Changes in Cognitive Function and in the Levels of Glycosylated Haemoglobin (HbA1c) in Older Women with Type 2 Diabetes Mellitus Subjected to a Cardiorespiratory Exercise Programme

Round 1

Reviewer 1 Report

This manuscript describes the effects of an exercise intervention on risk factors and function in women with type 2 diabetes compared with a group of women with type 2 diabetes who undertook no extra exercise beyond habitual daily activities. The study had a good design and the authors should be commended for engaging and retaining a large proportion of the control and intervention group.

The abstract would benefit from real data, rather than only p values.

The introduction and discussion are currently a little vague and the authors should not make too much about the link between HbA1C and cognitive function. These are unlikely to be causal and as currently written it might be interpreted as such.

I am unsure that the cited conversion from 6MWT to VO₂ is the best use of such conversion. Firstly, I am unsure how the provided equation (line 134) provides a suitable set of units. If you examine the equation the units remaining after the calculation is carried out are not in ml O₂ or ml O₂/kg. Also repeatability, whilst reassuring that the test is repeatable with some confidence, does not mean the data are necessarily true or real. Was there no independent check by the group that the measured value from indirect calorimetry worked in their lab setting? This could then be checked using a Bland-Altman analysis to see whether there was bias or systematic error to the measures taken.

Could the increase in VO₂ be accounted for by the change in BMI as this is integral to the calculation used it may invoke tautology? i.e. they do not get fitter, just leaner or lighter. See also line 210

Try to avoid emotive and superlative expressions, e.g. remarkably.

Some indication as to the time since diagnosis of diabetes and average drug regime since then would help. Were the control and exercise groups diabetic for similar durations of their lives? Metformin is a known to affect cell metabolism and it may have effects on neural function as a consequence. Is there any evidence of a relationship of cognitive function to duration of disease or duration of drug treatment?

The changes in HbA1C could also arise from dietary changes and the glycaemic index of the foods they ate. How was diet controlled for or checked?

Author Response

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Reviewer 2 Report

For the manuscript “Changes in cognitive function and in the levels of 3 glycosylated hemoglobin (HbA1c) in older women 4 with Type 2 Diabetes Mellitus subjected to a 5 cardiorespiratory exercise programme”, I have some comments and suggestions listed as below:

1. Table 1, height unit is “cm”, but the value seems to be the meter.
2. The participants baseline does not contain information about work/retirement status, is there any data to show if the control group and experimental group differ for activities of daily living before the experiment? I think this is very important before we can compare the two groups' results.
3. The inclusion criteria 4, why the author decide to include participants only with pharmacological treatment of 3-5 months since diagnosis?
4. What MET in Table 2 stands for?
5. The results part of the current manuscript only described the experiment group and the control group are significantly different but do not have any detailed description of the data. I think this part needs to be revised carefully.
6. My main concern about this work is that the control group showed a significant increase in VO2max, BMI, and HbA1c, and the author seems not to explain why this happened in this study. I am just curious that how to explain these changes for the control group with unchanged usual daily activities.

Author Response

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Reviewer 3 Report

This manuscript describes an interesting study adding to the knowledge in an area where additional information is much needed.

However, some minor issues have to be addressed:

1. Could you please give more details on the sample size calculation? Now are stated only alpha and CI. Please state what was the difference planned to be detected and the sample calculated to observe the planned results.
2. Could you please clarify why the Ethics Committee approval was obtained in Spain and the study was performed in Chile?
3. How was evaluated the level of physical activity in the control group during the study?
4. Please discuss your findings in the context of other studies testing the effect of physical exercise on cognition in type 2 diabetes.

Author Response

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Round 2

Reviewer 2 Report

The author revised and improve the manuscript, but I think the author still did not provide a convincing explanation for the control group data.

Like the author noted, "All the women were pensioners and they claimed to have a sedentary lifestyle, therefore, they just carried out basic domestic activities for self-help". line 85-86. As a reader, I believe that means the control group keeps the same lifestyle and similar activities before and during the experiment. So the sedentary lifestyle can not be the reason that cardiorespiratory fitness got worse in control group.  

What's more, these participants just received 3-5 months of metformin treatment. According to the previous literature[1], metformin along can effectively reduce HbA1c by 1%-2% after3-4 months of treatment at similar dosage. So these participants kept their same lifestyle and used metformin during the experiment, however, their HbA1c and BMI increased and VO2 max decreased. I think the author should give a reasonable explanation for these changes.

[1]Garber, A. J., Duncan, T. G., Goodman, A. M., Mills, D. J., & Rohlf, J. L. (1997). Efficacy of Metformin in Type II Diabetes. The American Journal of Medicine, 103(6), 491–497. 

Author Response

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Round 3

Reviewer 2 Report

Thanks for the detailed reply regarding my concern.

I totally agree that the sedentary lifestyle has been extensively proven to have a negative effect on cardiorespiratory fitness and HbA1c in the long term perspective. But in this work, control group results under no change of lifestyle, with 6 months metformin treatment, showed a significant increase of HbA1c. To explain this change with sedentary lifestyle is not convincing. In Garber's paper, the participants are indeed younger than this work's sample, but they are more severe diabetic patients whose body weight is around 90 kg (BMI=31.9) and mean HbA1c% is around 10%. So I don't agree you mentioned that the 500mg Metformin group is the same as your control group, which received 850mg metformin for 24 weeks and with much lower BMI and basal HbA1c.  Compared to Garber's data, the author treated the control group with higher dosage of metformin for longer time. If 6 months of sedentary lifestyle under metformin treatment can solely induce the significant HbA1c% change, I hope the author can provide a reference or other research data to support this result. 

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