Exploring the Interplay between Fatty Acids, Inflammation, and Type 2 Diabetes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review article “Exploring the interplay between fatty acids, inflammation and Type 2 Diabetes” by Nicholas et al presents a thorough and up-to-date analysis of what is currently known on this topic and is of undoubted value to the research community. While the text might require some corrections (mostly in style, to avoid redundancies), the figures are very well structured and might be used in the textbooks. One important aspect is however missing: the authors do not discuss the role of fatty acids/inflammation in triggering insulin-secreting beta cells failure, that has now been considered a key event in T2D pathogenesis (not limited only to insulin resistance). A chapter (and a figure) on fatty acids promoting insulin secretion and yet contributing to multiple potentially pathological processes in beta cells (including but not limited to the changes in gene expression leading to compromised identity, cytokines acting on beta cells, induced ER stress and stress-induced nascent granule degradation leading to reduced secretion, altered autophagy, etc. etc.) will be a valuable addition to the manuscript.

Minor but important point: the authors solely credit Banting and Best with the discovery of insulin, yet the story behind this is very convoluted; perhaps, Macleod and Collip’ names should be mentioned too (see, for example, here: https://www.canadaswalkoffame.com/inductee/banting-best-macleod-and-collip).

Comments on the Quality of English Language

In reviewer’s opinion, the manuscript is understandable for the English-speaking audiences. Some proof-reading and style modifications to make the text more concise would be helpful.

Author Response

Dear Reviewer,

We sincerely appreciate your thoughtful and constructive feedback on our review article titled "Exploring the interplay between fatty acids, inflammation, and Type 2 Diabetes." Your acknowledgment of the thoroughness and currency of our analysis is gratifying, and we are delighted that you found the structure of our figures to be commendable.

Your suggestion regarding the missing discussion on the role of fatty acids and inflammation in triggering beta-cell failure in T2D pathogenesis is duly noted and has been addressed. We agree that this is a crucial aspect that warrants inclusion in our manuscript. We have incorporated a section to this point "2.2. The Role of Fatty Acids in Triggering Insulin-secreting beta cells Failure."elucidating how fatty acids influence insulin secretion while simultaneously contributing to various pathological processes in beta cells. We have presented the intricacies of these mechanisms, including changes in gene expression compromising beta-cell identity, induced ER stress, and other relevant factors.

Thank you for bringing attention to this significant aspect, which will undoubtedly enhance the comprehensiveness and relevance of our manuscript.

Regarding the historical credit for the discovery of insulin, we appreciate your insight into the convoluted nature of this narrative and the suggestion to include the names of Macleod and Collip alongside Banting and Best. Another reviewer deemed the first part of our introduction unnecessary and suggested it be removed from the review, which was done.

Your input is invaluable to us, and once again, we express our gratitude for your time and thorough review.

Reviewer 2 Report

Comments and Suggestions for Authors

The present review by Nicholas et al described most relevant studies exploring the interplay between fatty acids, inflammation,  and type 2 diabetes. The authors appeared to be one of research groups actively involved in the FFA research area and its influence on the inflammation.This review thoroughly discussed the influence of elevated dietary free saturated fatty acids and examines cellular and molecular factors associated with insulin resistance in the initiation of inflammation induced by obesity. Furthermore, it explores novel concepts related to diet-induced inflammation and its relationship with type 2 diabetes

The contribution of various immune cells and cytokines is discussed in details. The emerging role of specific responses from the adaptive immune system suggests that antigen presenting B cells may play a key role in the development of obesity-induced inflammation

As for the novelties, authors discussed that their laboratory has recently demonstrated that PA is an actual TLR4 ligand and identified IgG antibodies in human serum that can recognize non-esterified saturated FAs. Although the role of these antibodies are unknown, their presence indicates lipids may somehow be involved in the immune responses seen in type 2 diabetes.

 

 Overall, the review study is interesting, timely and provides useful insights. I have a concern/suggestion to the authors.

