Association of Netrin 1 with hsCRP in Subjects with Obesity and Recent Diagnosis of Type 2 Diabetes

Round 1

Reviewer 1 Report

Garcia-Galindo measured netrin 1 in healthy , with obesity 2 and a recently diagnosed T2D persons. The authors found an increased levels in individuals with T2D along with same pattern for CRPs levels. Even though the finding can be of big intreset in the clinical field of diabetes, the results are over-interpreted. I think such results is not sufficient for suggesting biomarkers. 

Here my major concerns>

The study can be underpowered. Is there any possiblities to increase the size of the cohort? It will be necessary to increase the size of the cohort to draw stronger conclusions.

The study design is unclear. Why the authors measured cardiometabolic charateristics? The authors should explain the hypothesis behind those measurements and the related calculations and correlations.

I dont understand the link that the authors made to PPARG from line 43 to 48. it is confusing.

I recommend the authors to attenuate their statements when they claimed that Netrin 1 is a biomarker for early onset of obesity.

The authors have to further explain the discrapency between their findings and those found in previous studies. At least speculating on potential causes.

The entire manuscript must be revised by an expert of english languages. There is so many mistakes and style problems.

Author Response

We thank the reviewer 1 questions and suggestions regarding to our manuscript cimb-1988022, entitled: Association of netrin 1 with hsCRP in subjects with obesity and a recent diagnosis of type 2 diabetes.

We are submitting the new version of the manuscript above-mentioned. All the recommendations and suggestions made by the reviewers were taken into account, and the questions were answered. In the following lines, we describe point by point the details of the revisions to the manuscript and our responses to the referees´ comments.

 

General modifications:

 

We submitted the manuscript to the MDPI english editing service, ID: english-53387. This is a new and improved version of the manuscript, with all the corrections made by your MDPI English editing services.

 

Reviewer 1 questions, observations, and suggestions:

 

1. The study can be underpowered. Is there any possiblities to increase the size of the cohort? It will be necessary to increase the size of the cohort to draw stronger conclusions.
   1. Thank you for your comment. The study is a pilot of a cohort study to be conducted next year with follow-up of patients with various treatments for T2D and seeing the change over-time of Ntn1 concentrations.
   2. That is the reason why a total of 30 subjects per group was taken as a sample and although by increasing its size we could give it more power it is not the objective of the study.

 

2. The study design is unclear. Why the authors measured cardiometabolic charateristics? The authors should explain the hypothesis behind those measurements and the related calculations and correlations.
   1. Thank you for your comments. We agree with you that using those words can be misleading to readers. We changed the term to clinical variables which will make it easier to understand. The objective in the analysis was to look for the correlation of the different clinical variables with serum netrin 1 concentration, with glucose being the only one that correlated positively.

 

3. I dont understand the link that the authors made to PPARG from line 43 to 48. it is confusing
   202. Thank you for your comment. We did modification in the text by explaining how Ntn1 binding UNC5B activated PPARγ and inhibited NFκB signaling pathway, which explains how netrin 1 reduces the inflammation. Brain Behav Immun. 2018 Mar;69:190-202. doi: 10.1016/j.bbi.2017.11.012.

 

 

4. I recommend the authors to attenuate their statements when they claimed that Netrin 1 is a biomarker for early onset of obesity.
   1. Thank you for your comments. We agree with your comment and will change the wording of the text accordingly.

 

5. The authors have to further explain the discrapency between their findings and those found in previous studies. At least speculating on potential causes
   1. Thank you for your comments. The article has been modified in the part of the discussion in which these points are addressed in more detail.
   2. The main differences lie in the difference in age, type of netrin 1 kits and whether they are on previous hypoglycemic treatment.

 

6. The entire manuscript must be revised by an expert of english languages. There is so many mistakes and style problems.
   53387. Thank you for your comment. We agree and send to MDPI English editing services. ID: english-53387.

Author Response File: Author Response.docx

Reviewer 2 Report

This study provides evidence that netrin-1 can be used as a novel biomarker for early T2D. Netrin-1 is a protein with anti-inflammatory properties that inhibits NFkB and therefore results in reduced expression of its targets. The authors show that netrin-1 levels positively correlate with hsCRP and presence of T2D (early after the diagnosis).

This is a potentially interesting study but it has some negative aspects to it. If netrin-1 is suggested as a target, would one want to increase or decrease its levels? Since netrin-1 has anti-inflammatory roles one would expect that the increase seen in early T2D might be protective. What are the levels in patients with long term T2D? The authors should discuss. From the conclusions of the study it sounds more like netrin-1 to be depicted as a negative player that its levels would need to be decreased, if targeted, this needs to be discussed too.

There are multiple mistakes throughout the manuscript, not just in English but also in the number of subjects in each group, eg. line 93, are patients in each group 20 as stated there? Or 30 as stated elsewhere in the manuscript? 

The introduction can be more thorough, same as the discussion. What is the benefit of netrin-1 over other biomarkers?

 

 

Author Response

We thank the reviewer 2 questions and suggestions regarding to our manuscript cimb-1988022, entitled: Association of netrin 1 with hsCRP in subjects with obesity and a recent diagnosis of type 2 diabetes.

We are submitting the new version of the manuscript above-mentioned. All the recommendations and suggestions made by the reviewers were taken into account, and the questions were answered. In the following lines, we describe point by point the details of the revisions to the manuscript and our responses to the referees´ comments.

 

General modifications:

 

We submitted the manuscript to the MDPI english editing service, ID: english-53387. This is a new and improved version of the manuscript, with all the corrections made by your MDPI English editing services.

 

Reviewer 2 questions, observations, and suggestions:

 

 

1. If netrin-1 is suggested as a target, would one want to increase or decrease its levels?
   1195. Thank you for your comment. In a study using serum and urinary Ntn1 concentrations to detect tubular damage, low concentrations were found. At the onset of T2D we may find elevated Ntn1 concentrations as a compensatory mechanism for the inflammatory state present. Journal of Investigative Medicine 2021;69:1189-1195.

 

2. What are the levels in patients with long term T2D?
   1. Thank you for your comment. There is no consensus on this value of Nt1 in subjects with long-standing diabetes as it has not been fully described in the literature. We found ROC curve values of 0.51. Indian Heart J. 2022 Jan-Feb;74(1):72-75.

 

3. Study it sounds more like netrin-1 to be depicted as a negative player that its levels would need to be decreased, if targeted, this needs to be discussed too.
   2018. Thank you for your comment. In the presence of inflammatory states, Ntn1 employs an anti-inflammatory mechanism and elevates its concentrations, but it is still unknown at what point this compensatory mechanism takes place and reduces its serum concentration. Molecular Immunology, Volume 103, 2018. Pages 166-172, https://doi.org/10.1016/j.molimm.2018.08.021.

 

4. What is the benefit of netrin-1 over other biomarkers?
   1. Thank you for your comment. Although there is very little explored research on Ntn1, it´s a low cost biomarker of inflammation compared to others, this may be a great advantage against other markers of inflammation.

Author Response File: Author Response.docx