Thank you for the opportunity to review this manuscript titled "The fluoroquinolone moxifloxacin blocks the voltage-gated potassium channel Kv11.1, decreases plasma glucose, and increases insulin sensitivity in healthy participants – a randomised, double-blind, crossover study".

The authors aim to demonstrate the effect of moxifloxacin on voltage gated potassium channels in muscle and pancreatic alpha and beta cells, and demonstrate the resulting impact on glucose levels and insulin sensitivity in muscle within a healthy participant cohort.

This study is novel in that this effect has only been demonstrated before in those who are already being treated with hypoglycemia causing medications for diabetes, and here the authors present findings in a healthy cohort.

Overall the paper is well written and the authors provide a CONSORT statement list identifying all components necessary for trial reporting.

The abstract is concise and relevant, describing the study and results appropriately. The conclusion is valid and consistent with the results.

The introduction appropriately describes the need for the study and the current holes in published literature that it will address.

The methodology includes a detailed description of the study including specific sub-headings relevant to this study. All necessary data for reporting are included and confirmed in the supplementary reporting tool. Statistical analysis is appropriate for this study.

The reported results are consistent with the data included in the figures and tables

There are a few points that I believe should be addressed before final consideration for publication, as follows:

Title:
- Please consider that the title includes interpreted results of the study rather than describing the study itself and presents a bias to the reader at the very start.

I would recommend changing the title to reflect what the study is testing instead, such as "A randomised, double-blind, crossover study of the effect of moxifloxacin on glucose levels and insulin sensitivity in healthy participants".

Introduction:
- Some of the abbreviations are mentioned prior to their definition (LQTS, line 58, page 4).

• Hypoglycemia limits are not defined in the introduction and the discussion of the studies that demonstrate hypoglycemia with the fluoroquinolones should include some note on the degree of hypoglycemia seen with these agents (lines 60 - 69, page 4).

Methodology:
- A minor point that the sub-headings appear to be extraneous and can be grouped into larger sub-headings that are more commonly seen in manuscripts. Not a required change, just a note.

• It is not clear in the methodology why the investigators include paracetamol in the OGTT and the purpose of measuring acetaminophen levels. It might be helpful to hint at the purpose of the acetaminophen test in the section on the OGTT.

Results:
- My only concern with the result section is similar to my concern with the title, in that the authors include statements for each section that interpret the effect as directly due to moxifloxacin, when the section headers should simply correlate the results with the cohort that used moxifloxacin.

Although subtle, this difference is important in limiting reader bias by including the possibility of chance association (some other factor within this cohort causing the effect).

For example, changing "Moxifloxacin increase QTcF confirming Kv11.1 block" to "Increased QTcF in the cohort using moxifloxacin". It is best to leave the final interpretation of the data to the discussion.

Discussion:
- There are other important limitations of the study that should be identified for readers, including the sample size being somewhat small, the limitations of using calculated values for insulin sensitivity without standard clamp measurement, potential limitation of glucose sensor accuracy especially within the lower ranges, limitations of using acetaminophen for assessing gastric emptying, and others.

Conclusion:
- No recommended edits.

In summary, the recommended edits are all relatively minor and do not detract from the novelty of this excellent study and manuscript. It was a pleasure to review this paper and I wish the authors all the best in their future endeavors.

Thank you for the opportunity to re-review this manuscript, now titled "A randomised, double-blind, crossover study of the effect of the fluoroquinolone moxifloxacin on glucose levels and insulin sensitivity in young men and women". The authors have appropriately responded to and addressed my, and the other reviewers', concerns. I do not have any further edits to suggest, thank you.

I wish the authors all the best in their future endeavors.