The Effect and Mechanism of Regular Exercise on Improving Insulin Impedance: Based on the Perspective of Cellular and Molecular Levels

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Comments to the Authors of manuscript number ijms-3555345 entitled “The Effect and Mechanism of Regular Exercise on Improving Insulin Impedance: Based on The Perspective of Cellular and Molecular Levels”

1. 14–17“The most important pathway in carbohydrate metabolism is the translocation of protein GLUT4 to the cell membrane by glucose…” - It is not glucose that moves GLUT4
2. 20“…phosphatidyl alcohol 3 kinase (PI3K)” - phosphoinositide 3-kinase.
3. 22–23“…glucose uptake by skeletal muscle insulin…” makes no sense. It should read: "…glucose uptake by skeletal muscle is impaired due to insulin signaling dysfunction…"
4. 54–59 Lack of systematics and inconsistency of definitions, the description does not correspond to the classic three-stage development of T2DM. The Authors do not refer to the current ADA/EASD classifications.
5. 94–95 Too general and clinically questionable. In clinical practice, even with a defect in the IRS/PI3K pathway, the effects of training (e.g. AMPK, NO, Ca2+) are significant – it needs to be clarified and sources provided.
6. The entire chapter 3-No separation of adaptation mechanisms in healthy vs. T2DM individuals. The authors describe changes in IRS1, IRS2, AMPK, MAPK, GLUT4, etc. in a generalized manner, without distinguishing between the effects in: healthy individuals, individuals with metabolic syndrome, patients with advanced T2DM.
7. No clinical division of T2DM (early vs. late, with vs. without complications).
8. No references to drugs affecting AMPK (e.g. metformin).
9. No discussion of the safety of physical exercise in patients with complications (e.g. retinopathy, nephropathy, neuropathy).
10. No tabular comparison of the effects of different types of activity (aerobic vs. strength vs. interval) on insulin resistance.
11. Included mechanisms AMPK, IRS, MAPK, FABP, ROS – well selected from the point of view of physiology.
12. Well-organized chapter on molecular mechanisms.
13. The paper touches on an important clinical problem, but requires improvement in substantive precision, terminology and better integration of clinical and physiological aspects. It is necessary to logically organize the content, supplement it with practical aspects and eliminate terminological errors.

Author Response

 

1、 14–17“The most important pathway in carbohydrate metabolism is the translocation of protein GLUT4 to the cell membrane by glucose…” - It is not glucose that moves GLUT4

Reply: Expert guidance is correct. This is indeed a translation error and has been corrected

2、 20“…phosphatidyl alcohol 3 kinase (PI3K)” - phosphoinositide 3-kinase.

Reply: The expert's opinion is correct and has been revised

3、 22–23“…glucose uptake by skeletal muscle insulin…” makes no sense. It should read: "…glucose uptake by skeletal muscle is impaired due to insulin signaling dysfunction…"

 Reply: The expert's opinion is correct and has been revised

4、54–59 Lack of systematics and inconsistency of definitions, the description does not correspond to the classic three-stage development of T2DM. The Authors do not refer to the current ADA/EASD classifications.

   Reply: The expert opinion is very fair. According to the latest ADA/EASD classifications, insulin resistance can be divided into four stages Modifications have been made.

5、 94–95 Too general and clinically questionable. In clinical practice, even with a defect in the IRS/PI3K pathway, the effects of training (e.g. AMPK, NO, Ca2+) are significant – it needs to be clarified and sources provided.

Reply: The expert's thinking is agile, but the wording in this area is incorrect. Corrected.

6、The entire chapter 3-No separation of adaptation mechanisms in healthy vs. T2DM individuals. The authors describe changes in IRS1, IRS2, AMPK, MAPK, GLUT4, etc. in a generalized manner, without distinguishing between the effects in: healthy individuals, individuals with metabolic syndrome, patients with advanced T2DM.

