PONE-D-19-24296

Effect of short-term prednisone on beta-cell function in subjects with type 2 diabetes mellitus and healthy subjects

PLOS ONE

Dear Dr Guerra,

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Academic Editor

PLOS ONE

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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: No

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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: Although the authors addressed a clinical issue about the effect of prednisone on beta-cell function between T2DM patients and healthy people, the sample size was too small to support the conclusion, and the mismatch of age and gender lead to large sample bias. To the reviewer's opinion, more rigorous experiments and data were needed to confirm the conclusions.

Reviewer #2: Shah and colleagues drew a preliminary but interesting study concluding high-dose prednisone resulting in suppressed insulin secretion rather than increasing insulin resistance. The conclusion seems result-based, but some concerns should be noted before its publication.

1. How did the author confirm the diagnosis of type 2 diabetes? As this is a very small sample trial, the representation of the study is exclusively important (authors may wish to add differentiating information like auto-antibodies, baseline 8 am cortisol and other MODY phenotypes).

2. The therapeutic regimens need to be provided including a daily dose of metformin. If there is any dose change of metformin during the trial, it should be reported.

3. Are there any other safety issues reported in the trial, such as hypertension, insomnia, etc?

4. The reduction of AUC C-peptide and AUC Insulin is not totally in line. Please explain.

5. The authors may wish to provide some clinical interpretations in steroid usage, especially the clinical context of a three-day prescription of 40mg/d prednisone.

6. The authors may also wish to discuss the underlying pathophysiological mechanism of the study result in more detail.

7. This trial does not include a dose gradient of prednisone, which is also a limitation needing stated.

8. I think "emergent response of beta-cell function" rather than "short-short effects" may more fit the study context.

9. Please note some typos like OGGT in the manuscript.

Reviewer #3: In their manuscript entitled “Effect of short-term prednisone on beta-cell function in subjects with type 2 diabetes mellitus and healthy subjects," Shah and colleagues report that that a short course of high-dose glucocorticoids in those with T2DM leads to a significant decrease in insulin secretion. However, the healthy controls did not have significant decreases in beta-cell insulin secretion parameters after prednisone exposures. The authors believe that subjects with T2DM have an increased beta-cell impairment and reduced ability to recover after glucocorticoid exposure.

Overall, the authors report a very interesting results; however, a few issues do require attention in my opinion.

1. In fact, lots of studies have demonstrated that glucocorticoids treatment may lead to insulin resistance, increased hepatic gluconeogenesis and hyperglycemia in animals and human. Of note, these effects of glucocorticoids are dependent on long term treatment (for example, 2 weeks or 3 weeks). However, in the present study, human subjects were treated with glucocorticoid for 3 days. Thus, the authors just observed a short effects of glucocorticoid treatment. These data are interesting. However, when the authors make conclusion, they should be more objective and fair. In my opinion, they should conclude that short-term glucocorticoid treatment may impair insulin secretion and beta cell in patients with type 2 diabetes. They can not deny the long term effects of glucocorticoids on insulin resistance and hepatic gluconeogenesis.

2. The mechanism of this study is completely unclear, and the mechanism of how glucocorticoid affects the decrease of insulin secretion by beta cells in diabetic patients is unclear. The authors should discuss this issue, based on the previous literatures.

3. The number of participants is not enough. The author also mentioned this point and acknowledged this weakness.

4. What were the results in animals? Has the authors performed similar experiments in mice?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Effect of short-term prednisone on beta-cell function in subjects with type 2 diabetes mellitus and healthy subjects

PONE-D-19-24296R1

Dear Dr. Guerra,

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

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Zhiming Zhu

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

Reviewer #3: 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: Partly

Reviewer #2: No

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #3: Yes

**********

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: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

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: Thanks for the careful revision from the authors. However, I would doubt the credibility of the study results as the authors suggested that the AUC of CP and insulin may lie when there the sample size is too small. Meanwhile, I saw only diabetes but not type 2 diabetes in this study. Both issues may lead to the study results, which are different from our clinical impression.

I would suggest the authors to add sample size based on the current results and rigorously exclude potential MODY and LADA patients.

Reviewer #3: (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.

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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

Reviewer #3: No