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  • Yeong-Min Yoo 1,* and
  • Seong Soo Joo 2,*

Reviewer 1: Anonymous Reviewer 2: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript by Yoo et al. reviews the physiological implications of pancreatic amyloid polypeptide aggregation and its inhibition by melatonin. One of the major pathological hallmarks of Type 2 Diabetes (T2D) is the abnormal misfolding and aggregation of human islet amyloid polypeptide (hIAPP), also known as amylin, within pancreatic β-cells. Under normal physiological conditions, hIAPP is co-secreted with insulin; however, under pathological conditions it can misfold and form toxic oligomers and amyloid fibrils that contribute to β-cell dysfunction and apoptosis. The review discusses the potential role of melatonin, an endogenous neurohormone, in modulating the aggregation pathways of hIAPP and interfering with β-sheet formation, thereby suggesting a possible protective role against amyloid toxicity. Overall, the review is well written and the references are appropriate and comprehensive. The manuscript is suitable for publication in the IJMS after addressing the following minor revisions:

  • The authors should include recent theoretical and computational studies on amylin aggregation to provide a more balanced perspective of current research in the field.

  • The Introduction would benefit from a slightly expanded discussion of the pathophysiology of T2D and its relationship with amylin aggregation.

  • Additional schematic figures illustrating the molecular mechanism of amylin aggregation and its potential connection with neurodegenerative diseases such as Alzheimer's disease and T2D would further improve the clarity and impact of the review.

Author Response

March 16, 2026

Dear Reviewer 1,

Thank you for your letter and for the reviewers’ comments regarding our manuscript entitled " Physiological implications of pancreatic amyloid polypeptide aggregation and its inhibition by melatonin."

We completely agree with your suggestions regarding our manuscript. The manuscript is completely revised as you and your colleague requested.

The corrections and revisions are as follows:

The manuscript by Yoo et al. reviews the physiological implications of pancreatic amyloid polypeptide aggregation and its inhibition by melatonin. One of the major pathological hallmarks of Type 2 Diabetes (T2D) is the abnormal misfolding and aggregation of human islet amyloid polypeptide (hIAPP), also known as amylin, within pancreatic β-cells. Under normal physiological conditions, hIAPP is co-secreted with insulin; however, under pathological conditions it can misfold and form toxic oligomers and amyloid fibrils that contribute to β-cell dysfunction and apoptosis. The review discusses the potential role of melatonin, an endogenous neurohormone, in modulating the aggregation pathways of hIAPP and interfering with β-sheet formation, thereby suggesting a possible protective role against amyloid toxicity. Overall, the review is well written and the references are appropriate and comprehensive. The manuscript is suitable for publication in the IJMS after addressing the following minor revisions:

1. The authors should include recent theoretical and computational studies on amylin aggregation to provide a more balanced perspective of current research in the field.
Answer: Thank you very much for your good comments.

The computational research direction on amylose aggregation suggested by the reviewer is outside my area of expertise, and since I am not familiar with it, I did not mention it, as I had not consulted the relevant literature. Please understand that I chose not to comment on this area, as discussing a field I am not well-versed in could alter the direction of the review paper or compromise its quality. Of course, I cannot claim to have covered all recent theoretical directions on amylin aggregation, but I believe I have incorporated nearly all papers published to date. I hope the reviewer will understand this.

  1. The Introduction would benefit from a slightly expanded discussion of the pathophysiology of T2D and its relationship with amylin aggregation.

Answer: Thank you very much for your good comments.

Although the reviewer may not be entirely satisfied, I believe I have done my best to incorporate nearly all of the most recently published papers in the section titled “2. Physiological and Pathophysiological Significance of IAPP Aggregation,” which discusses the pathophysiology of type 2 diabetes and its relationship to amylin aggregation. Of course, the reviewer may feel that this is insufficient, but I hope the reviewer will understand my position on this matter.

  1. Additional schematic figures illustrating the molecular mechanism of amylin aggregation and its potential connection with neurodegenerative diseases such as Alzheimer's disease and T2D would further improve the clarity and impact of the review.

Answer: Thank you very much for your good comments.

We have added an additional schematic diagram explaining the molecular mechanism of amyloid aggregation and its potential association with conditions such as T2D and AD.

 

 

 

 

 

 

 

 

 

 

 

 


**All of the edited sections and references were changed with the blue words.

I hope that the revised manuscript is now acceptable for publication in the IJMS. We are looking forward to receiving your answer soon.

