Capsaicin and Zinc Signalling Pathways as Promising Targets for Managing Insulin Resistance and Type 2 Diabetes

Round 1

Reviewer 1 Report

Reviewer’s Comments:

The manuscript “Capsaicin- and Zinc-induced Signalling: Potential Therapeutic Targets for Insulin Resistance and Type 2 Diabetes” is a very interesting work. In this work, The global burden of type 2 diabetes (T2DM) has led to significant interest in finding novel and effective therapeutic targets for this chronic disorder. Bioactive food components have been shown to effectively improve abnormal glucose metabolism associated with this disease. Capsaicin and zinc are such food components that have shown the potential to improve glucose metabolism through the activation of signalling events in the target cells. Capsaicin and zinc stimulate glucose uptake through the activation of distinct pathways (AMPK and AKT respec-tively); however, calcium signal transduction seems to be the common pathway between the two. While I believe this topic is of great interest to our readers, I think it needs major revision before it is ready for publication. So, I recommend this manuscript for publication with major revisions.

1. In this manuscript, the authors did not explain the importance of the Insulin Resistance in the introduction part. The authors should explain the importance of Insulin Resistance.

2) Title: The title of the manuscript is not impressive. It should be modified or rewritten it.

3) Correct the following statement “Studying molecular pathways activated by capsaicin and zinc could potentially result in the development of novel therapeutic targets for T2DM. Accordingly, throughout this literature re-view we summarise the key signalling pathways stimulated by capsaicin and zinc in glucose metabolism”.

4) Keywords: Insulin Resistance are missing in the keywords. So, modify the keywords.

5) Introduction part is not impressive. The references cited are very old. So, Improve it with some latest literature like 10.3390/molecules27217368, 10.3390/pr10081455

6) The authors should explain the following statement with recent references, “Insulin binding to its receptor’s extracellular α subunit causes a conformational change in the β subunit of the receptor which facilitates the binding of ATP to the β subunit”.

7) Add space between magnitude and unit. For example, in synthesis “21.96g” should be 21.96 g. Make the corrections throughout the manuscript regarding values and units.

8) The author should provide reason about this statement “Extracellular zinc triggers calcium release from intracellular calcium stores in HT29 cells. Zinc action on calcium flux is mediated by G proteins that activate phospholipase-C (PLC) of the extracellular G-coupled zinc sensing receptors”.

9. Comparison of the present results with other similar findings in the literature should be discussed in more detail. This is necessary in order to place this work together with other work in the field and to give more credibility to the present results.

10) Conclusion part is very long. Make it brief and improve by adding the results of your studies.

11) There are many grammatic mistakes. Improve the English grammar of the manuscript.

Author Response

Reviewer 1 comments:

General comments:

Reviewer 1

Comments and Suggestions for Authors

Reviewer’s Comments:

The manuscript “Capsaicin- and Zinc-induced Signalling: Potential Therapeutic Targets for Insulin Resistance and Type 2 Diabetes” is a very interesting work. In this work, The global burden of type 2 diabetes (T2DM) has led to significant interest in finding novel and effective therapeutic targets for this chronic disorder. Bioactive food components have been shown to effectively improve abnormal glucose metabolism associated with this disease. Capsaicin and zinc are such food components that have shown the potential to improve glucose metabolism through the activation of signalling events in the target cells. Capsaicin and zinc stimulate glucose uptake through the activation of distinct pathways (AMPK and AKT respec-tively); however, calcium signal transduction seems to be the common pathway between the two. While I believe this topic is of great interest to our readers, I think it needs major revision before it is ready for publication. So, I recommend this manuscript for publication with major revisions.

1. In this manuscript, the authors did not explain the importance of the Insulin Resistance in the introduction part. The authors should explain the importance of Insulin Resistance.

Lines 49-53, we emphasize the significance of insulin resistance (IR) in the development of preventive and therapeutic approaches for Type 2 diabetes mellitus (T2DM).