Reply: The adaptation mechanism of healthy individuals and type 2 diabetes individuals is similar. The author believes that it is unnecessary to distinguish the impact of exercise on healthy individuals, patients with metabolic syndrome, and patients with advanced type 2 diabetes when describing the change rules of IRS 1, IRS 2, AMPK, MAPK, GLUT4, etc. Experts are also invited to investigate.

7、No clinical division of T2DM (early vs. late, with vs. without complications).

   Reply: Type II diabetes itself is a type of diabetes. In clinical practice, type II diabetes can be divided into insulin resistance type and insulin secretion insufficiency type according to the patient's condition. Insulin resistance is characterized by insulin resistance and insufficient insulin secretion, and patients may have symptoms such as obesity and pre meal hypoglycemia. The insulin secretion deficiency type is characterized by mild insulin resistance and symptoms such as frequent urination and thirst. It has been explained in the text.

8、No references to drugs affecting AMPK (e.g. metformin).

Reply: The author has repeatedly considered the expert's intention and, considering the importance of AMPK, has added the role of metformin.

 

9、No discussion of the safety of physical exercise in patients with complications (e.g. retinopathy, nephropathy, neuropathy).

Reply: The main topic discussed in Chapter 3 is not the safety of exercise for patients with type II diabetes, but it can certainly be mentioned slightly. Based on expert opinions, this revision has added some content.

 

10、No tabular comparison of the effects of different types of activity (aerobic vs. strength vs. interval) on insulin resistance.

Reply:  Based on this study, it belongs to a general review and generally does not require a list of literature. If we want to group the list according to aerobic exercise, resistance exercise, and high-intensity interval exercise, this article will be quite complex and the content will be stretched out. I hope the experts can investigate. thank you!

11、Included mechanisms AMPK, IRS, MAPK, FABP, ROS – well selected from the point of view of physiology.

Reply: The author believes that this is done because there are many biochemical indicators, and the analysis process can only focus on the key points. Thank you, expert!

12、Well-organized chapter on molecular mechanisms.

Reply: Thank you for the expert's appreciation

 

13、The paper touches on an important clinical problem, but requires improvement in substantive precision, terminology and better integration of clinical and physiological aspects. It is necessary to logically organize the content, supplement it with practical aspects and eliminate terminological errors.

Reply: Thank you for the expert's correction. I have made every effort to revise the relevant terminology based on the expert's opinions.

Reviewer 2 Report

Comments and Suggestions for Authors

The review by Zhang et al is an interesting work discussing in depth the molecular aspects underlying the relationship between physical activity and insulin resistance. 

This is a very well written paper and thorough. The reviewer would only like to offer a couple of points for the authors' consideration below:

1. Consider discussing the protein/dietary intake in regards to activity.\

Here is a paper that you might find useful to that end:

Maykish, A.; Sikalidis, A.K. Utilization of Hydroxyl-Methyl Butyrate, Leucine, Glutamine and Arginine Supplementation in Nutritional Management of Sarcopenia—Implications and Clinical Considerations for Type 2 Diabetes Mellitus Risk Modulation. J. Pers. Med. 2020, 10, 19. https://doi.org/10.3390/jpm10010019.

2. Consider discussing the aspect of the microbiome and how that might also influence the outcome of IR. 

Good work overall. 

Author Response

 1、 Consider discussing the protein/dietary intake in regards to activity.\ Here is a paper that you might find useful to that end: Maykish, A.; Sikalidis, A.K. Utilization of Hydroxyl-Methyl Butyrate, Leucine, Glutamine and Arginine Supplementation in Nutritional Management of Sarcopenia—Implications and Clinical Considerations for Type 2 Diabetes Mellitus Risk Modulation. J. Pers. Med. 2020, 10, 19. https://doi.org/10.3390/jpm10010019. 

Reply: Thank you to the expert for recommending the literature. The author carefully studied it and gained some inspiration

2、Consider discussing the aspect of the microbiome and how that might also influence the outcome of IR. 
Reply: The expert's suggestion is very good, thank you for your help.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

many corrections were made