PONE-D-22-01443Association of C-peptide and lipoprotein(a) as two predictors with cardiometabolic biomarkers in patients with type 2 diabetes in KERCADR population-based studyPLOS ONE

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PLOS ONE

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(The authors are grateful to Vice chancellor for Research of Kerman University of Medical Sciences in this study. The authors are also grateful to participants that contributed in this study. We special thank Dr. Yaser Masoumi-Ardakani for measuring and determining C-peptide and Lp(a) levels. )

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 (NO. The Vice chancellor for Research of Kerman University of Medical Sciences had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript)

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Additional Editor Comments:

Although the reviewers have found this study interesting, they have raised some concern about the significance and novelty of this study. Please also elaborate about the guidelines being used to treat patients with T2DM in your population.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Ref: PONE-D-22-01443

In the present article entitled “Association of C-peptide and lipoprotein(a) as two predictors with cardiometabolic

biomarkers in patients with type 2 diabetes in KERCADR population-based study” authors have explored the association between serum Lp(a) and C-Peptide levels as two predictors with cardiometabolic biomarkers in patients with type 2 diabetes mellitus (T2DM). The study design is simple and the results are well supported by the data. However, some points need to be addressed to make the study robust for the publication.

Major concerns:

1. Giving clinical perspective to the paper: Existing medicines already are know to lower C-peptides and lipoprotein levels, so the study does little in terms of adding to the solution for these Laboratory test. Kindly mention what are the current guidelines followed in Middle East to treat T2DM

2. Methodology: Addressing the Latent period of pre-diabetes: consider giving latest references of how this is affecting the biomarker levels

2. Novelty concerns: existing biomarker for management of Type 2 DM, that is C-peptide level is well controlled with injectable Insulin and SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin. Please mention these in the manuscript

Minor concerns:

1. Abbreviations need to be defined at the start of abstract: line 28: Lp(A),

Line 34: AIP, CRI

2. Fig 1,2: AIP, CRI, CRII

legends do not represent the abbreviations properly

Best regards,

Reviewer #2: In this manuscript the authors are looking at the role of Lp(a) and C-peptide levels as biomarkers for assessing cardiovascular risk. The study is being performed with both healthy and T2DM patients to understand if there is any association between these biomarkers along with other atherogenic indices of plasma for predicting the risk of cardiovascular diseases.

Overall, the manuscript is well drafted and the methods used are appropriate. The findings are well supported by the data. There are a few minor suggestions that I have highlighted below.

1. The authors mention that the data is fully available without restriction, but also mention that restrictions apply due to licensing issues. Please clarify this point.

2. Line 101-102, please briefly explain the study design here. Interested readers can look up the citations, however, a brief explanation here can help the readers move along this manuscript.

3. Line 115-116, for the T2DM eligibility criteria, the authors mention ‘6) participants with T2DM receive either therapeutic diet or therapeutic diet with a combination of oral anti glycemic drugs’. Was this only for selecting participants, or were the study participants given this diet? I did not see this data point being used anywhere in the remaining manuscript, hence, the question.

4. Materials and methods, for ‘Determination of serum lipoprotein (a)’, ELISA has been explained in detail, whereas, for ‘Determination of serum C-peptide’, that is not the case. Given the order of occurrence, details should be mentioned for serum C-peptide and in the case of Lp(a), authors can reference the C-peptide assay.

5. Line 376-377, the limitations of the study are not defined adequately. Dropping out participants was due to their ineligibility for the study. How is that a limitation? Please define.

6. Line 392-393, please combine both the sentences. Also, kindly have a final concluding statement for the manuscript.

7. Line 56, should be ‘and has been revealed to display…’.

8. Line 58, should be ‘as a biomarker for…’.

9. Line 90, please define ‘CHD’.

10. Line 289, ‘on the one hand’, does not go along with the sentence. Please modify accordingly.

11. Line 383-384, should be ‘had exposure to…’.

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Reviewer #1: No

Reviewer #2: No

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Association of C-peptide and lipoprotein(a) as two predictors with cardiometabolic biomarkers in patients with type 2 diabetes in KERCADR population-based study

PONE-D-22-01443R1

Dear Dr. Mahmoodi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Kanhaiya Singh, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No