-year period.
The Look AHEAD study
Look AHEAD was a multicentre, randomised controlled trial designed to test the effect of an intensive lifestyle intervention (intended to produce 7-10% weight loss) on a composite outcome of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for angina. Participants had type 2 diabetes and a BMI of ≥ 25 kg/m2 (≥ 27 kg/m2 if on insulin). The intervention group were to increase physical activity and reduce calorie intake in order to achieve their goals, supported by counselling to help with behaviour change. Year one was the most intensive, with weekly individual and group counselling for the initial six months, followed by two group sessions and one individual session per month for the second six months. The remaining three years included two contacts per month to encourage participants to keep up the intervention. Of the 5,145 participants in Look AHEAD, 2,557 took part in this substudy, wearing an accelerometer to assess their physical activity, which generated data for 1,855 participants at year one and 2,200 at year four.
Timing of MVPA
This study measured bout-related MVPA, where a bout was defined as any activity expending ≥ 3 metabolic equivalents (METs) and lasting ≥ 10 minutes. A MET is the amount of energy someone uses when sitting quietly. To determine the timing of the MVPA, the researchers excluded the overnight hours between midnight and 5am and divided the remaining 19 clock hours into four time windows, such that each one had a quarter of the total MVPA bouts. This gave morning, midday, afternoon and evening windows for year one and year four. This data-driven approach allows each time window to have a comparable number of participants and avoids misinterpretation arising from a small subgroup size in any one time window.
They also recorded the weekly MVPA volume and the MVPA intensity (METs/bout) to see if these factors influenced HbA1c. The primary outcome was change in HbA1c from baseline to year one, and from year one to year four, while secondary outcomes were changes in fasting glucose and in use of glucose-lowering medication.
Afternoon exercise wins it
The researchers found significant variation in HbA1c from baseline to year one across the four MVPA timing groups. The relationship between HbA1c and timing was also independent of volume and intensity of MVPA and of BMI. The afternoon group had the greatest decrease in HbA1c at the end of year one. The mean reduction was 0.22%, which was 30-50% larger than in the other three groups. There were no further significant changes in HbA1c from year one to year four. The afternoon group were also more likely to be able to discontinue glucose-lowering medication after year one. There were no significant differences in fasting glucose across the four timing groups over the four years of the study. There was no further reduction or rebound increase in HbA1c from year one to year four.
These findings suggest that being active in the afternoon may confer the most metabolic benefit, particularly during the initial year of taking up an intervention like the one in the Look AHEAD study. The study may therefore have important clinical implications for blood glucose management by lifestyle interventions, the authors say.
Looking at other research, there have been several small controlled trials looking at time-of-day-dependent effects of exercise on glycaemic control. For instance, one study found that two weeks of high-intensity interval training in the afternoon was better than the same training in the morning at lowering 24-hour glucose in 11 men with type 2 diabetes. Another study reported similar results, in which 32 men had greater reduction in insulin resistance and fasting glucose after 12 weeks of exercise training in the afternoon versus the morning. All of this – together with these new findings – is encouraging as it suggests that the impact of physical activity can be optimised by adjusting its timing.
The authors note that the HbA1c reduction of 0.20% to 0.29% conferred by afternoon MVPA is similar to that found for intensive lifestyle intervention after 10 years of follow up and is about one-third the effect size seen after one year of such intervention. The finding of a change in HbA1c, but not fasting glucose, suggests that the link between exercise timing and HbA1c might relate more to postprandial glucose tolerance than to fasting glucose. Future studies should therefore include assessment of glucose tolerance as an outcome to check out this hypothesis.
Furthermore, the association between MVPA and changes in HbA1c at year one was independent of glucose-lowering medication use. This made the results perhaps more meaningful because the afternoon group were more likely to reduce their medication, which might be expected to work against the decrease seen in their HbA1c. Similarly, the reduction in HbA1c was independent of amount and intensity of MVPA and, in fact, the afternoon group actually had the second lowest amount of MVPA among all the groups. This, again, emphasises the link between timing and HbA1c reduction.
The circadian system may play a role in the time-specific benefits of MVPA. Previous research in animals and humans shows that metabolic responses to exercise depend on time of day and are under the control of circadian clock genes. Other behavioural factors, such as fasting/postprandial states and sleep-wake cycles, might also contribute to the diurnal variation in response to MVPA. For instance, we know that post-meal physical activity, which could mean after lunch in the afternoon group, is an effective way of managing post-prandial glucose excursions in type 2 diabetes. Furthermore, MVPA may interact with the ‘dawn phenomenon’, which is an increase in blood glucose and a decrease in insulin sensitivity in the early-morning fasted hours in people with type 2 diabetes. Further human experimental studies are needed to investigate the actual mechanisms underlying these time-specific associations between exercise and metabolic changes.
The authors point out that their study does not have data on sleep, dietary intake or meal timing, which can all affect glucose control. It’s also possible that people who exercise in the afternoon have better health or health behaviours than those who exercise at different times of the day. Furthermore, causality cannot be inferred from these findings. Further investigation of the interaction between MVPA and time of day and glycaemic outcomes in people with type 2 diabetes should now be carried out in large randomised controlled trials.
Meanwhile, the authors used clock time to define the timing of MVPA, but note that there are individual differences in circadian rhythms. It might, therefore, have been more physiologically relevant to use the timing with respect to endogenous circadian timing, rather than the clock. Finally, the participants were in the 45-75 age group and had both overweight/obesity and type 2 diabetes. It will be important to validate these findings in the wider population and among those with early-onset type 2 diabetes.
In conclusion, this study shows that participants who performed more bout-related MVPA in the afternoon had the greatest reduction in HbA1c during the first year of an intensive lifestyle intervention programme compared with those exercising at other times. Further research on this association with information on sleep patterns and nutrient intake is now needed to better understand the relationship between timing of exercise and glycaemic control in type 2 diabetes. This study, along with other recent research, highlights a new frontier of interdisciplinary research on lifestyle intervention and circadian biology that could help improve outcomes in type 2 diabetes.
To read this paper, go to: Qian J, Xiao Q, Walkup MP, Coday M, Erickson ML, Unick J, Jakicic JM, Hu K, Scheer FA, Middelbeek RJ, Look AHEAD Research Group. Association of Timing of Moderate-to-Vigorous Physical Activity With Changes in Glycemic Control Over 4 Years in Adults With Type 2 Diabetes From the Look AHEAD Trial. Diabetes Care 2023; 46: 1417–1424. https://doi.org/10.2337/dc22-2413
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.