PONE-D-23-09111Correlation between Acute Glucose Variability and Cognitive decline in Type 2 Diabetes: A Systematic Review and Meta-AnalysisPLOS ONE

Dear Dr. Chi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 30 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Victor Manuel Mendoza-Nuñez, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.2.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- 10.1055/a-1837-0141

- https://doi.org/10.1186/s13098-022-00826-9

- 10.1001/jamaneurol.2017.2180

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. Thank you for stating in your Funding Statement:

“This work was supported by Qilu Hospital Geriatric Diseases Chinese and Western Integration Academic School Inheritance Project(NO.2022-93-1-10) and The Development Plan of Medical Sciences of Shandong Province (2019 WS225).”

Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.  Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

**********

4. 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

**********

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: The study identified the relationship between acute glucose variability and cognitive decline in people with type 2 diabetes. The introduction, method and discussion sections meet the information requirements for publication. In the results section, it is convenient to make some modifications to demonstrate the consistency of what the authors found, and to making modifications in the wording and figures to highlight the findings. Considering the above, major and minor modifications are suggested.

1. Major modifications

1.1. In the results section, few papers are included. The document indicated that they found "928" articles and after removing duplicates, 307. Perform a search in PubMed using the criteria proposed by the authors, including the filter by date, I found 2305 articles. If a search strategy was used in each database, it is necessary to place it. On the other hand, the number of duplicates that are reported seems high to me, it would be useful to indicate in figure 1 how many articles were found in each database.

1.2. In the results section, it failed to mention the cognitive instruments used to identify the effect of glucose variability in a meta-analysis. Table 1 indicates screening instruments such as the MMSE and the MoCA, as well as instruments to assess more specific cognitive functions such as the Trail Making Test. When carrying out the meta-analysis, they do not indicate whether they included all the indicators or only some. In addition, they could carry out the analysis by subgroups of the cognitive indicators. In case of not finding differences between cognitive instruments, just mention it in results and in discussion analyze if an analysis by specific cognitive processes or with a general instrument is different.

1.3. Evaluate the advisability of changing "cognitive imparitment" and "risk of cognitive impairment" to "cognitive decline" in the title and the different sections. The term "cognitive impairment" can be confused with the diagnosis of "mild cognitive impairment" which has specific characteristics that are not included in the study performed.

1.4. It would be interesting to highlight the conditions in which the relationship between glycemic variability and cognitive performance is found, particularly when comparing the conditions of hyperglycemia and hypoglycemia. If it is in both, make an explanation of the mechanisms under discussion separately.

1.5. In the title, change "correlation" to "relationship". The word correlation is more associated with a statistical term.

2. Minor modifications

2.1. Abstract

2.1.1. In results, you need to write what is related, not just the statistical value found. Example: "a lower cognitive performance was found in the subjects with greater glucose variation, which has statistical significance..."

2.2 Introduction

2.2.1. To facilitate reading, write paragraphs in a size of 4 to 8 lines.

2.2.2. In the last paragraph it is indicated that there are inconsistencies in the studies of the effect of glucose variability on cognitive variability, however, it is necessary to place references that support these affirmations. In this section you can consider other related topics, for example, cardiovascular health. This allows to write the inconsistencies avoiding including the articles of the results section.

2.2.3 End the introduction with the purpose of the article. Information on social relevance (in which he writes “Given the high prevalence of cognitive dysfunctions in patients with T2DM and its serious consequences [24, 25], it is crucial to explore the role of acute GV as a modifiable risk factor”) can match it with the information presented at the beginning of the document.

2.2.4. The following information can be removed without affecting the text content:

“Central nervous system-related complications of diabetes have been known for more than 100 years by clinicians and researchers as patients have constantly complained of memory loss and inattentiveness. With a growing epidemic of diabetes and an aging population, neural complications of T2DM are expected to rise rapidly and become challenges for future public health implications.”

2.2.5 In the introduction, the abbreviation "GV" is used before indicating what it means.

2.3 Method

2.3.1. In the "Search strategy and selection criteria" section, include the question with the PEO (Population, Exposition and Outcome) format.

2.3.2. In the "bias risk assessment" section, include the score range of the Newcastle-Ottawa Scale (0-8), to facilitate the reader's interpretation. Risk of bias assessment table can be added as supplementary material.

2.3.3 In the results synthesis section, reference values are indicated to interpret "r" as correlation, it is pertinent to place reference values as effect size, in which r= 0.1, r=0.3 and r=0.5 are considered small, moderate and large respectively.

2.4 Results

2.3.1. Verify data. In the text it indicates that 64 studies were reviewed, but in figure 1 46 reviewed studies are mentioned.

2.3.2. Mention the relationship of the data found and the impact of the association, before the significance values, for example, "a lower cognitive performance was found in the subjects with greater glucose variation, which has statistical significance... and an effect size…”

2.3.3. Also mention the negative results of the glucose variability indicators in the text.

2.3.4. Figure 2 can be omitted.

2.3.5. Add a subgroup analysis with the MMSE and MoCA..

2.4 Discussion

2.4.1. Write paragraphs of 4 to 8 lines to facilitate reading

2.4.2. It is necessary to write in the first paragraph the main results, that is, the relationship between glycemic variability and cognitive performance. Not only that 9 studies were found.

2.4.3 It is not relevant to indicate the brand of the glucose monitor (“Abbott” flash glucose monitor) and it creates a conflict of interest, so I suggest removing it.

2.4.4. Differences were found between the indicators of glucose variability and its relationship with cognitive functions. Although there are few studies, a description or explanation of why there are differences between the indicators can be made.

2.4.5. The paragraph on the controversies regarding the relationship of glucose variability to complications delves into cardiac problems that are not relevant to the topic, so it is necessary to explicitly state their relevance to cognitive performance or eliminate that information.

2.4.5. The writing can be finished highlighting the main results and adding the clinical implications.

Reviewer #2: The manuscript is technically sound, its methodology is appropriate, the statistical analysis was adequate, all the results obtained are presented, and it meets the publisher's criteria for publication.

**********

6. 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: Yes: Sánchez-Nieto José Miguel

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Relationship between Acute Glucose Variability and Cognitive decline in Type 2 Diabetes: A Systematic Review and Meta-Analysis

PONE-D-23-09111R1

Dear Dr. Haiyan Chi

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Victor Manuel Mendoza-Nuñez, PhD

Academic Editor

PLOS ONE