Plant-Derived Flavonoids as AMPK Activators: Unveiling Their Potential in Type 2 Diabetes Management through Mechanistic Insights, Docking Studies, and Pharmacokinetics

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript titled "Plant-Derived Flavonoids as AMPK Activators: Unveiling Their Potential in Type 2 Diabetes Management Through Mechanistic Insights, Docking Studies, and Pharmacokinetics" is a well-structured and comprehensive review. It covers the potential of plant-derived flavonoids as AMPK activators in the treatment of Type 2 Diabetes (T2DM). The manuscript discusses the mechanisms of action, docking studies, and pharmacokinetic properties (ADME) of various flavonoids. Several areas could benefit from additional detail and clarification to enhance the overall quality and impact of the review.

1. Abstract:

• Consider expanding the keywords.

2. Introduction

• Add a brief reference to the historical use of flavonoids in herbal therapies, highlighting how this background supports their potential as natural treatments for diabetes.
• Elaborate on the mechanisms by which AMPK modulates inflammation and oxidative stress, with appropriate references to recent studies.
• Introduce a transition section to connect the discussion on AMPK with flavonoids more fluidly, ensuring that the narrative is easy to follow.
• Summarize key findings from recent animal studies and preliminary clinical trials that have demonstrated the potential of flavonoids in managing T2DM.

3. Methodology

• Provide a more thorough explanation of the inclusion and exclusion criteria used to select the reviewed studies, improving the transparency and reproducibility of the review.

4. Body of the Manuscript

• Include a discussion on the limitations of molecular docking, particularly its ability to predict interactions in the complex biological environment of the human body.
• Where possible, provide data (e.g., percentage improvements in glucose uptake, AMPK activation) to help readers understand the relative effectiveness of each flavonoid. This could also enhance the value of Table 1.
• Delve deeper into the clinical implications of using flavonoids as diabetes therapies. Discuss challenges like bioavailability, drug interactions, and solubility, and propose potential solutions to overcome these barriers.
• Include a section discussing possible adverse effects of long-term flavonoid use, referencing toxicology studies if available.
• Add a comparison between the efficacy of the flavonoids and conventional drugs, particularly in terms of effectiveness and side effects, to provide readers with valuable context on the therapeutic potential of flavonoids.

5. Future Directions

• Create a section outlining clear future research directions, such as the need for clinical trials and studies examining the combined use of flavonoids with conventional diabetes therapies.

Comments on the Quality of English Language

No comments

Author Response

Reviewer1

Thank you for your thoughtful and constructive feedback. I have carefully addressed each of your points in the revised manuscript as follows:

1. Abstract:

• Consider expanding the keywords.

⟶ I have expanded the keywords.

 

2. Introduction

• Add a brief reference to the historical use of flavonoids in herbal therapies, highlighting how this background supports their potential as natural treatments for diabetes.

⟶ A brief reference to the historical use of flavonoids in herbal therapies has been added.

 

• Elaborate on the mechanisms by which AMPK modulates inflammation and oxidative stress, with appropriate references to recent studies.

⟶ The mechanisms by which AMPK modulates inflammation and oxidative stress have been elaborated.

 

• Introduce a transition section to connect the discussion on AMPK with flavonoids more fluidly, ensuring that the narrative is easy to follow.

⟶ A transition section has been introduced to smoothly connect the discussion on AMPK with flavonoids, improving the narrative flow.

 

• Summarize key findings from recent animal studies and preliminary clinical trials that have demonstrated the potential of flavonoids in managing T2DM.

⟶ Key findings from recent animal studies and preliminary clinical trials that highlight the potential of flavonoids.

 

 

3. Methodology

• Provide a more thorough explanation of the inclusion and exclusion criteria used to select the reviewed studies, improving the transparency and reproducibility of the review.

⟶ I made corrections.

4. Body of the Manuscript

• Include a discussion on the limitations of molecular docking, particularly its ability to predict interactions in the complex biological environment of the human body.

⟶ I made corrections.

 

• Where possible, provide data (e.g., percentage improvements in glucose uptake, AMPK activation) to help readers understand the relative effectiveness of each flavonoid. This could also enhance the value of Table 1.

⟶ I would like to include the percentage improvements in glucose uptake and AMPK activation in Table 1 as per your request. However, most of the references cited in Table 1 do not provide exact quantitative values. For example, as shown below (please refer to the attached), references 53 and 54, like many others, do not present specific numerical data either in the main text or in the results section. I kindly ask for your understanding regarding the inability to modify the table accordingly due to the lack of precise data in the cited studies.

• Delve deeper into the clinical implications of using flavonoids as diabetes therapies. Discuss challenges like bioavailability, drug interactions, and solubility, and propose potential solutions to overcome these barriers.

⟶ I have revised.

 

• Include a section discussing possible adverse effects of long-term flavonoid use, referencing toxicology studies if available.

