Dear Dr Sano,

Thank you for submitting your Review Commons manuscript entitled "The polyol pathway is an evolutionarily conserved system for sensing glucose uptake" for consideration as a Research Article by PLOS Biology. Please accept my sincere apologies for the great delay in getting back to you as we consulted with an academic editor about your submission.

Your manuscript has now been evaluated by the PLOS Biology editorial staff, as well as by an academic editor with relevant expertise, and I am writing to let you know that we would like to invite you to submit a revision that addresses the remaining reviewer comments.

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Kind regards,

Richard

Richard Hodge, PhD

Associate Editor, PLOS Biology

rhodge@plos.org

PLOS

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Dear Dr Sano,

Thank you very much for submitting your manuscript "The polyol pathway is an evolutionarily conserved system for sensing glucose uptake" for consideration as a Research Article at PLOS Biology. As you know, your partly-revised manuscript and plan of revision have been evaluated by the PLOS Biology editors and by an Academic Editor with relevant expertise.

Based on your responses to the reviews from Reviews Commons, we would welcome re-submission of a revised version that takes into account the remaining comments from the reviewers. In addition, the Academic Editor has provided some additional comments regarding the in vivo mouse data (comments provided below my signature).

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent for further evaluation by the original Review Commons reviewers.

We expect to receive your revised manuscript within 3 months. Please email us (plosbiology@plos.org) if you have any questions or concerns, or would like to request an extension. At this stage, your manuscript remains formally under active consideration at our journal; please notify us by email if you do not intend to submit a revision so that we may end consideration of the manuscript at PLOS Biology.

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https://blogs.plos.org/plos/2019/05/plos-journals-now-open-for-published-peer-review/

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Thank you again for your submission to our journal. We hope that our editorial process has been constructive thus far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Richard

Richard Hodge, PhD

Associate Editor, PLOS Biology

rhodge@plos.org

-----------------------------

COMMENTS FROM THE ACADEMIC EDITOR:

The authors should show (1) body weights of the mice and (2) blood glucose and insulin levels at the time of tissue harvest. (3) Preferably, the authors should also show liver triglyceride levels.

Dear Dr Sano,

Thank you for submitting your revised Research Article entitled "The polyol pathway is an evolutionarily conserved system for sensing glucose uptake" for publication in PLOS Biology. I have now obtained advice from the original reviewers from Review Commons and have discussed their comments with the Academic Editor.

As you can see, the reviewers appreciated the additional data included in the revised manuscript to address their comments. Based on the reviews, I am pleased to say that we will probably accept this manuscript for publication, provided you address the remaining concerns outlined by Reviewer #2. In addition, please make sure to address the following data and other policy-related requests that I have provided below (points A-D):

(A) Please ensure that the data deposited in the GEO database (accession number GSE195759) is made publicly available at this stage.

(B) Please also ensure that each of the relevant figure legends in your manuscript include information on *WHERE THE UNDERLYING DATA CAN BE FOUND*, and ensure your supplemental data file/s has a legend.

(C) Thank you for already providing the raw image of the blot presented in Figure S7B. However, we note that this may not be the fully uncropped version. If this is the case, we ask that you please provide the original, uncropped and minimally adjusted image, even if the image contains data that is not relevant to this work.

(D) Finally, please ensure that your Data Statement in the submission system accurately describes where your data can be found and is in final format, as it will be published as written there. This includes referring to underlying data provided in the Supplementary Information and the data deposited in the GEO.

--------------------------

As you address these items, please take this last chance to review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the cover letter that accompanies your revised manuscript.

We expect to receive your revised manuscript within two weeks.

To submit your revision, please go to https://www.editorialmanager.com/pbiology/ and log in as an Author. Click the link labelled 'Submissions Needing Revision' to find your submission record. Your revised submission must include the following:

- a cover letter that should detail your responses to any editorial requests, if applicable, and whether changes have been made to the reference list

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- a track-changes file indicating any changes that you have made to the manuscript.

NOTE: If Supporting Information files are included with your article, note that these are not copyedited and will be published as they are submitted. Please ensure that these files are legible and of high quality (at least 300 dpi) in an easily accessible file format. For this reason, please be aware that any references listed in an SI file will not be indexed. For more information, see our Supporting Information guidelines:

https://journals.plos.org/plosbiology/s/supporting-information

*Published Peer Review History*

Please note that you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. Please see here for more details:

https://blogs.plos.org/plos/2019/05/plos-journals-now-open-for-published-peer-review/

*Early Version*

Please note that an uncorrected proof of your manuscript will be published online ahead of the final version, unless you opted out when submitting your manuscript. If, for any reason, you do not want an earlier version of your manuscript published online, uncheck the box. Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us as soon as possible if you or your institution is planning to press release the article.

*Protocols deposition*

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. 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

Please do not hesitate to contact me should you have any questions.

Sincerely,

Richard

Richard Hodge, PhD

Associate Editor, PLOS Biology

rhodge@plos.org

------------------------------------------------------------------------

REVIEWS:

Reviewer #1: I am satisfied with the revision experiments performed.

Reviewer #2: Here, authors use data from experiments in Drosophila and mice to argue that the polyol pathway, which converts glucose to fructose via sorbitol, has a conserved function in glucose-sensing. Although this pathway is well conserved, it had not been previously attributed to glucose-sensing, and thus the results are potentially broadly important.

The manuscript is a revised version, after being reviewed at Review Commons. The authors have made considerable improvements to the manuscript and have addressed my previous comments. I have only the following minor comments:

1. When describing the phenotype on larval growth of the AR and Sodh mutants, the authors describe "weight loss" on several occasions, but actually it's just a decline in growth rate (there is not a loss or decline in the actual weight).

2. The authors have mostly addressed my previous comment that the polyol pathway is not absolutely required (depends on fed/starved state) -- but there is still rather strong language in the abstract: lines 42-3 "depends on", 45-6 "is required". Consider softening/qualifying these statements.

3. There is still something I don't understand in the discussion: you mention that the affinity of AR for glucose is very low compared to that of hexokinase (339-40), but then you say that "glucose flows into the polyol pathway before being metabolized to G6P..." (no reference for this statement by the way). Can you please explain how that works for me -- and/or maybe cite a reference?

Reviewer #3 (Gabriel Leprivier, signs review): The authors adequately answered all my points.

Dear Dr Sano,

On behalf of my colleagues and the Academic Editor, Rebecca Haeusler, I am pleased to say that we can accept your Research Article "The polyol pathway is an evolutionarily conserved system for sensing glucose uptake" for publication in PLOS Biology, provided you address any remaining formatting and reporting issues. These will be detailed in an email that will follow this letter and that you will usually receive within 2-3 business days, during which time no action is required from you. Please note that we will not be able to formally accept your manuscript and schedule it for publication until you have completed any requested changes.

Please take a minute to log into Editorial Manager at http://www.editorialmanager.com/pbiology/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with biologypress@plos.org. If you have previously opted in to the early version process, we ask that you notify us immediately of any press plans so that we may opt out on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for choosing PLOS Biology for publication and supporting Open Access publishing. We look forward to publishing your study. 

Sincerely,

Richard 

Richard Hodge, PhD

Associate Editor, PLOS Biology

rhodge@plos.org

PLOS

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Carlyle House, Carlyle Road, Cambridge, CB4 3DN, United Kingdom

ORCiD I plosbio.org I @PLOSBiology I Blog

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