2) Title: The title of the manuscript is not impressive. It should be modified or rewritten it.

The title has been revised based on the reviewer’s comment.

3) Correct the following statement “Studying molecular pathways activated by capsaicin and zinc could potentially result in the development of novel therapeutic targets for T2DM. Accordingly, throughout this literature re-view we summarise the key signalling pathways stimulated by capsaicin and zinc in glucose metabolism”.

The mentioned statement has been revised in lines 16-19.

4) Keywords: Insulin Resistance are missing in the keywords. So, modify the keywords.

Has been revised.

The keyword “insulin resistance”  has been added. Please see line 20.

5) Introduction part is not impressive. The references cited are very old. So, Improve it with some latest literature like 10.3390/molecules27217368, 10.3390/pr10081455

We have cited the newer references throughout the manuscript.

6) The authors should explain the following statement with recent references, “Insulin binding to its receptor’s extracellular α subunit causes a conformational change in the β subunit of the receptor which facilitates the binding of ATP to the β subunit”.

The statement has been revised and the related reference has been added. Please see lines 134-136.

7) Add space between magnitude and unit. For example, in synthesis “21.96g” should be 21.96 g. Make the corrections throughout the manuscript regarding values and units.

The authors reviewed the values and units for any errors.

8) The author should provide reason about this statement “Extracellular zinc triggers calcium release from intracellular calcium stores in HT29 cells. Zinc action on calcium flux is mediated by G proteins that activate phospholipase-C (PLC) of the extracellular G-coupled zinc sensing receptors”.

The statement has been revised. Please see lines 322-327.

9. Comparison of the present results with other similar findings in the literature should be discussed in more detail. This is necessary in order to place this work together with other work in the field and to give more credibility to the present results.

Additional information has been included in the manuscript text through amendments. Please refer to lines 373, 374, 386-390, 400, and 402-404 for the specific changes.

10) Conclusion part is very long. Make it brief and improve by adding the results of your studies.

The conclusion part has been revised based on the reviewer’s comment. Please see lines 424-427.

11) There are many grammatic mistakes. Improve the English grammar of the manuscript.

The manuscript's English grammar has been revised.

Reviewer 2 Report

The review is well written even if part of this is a little bit redundant in scholastic  topic. I suggest to remove figure 1 and to avoid repetitions in the clinical complications introduction.

I would like that authors discuss the role of GLUTs and not only the 4 one in IR status and diabetes.

Title or co-title GLUCOSE METABOLISM is not appropriate. It is molecular signalling and not metabolism that is described by authors. 

It is not clear if the actions shown in figures 3 and 4 are only of skeletal muscle cells.

Author Response

Reviewer 2 comments:

General comments:

Reviewer 2

Comments and Suggestions for Authors

1) The review is well written even if part of this is a little bit redundant in scholastic  topic. I suggest to remove figure 1 and to avoid repetitions in the clinical complications introduction.

Thank you very much for your comments. The authors incorporate the comments from the reviewer to enhance the quality of the manuscript. All the changes have been highlighted for the reviewer’s kind consideration.

Figure 1 graphically demonstrates insulin signal transduction. Throughout the manuscript, insulin-independent signalling events and signal transduction stimulated by capsaicin and zinc are also shown graphically. Therefore, the authors believe that keeping Figure 1 will help maintain consistency throughout the manuscript.

2) I would like that authors discuss the role of GLUTs and not only the 4 one in IR status and diabetes.

We have incorporated information regarding the role of GLUTs, as suggested by the reviewer. Please see lines 129-132.

3) Title or co-title GLUCOSE METABOLISM is not appropriate. It is molecular signalling and not metabolism that is described by authors.

The title has been revised. Please see lines 2 and 3.

4) It is not clear if the actions shown in figures 3 and 4 are only of skeletal muscle cells.

More details have been added. Please see lines 247, 266, and 363.