Sincerely,

Yeong-Min Yoo Ph.D 

Institute of Environmental Research,

Kangwon National University,

Chuncheon 24341, Republic of Korea

Email: yyeongm@hanmail.net

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review focuses on the last few years where emerging evidence suggests misfolding and aggregation of human IAPP not only impacts pancreatic beta cells and Type 2 diabetes but may be relevant to Alzheimer’s Disease (AD). The role of melatonin in inhibiting IAPP misfolding and other events is considered.

The connection to AD is a major feature of this review. I think this should be mentioned in the abstract and perhaps the title. It is important to do this to make sure the article is found by search engines.

The article appears to assume all conclusions reported in the literature are true. Some acknowledgement that some conclusions are controversial would be welcomed.

Otherwise, I liked the focus and length as well as the number of references cited.

 

Minor points: line 347, Melatonin inhibits the formation…

Line 434, remove italicized text ‘Research manuscripts….’

Line 444, ‘T2DM’ is mentioned. Is this a mistake or is it undefined ?

Author Response

March 16, 2026

Dear Reviewer 2,

Thank you for your letter and for the reviewers’ comments regarding our manuscript entitled " Physiological implications of pancreatic amyloid polypeptide aggregation and its inhibition by melatonin."

We completely agree with your suggestions regarding our manuscript. The manuscript is completely revised as you and your colleague requested.

The corrections and revisions are as follows:

This review focuses on the last few years where emerging evidence suggests misfolding and aggregation of human IAPP not only impacts pancreatic beta cells and Type 2 diabetes but may be relevant to Alzheimer’s Disease (AD). The role of melatonin in inhibiting IAPP misfolding and other events is considered.

1. The connection to AD is a major feature of this review. I think this should be mentioned in the abstract and perhaps the title. It is important to do this to make sure the article is found by search engines.
Answer: Thank you very much for your good comments.

We have accepted your suggestion and changed the Abstract section and keywords as follows.

Abstract: Type 2 Diabetes (T2D) is characterized by the toxic aggregation of human islet amyloid polypeptide (hIAPP or amylin) within pancreatic β-cells. IAPP is also a neuropancreatic hormone that plays a significant role in Alzheimer's disease (AD) by co-depositing with amyloid-beta (Aβ) and Tau, supporting the Type 3 Diabetes (T3D) hypothesis. Soluble IAPP accelerates Aβ aggregation through cross-seeding and causes neurotoxicity by impairing the blood-brain barrier and activating neuroinflammation. Melatonin inhibits these processes by disrupting hydrophobic interactions in both hIAPP and Aβ, preventing the formation of toxic β-sheet structures. Furthermore, melatonin promotes amyloid clearance via the glymphatic and lymphatic systems, protects neurons from oxidative damage, and reduces Tau hyperphosphorylation. This suggests that melatonin serves as a promising multitarget therapeutic agent for both metabolic and neurodegenerative disorders by modulating structural protein transformations.

Keywords: Human Islet Amyloid Polypeptide (hIAPP); Type 2 Diabetes (T2D); Alzheimer's disease (AD); Type 3 Diabetes (T3D); Melatonin; Protein Aggregation; Beta-sheet formation; Amyloid inhibition

  1. The article appears to assume all conclusions reported in the literature are true. Some acknowledgement that some conclusions are controversial would be welcomed.

Answer: Thank you very much for your good comments.

I acknowledge the reviewer's suggestion to some extent.

I compiled papers published up to 2025, excluded controversial ones, and wrote the review using only reliable journals (primarily PubMed). Of course, the possibility of controversy cannot be entirely ruled out, but if we focus on melatonin's function, it is best to view it conservatively.

The following was added to the last lines 501-504:

While some conclusions may be controversial, advancing this field of research can lead to a deeper understanding of amyloid pathogenesis and the identification of melatonin's therapeutic potential, laying the foundation for new and effective strategies to combat debilitating diseases.

  1. Otherwise, I liked the focus and length as well as the number of references cited.

Minor points: line 347, Melatonin inhibits the formation…

Answer: Thank you very much for your good comments. I rewrote it.

 

Line 434, remove italicized text ‘Research manuscripts….’

Answer: Thank you very much for your good comments.

I searched for Research manuscripts… on line 434, but could not find them.

 

Line 444, ‘T2DM’ is mentioned. Is this a mistake or is it undefined?

Answer: Thank you very much for your good comments. I rewrote it: T2D.


*All of the edited sections and references were changed with the blue words.

 

I hope that the revised manuscript is now acceptable for publication in the IJMS. We are looking forward to receiving your answer soon.

 

Sincerely,

 

Yeong-Min Yoo Ph.D 

Institute of Environmental Research,

Kangwon National University,

Chuncheon 24341, Republic of Korea

Email: yyeongm@hanmail.net

Author Response File: Author Response.pdf