1.    It will be useful to add a part which briefly discusses  the therapeutic strategies against saturated FFA, including  addition of dietary non saturated FFA and FFA’s receptor agonists in the treatment of obesity and type 2 diabetes.

Author Response

Dear Reviewer,

We sincerely appreciate your insightful and comprehensive assessment of our review on the interplay between fatty acids, inflammation, and type 2 diabetes. Your recognition of our active involvement in this research area is greatly valued.

Your detailed evaluation highlights the thorough exploration of the influence of elevated dietary free saturated fatty acids and the examination of cellular and molecular factors contributing to insulin resistance-induced inflammation, particularly in the context of obesity. We are delighted that our review also resonated with you in exploring novel concepts concerning diet-induced inflammation and its intricate relationship with type 2 diabetes.

Furthermore, we are encouraged by your acknowledgment of our discussion regarding the contribution of various immune cells and cytokines, particularly the emerging role of antigen presenting B cells in obesity-induced inflammation. We agree that understanding these specific responses from the adaptive immune system holds significant promise in unraveling the complexities of inflammation in type 2 diabetes.

Regarding the novelties highlighted in our review, we are thrilled to hear your interest in our laboratory's recent findings, particularly the identification of PA as an actual TLR4 ligand and the discovery of IgG antibodies in human serum capable of recognizing non-esterified saturated FAs. While the precise role of these antibodies remains to be elucidated, their presence underscores the potential involvement of lipids in the immune responses observed in type 2 diabetes.

Your thoughtful comments provide valuable insights and encouragement for our continued research efforts in this dynamic field. We will certainly take your feedback into consideration for future revisions and endeavors. Once again, we extend our gratitude for your time and thorough review.

1. We have added a brief discussion on therapeutic strategies against saturated FFA, including  specifically FFA’s receptor agonists in the treatment of obesity and type 2 diabetes in the last paragraph of section "Dietary Fatty Acids and Type 2 Diabetes"

Reviewer 3 Report

Comments and Suggestions for Authors

The study is well conducted and well written and sheds light on some key points of the topic. The relationship between the immune response and diabetes is complex and multifaceted. In particular the review explains well the mechanisms differ between type 1 and type 2 diabetes, immune system dysregulation and inflammation play important roles in both conditions.

 

In my opinion, the text from line 29 to line 47, which highlights general information that is not useful to the discussion of the review which has as its direct thread the relationship between diabetes and inflammation, should be eliminated in the introduction.

 

Another topic that was not touched upon is the role of gender differences in the development of inflammatory responses in patients with diabetes mellitus. This issue is addressed in the following two reviews:

Ciarambino T, Crispino P, Leto G, Mastrolorenzo E, Para O, Giordano M. Influence of Gender in Diabetes Mellitus and Its Complication. Int J Mol Sci. 2022;23(16):8850. Published 2022 Aug 9. doi:10.3390/ijms23168850

 

Ciarambino T, Crispino P, Leto G, Minervini G, Para O, Giordano M. Microbiota and Glucidic Metabolism: A Link with Multiple Aspects and Perspectives. Int J Mol Sci. 2023;24(12):10409. Published 2023 Jun 20. doi:10.3390/ijms241210409

Comments on the Quality of English Language

Minor editing of English language required

Author Response

The authors thank the reviewer for their critical review and recommendations. We have thoroughly analyzed each of them and would like to defend or implement them as follows:

1. To the comment "the text from line 29 to line 47, which highlights general information that is not useful to the discussion of the review which has as its direct thread the relationship between diabetes and inflammation, should be eliminated in the introduction." We agree, and we have deleted that section from the introduction as it is already well-known.

 

2. The authors concur with the suggestion to incorporate a discussion on the impact of gender differences in the inflammatory responses of diabetes mellitus patients, acknowledging its potential to enhance the depth of the review article. However, they assert that integrating this topic into the current review would not permit a comprehensive exploration of its complexities. They propose addressing it in a separate review article to provide focused attention and thorough analysis.