⟶ I have revised.

 

• Add a comparison between the efficacy of the flavonoids and conventional drugs, particularly in terms of effectiveness and side effects, to provide readers with valuable context on the therapeutic potential of flavonoids.

⟶ I have revised.

 

5. Future Directions

• Create a section outlining clear future research directions, such as the need for clinical trials and studies examining the combined use of flavonoids with conventional diabetes therapies.

⟶ I have revised.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

When reading the review “ Plant-Derived Flavonoids as AMPK Activators: Unveiling Their Potential in Type 2 Diabetes Management Through Mechanistic Insights, Docking Studies, and Pharmacokinetics” by author Dong Oh Moon, I had the impression I read an already peer-reviewed and edited article. For me, the article was highly informative; being  deeply interested myself in diabetes and cancer, I wasn’t aware of the critical role of AMPK before, and, of course, I was delighted to learn more about two of my favourite polyphenols, dihydromyricetin and baicalein. I learned about the existence of several other flavonoids I wasn’t aware of, such as derrone or alpiniumisoflavone. The figures are convincing, the content of Table 1 also. However, I wonder if one could improve the stylishness of this table. You don’t have to show every border.

The ADME software is also exciting news, I wasn’t aware of. I am not sure the author can take it for granted that all interested readers know what it means. Thus, in line 22 of the abstract the abbreviation ADME could be explained (absorption, distribution, metabolism, excretion). I am not completely happy with Table 2. Can you assume that any reader can understand that table in full? What about a legend? Maybe non-essential rows, if they exist, could be deleted or made accessible elsewhere? But that’s up to the author and the editor.

 

As a personal note: Why looking for drugs when we already have them?  It’s true that the bioavailability of polyphenols such as curcumin is often small on average.  But we also learned in the past decade that our gut microbiome uses polyphenols as prebiotics and renders them into forms that then are bioavailable; take urolithin as an example: Of course, only a fraction of the population has the kind of gut microbiome that can turn what comes from walnuts or pommegranates into urolithin. Your choice is either to train your microbiome or to take urolithin as supplement. We also now already that dihydromyricetin (DHM) is incredibly effective. Is there still a need to develop a drug based on DHM?

Author Response

When reading the review “ Plant-Derived Flavonoids as AMPK Activators: Unveiling Their Potential in Type 2 Diabetes Management Through Mechanistic Insights, Docking Studies, and Pharmacokinetics” by author Dong Oh Moon, I had the impression I read an already peer-reviewed and edited article. For me, the article was highly informative; being  deeply interested myself in diabetes and cancer, I wasn’t aware of the critical role of AMPK before, and, of course, I was delighted to learn more about two of my favourite polyphenols, dihydromyricetin and baicalein. I learned about the existence of several other flavonoids I wasn’t aware of, such as derrone or alpiniumisoflavone. The figures are convincing, the content of Table 1 also. However, I wonder if one could improve the stylishness of this table. You don’t have to show every border.

⟶I modified the table.

 

The ADME software is also exciting news, I wasn’t aware of. I am not sure the author can take it for granted that all interested readers know what it means. Thus, in line 22 of the abstract the abbreviation ADME could be explained (absorption, distribution, metabolism, excretion). I am not completely happy with Table 2. Can you assume that any reader can understand that table in full? What about a legend? Maybe non-essential rows, if they exist, could be deleted or made accessible elsewhere? But that’s up to the author and the editor.

⟶ "I have revised the table by adding or removing certain items.

 

As a personal note: Why looking for drugs when we already have them?  It’s true that the bioavailability of polyphenols such as curcumin is often small on average.  But we also learned in the past decade that our gut microbiome uses polyphenols as prebiotics and renders them into forms that then are bioavailable; take urolithin as an example: Of course, only a fraction of the population has the kind of gut microbiome that can turn what comes from walnuts or pommegranates into urolithin. Your choice is either to train your microbiome or to take urolithin as supplement. We also now already that dihydromyricetin (DHM) is incredibly effective. Is there still a need to develop a drug based on DHM?

⟶ Thank you for your insightful question. While it’s true that natural compounds like polyphenols can be metabolized by the gut microbiome and rendered bioavailable, there are still several reasons why developing drugs based on these compounds is important.

First, the composition of the gut microbiome varies greatly between individuals, meaning not everyone can metabolize polyphenols in the same way. For instance, only a subset of people can convert compounds from pomegranates into urolithin. Developing a drug ensures that everyone, regardless of their microbiome, can benefit from these therapeutic effects.

Second, polyphenols like DHM often have low bioavailability. Creating a drug formulation can improve the stability, absorption, and targeted delivery of these compounds, leading to more consistent and reliable therapeutic outcomes.

For these reasons, there is still a strong need to explore drug development around compounds like DHM to maximize their potential and ensure more widespread, effective use.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

No comments