Proposed Mechanisms of Blood Flow Restriction Exercise for the Improvement of Type 1 Diabetes Pathologies

Round 1

Reviewer 1 Report

This review is invaluable in that it spotlights on the usefulness of the RE combined with blood flow restriction on type 1 diabetes patients. The requirement of lower load will probably decrease the risk of exercise-induced injury without compromizing the positive effect of exercise.

[Major]

1.Authors suggested that the RE results in acute increases in muscle-derived IL-6 expression, which promotes insulin secretion and reduces post-exercise hyperglycemia. Authors also suggested that the RE decreases systemic inflammation by reducing hs-CRP and ICAM-1. Those statements seem to conflict each other because the Increases in IL-6 is expected to upregulate the expression of the CRP gene which is indicative of systemic inflammation. There should be an explanation for this contradictory outcome of RE.

2.Figure 2 describes that the increase in ROS promotes mitochondrial biogenesis via the PGC1-alpha signaling. The ROS, however, is thought to remove mitochondria by apoptosis rather than to promote biogenesis. Actually, authors proposed that the phosphorylation of P38 MAPK and subsequent activation of PGC1-alpha is responsible for the increased biogenesis of mitochondria.

[minor]

1.It is interesting to know how more phosphorylation of p3 is able to reduce the chronic HbA1c level.

2.line 115: '(HDAC)5': typographical error of (HDAC5)?

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

This is a narrative review of the effects and mechanisms of blood flow restriction exercise. The topic is interesting. But there are several flaws in this manuscript.

1. I cannot understand which effects and mechanisms are specific for type 1 diabetes. Authors should delete “type 1 diabetes pathology” from their title or change their description to be type 1 diabetes specific. In this regard, authors should refer Trends Endocrinol Metab 2021; 32(2): 106-117.
2. Authors description is unclear which effects and mechanisms are blood flow restriction specific. I feel most of the descriptions are induced by simple resistance exercise. Please clarify the specific effects for blood flow restriction.
3. Page 1, line 24; “reference 1”: This paper should be one which describes the classification of diabetes, such as Diabetes Care 2021; 44(suppl 1): S15-S33
4. Page 1, line 25; “type 2 diabetes”: please use Arabic numeral.
5. Page 1, lines 27-30; This description should be based on human patients with type 1 diabetes. Reference 5 is a study of STZ-induced diabetes in NMRI mice. Please change the reference or delete this sentence.
6. Page 1, lines 35-37; Authors claimed that resistance exercise reduce HbA1c, increase IL-6, and lower exogenous insulin requirement, based on reference 7. But reference 7 (Diabetes Res Clin Pract 2014; 106(3): 393-400) is a systematic-review and meta-analysis of all types of exercise in type 1 diabetes. Furthermore, the conclusion of reference 7 is “There are currently insufficient well-designed studies to ascertain the true effect of exercise training on HbA1c in individuals with T1D.” Authors description is false or biased.
7. Page 1, lines 41-43; Authors claimed that resistance exercise is suggested to be equally as effective as aerobic exercise at increasing glycemic control and decreasing risk of cardiovascular events, based on reference 9. But reference 9 (Diabetes Res Clin Pract 2018, 144: 93-101) is a randomized controlled trial which compared aerobic exercise and resistance exercise in type 1 diabetes and showed no significant HbA1c changes in both groups. Authors description is false or biased.
8. Page 2, lines 48-53; Authors claimed that the lack of physical activity adherence is presumed to arise from 1 the multitude of diabetic complications, 2 a lack of education regarding glycemic management strategy, and 3 fear of hypoglycemia, based on reference 2. But in the CONCLUSION section of reference 2 (Diabetes Care 2008; 31(11): 2108-2109) described that the four main barriers to physical activity were 1 fear of hypoglycemia, 2 work schedule, 3 loss of control over diabetes, and 4 low fitness level. Furthermore, although authors described that fear of hypoglycemia was associated with HbA1c and perceived well-being in reference 2, this association was of BAPAD1 score which means BArriers to Physical Activity in Diabetes, but not fear of hypoglycemia. Authors description is false.

Author Response

Please see the attachment. 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

nothing to comment

Author Response

Dear Reviewer,   Thank you for your feedback. We have taken into consideration all of the prior comments and reorganized the manuscript per the EiC's suggestion. Further, all of the references have been carefully checked, and much information was eliminated to shorten the document. A paragraph on BFR implementation was also added per the EiC's suggestion.    We are looking forward to further review of this updated manuscript, as we believe it is significant to the field and a great fit for this journal.