COVID-19-Induced Diabetes Mellitus: Comprehensive Cellular and Molecular Mechanistic Insights

Round 1

Reviewer 1 Report

This manuscript is a comprehensive review of diabetes induced by SARS-CoV2 and how diabetic individuals are susceptible to SARS-CoV2 infection.

Pertinent mechanistic details explaining the biochemical and immunological changes during the SARS-CoV2 infection are adequately.

The following recommendations will help the authors to further improve the quality of the manuscript.

1. Combine epidemiology and incidence together

2. Line 121-140: The statements contradict the theme of the manuscript that normal levels of glucose will provide resistance to COVID-19. It is unclear why insulin treatment in patients with diabetes will increase the risks for susceptibility to SARS-CoV2. A detailed mechanistic explanation and a figure will help.

3. Inconsistent use of acronyms and abbreviations

4. Sentence 133: glycemic is misspelt.

5. Sentence 169- what is DENV infection. Please provide the acronym for DENV

6. Sentences 176-210- describes the effects of several viral infections on altered glucose metabolism but this information is not directly related to SARS-CoV2. Please condense this section to make it brief so that the manuscript can stay focussed.

7. Figure 2: Kerb cycle should be changed to Kreb cycle

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

1. Write the introduction by clearly differentiating type 1 and type 2 diabetes, and then talk about COVID-19 virus and its clinical manifestations. Also keep a figure here to show how these three are related.
2. General text knowledge about glucose transporters and glycolysis seem less significant in the paragraph starting from Page 141. Author can start directly from the paragraph that states virus disrupts host signaling pathways…or metabolic signaling pathways. But what are these pathways to be very specific. Is it PI3K/AKT pathway, Ras/MEK/MAPK pathway? Which insulin signaling pathway is most affected and how it connects to type 1 or type 2 diabetes.
3. The authors talk about virus infection increases GLUT-4 and GLUT-1 expression, which when increased should clear more glucose from circulation to the tissues reflecting these transporters, thus increasing insulin sensitivity, and contradicting authors own observation that viral infection induces diabetes. Please Explain this.
4. The authors have to be also specific that viral infection causes majorly type 1 diabetes or type 2 diabetes? Both diseases are very much different in their course of action, although the prognosis is similar. The authors talk first that viral infection induces pancreatic Beta-cell damage, then quickly jumps over to Type 2 diabetes. If Both diseases are affected, then author should discuss these in two different sections. 
5. Similarly, in Paragraph starting from Page 216, too much of text book knowledge about insulin signaling is not required. The author can start directly which organ is affected by COVID-19 virus apart from respiratory system, and how it is associated with diabetes. If Covid virus attacks pancreatic beta-cells, then author should keep their focus on type 1 diabetes. 
6. Same comment about the paragraph starting from Page 301. Details of these insulin signaling pathway or any background/textbook knowledge about Glucose transporters should come first (refer my 2nd comment). The author can keep this relatively short citing more useful references. Later on focus should be there own newer knowledge about how Covid virus tricks immune cells to damage pancreatic beta cells. Then talk about - Covid-19 induces insulin signaling defect, then talk about how it affects type 2 diabetes as well. The authors have to make meaningful connections here. 
7. Figure 1, 2, 3 is completely irrelevant in the context of this paper as this paper is not about Glucose transporters or insulin signaling pathway. Please provide relevant figures how Covid-19 virus manifests type 1 and type 2 diabetes. 
8. A tabular content is very necessary to provide previous knowledge about COVID-19 induced diabetes Mellitus with proper references. 

Quality of English is Okay. There are some typos which should be corrected in the revised version.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Hi, 

The manuscripts looks good to me. The figure 1 should be improved to reduce text, and focus more on pathways and signaling molecules.

I have found some typos in the manuscript. Therefore, authors are requested to do minor english editing before submitting the final version.

Author Response

Please see the attachment 

Author Response File: Author Response.pdf