Arginase 2 and Polyamines in Human Pancreatic Beta Cells: Possible Role in the Pathogenesis of Type 2 Diabetes

Round 1

Reviewer 1 Report

The paper entitled “Arginase 2, polyamines and the human pancreatic beta cells” includes potentially relevant data for the gastroenterological/metabolic pharmacology and also but in a lesser extent for the physiology and pathophysiology of pancreas. This publication describes the potential junction between arginase 2 expression and polyamine concentration with diabetes mellitus type 2 development.

However, I have a few remarks:

1. I did not find the convincing justification the choice of the indicated in the topic of the study ARG2;
2. I did not find in the study an attempt to link arginase 2 with the pathomechanism of type 2 diabetes
3. The Authors, writing about the role of arginase 2 and polyamines in the development of type 2 diabetes, should expand the publication with brief information concerning the risk factors and ethiopathogenesis of type 2 diabetes mellitus;
4. Authors should clarify the purpose of the paper;
5. Authors should indicate the methodology used in the course of searching the literature necessary for the preparation of the manuscript;
6. Due to the lack of a clearly defined goal of the paper, it is impossible to assess unequivocally the research conclusions proposed by the Authors
7. Considering the role of isoenzyme 2 arginase in the development of cancer – and as we know, heterogeneous carbohydrate metabolism disorder (diabetes) increases the risk of cancers development – the Authors should at least try briefly (in accordance to type 2 diabetes) to describe the role of ARG2 in oncogenesis.

Author Response

We acknowledge the insightful comments by this Reviewer. The manuscript does not intend to be a systematic review on ARG2 and polyamines. Rather, the choice of the topic was based on the growing evidence that ARG2 and polyamines could play a role in the pathophysiology of pancreatic beta cells, possibly contributing to the metabolic alterations of type 2 diabetes. In fact, the manuscript has been submitted to a special issue dealing with type 2 diabetes. This is also the reason why we did not focus on oncogenesis. Nevertheless, the new version has taken into consideration the needs of better dealing with points 1, 2, 4, and 6.

Reviewer 2 Report

This manuscript try to explain ARG2 and polyamine related to type 2 diabetes pathology.  The authors narrated lots of data which published already, but they seem to list fragments of information. There was not linkage of each section so that the purpose of this article was not appeared well in text.  Several specific comments are advised as following. 

1. Title: It will be great if the authors edit the title to show what they want to say in manuscript. Simple list of some words does not help to imagine the main concept of manuscript.
2. Abstract: Please explain importance of ARG2 and polyamine in detail and illustrate how they are related to T2D in detail with writing purpose of this review manuscript. 
3. Introduction: 1) The flow of the introduction is awkward. For instance, the introduction is a saying that ARG2 is expressed in the hepatic site so it involves in the urea cycle. And then there is a saying that ARG2 is localized in mitochondria. At this point, readers expect to read about contents of what ARG2 does in mitochondria and how ARG2 expression in liver related to localization of ARG2 in mitochondria.  However, the paragraph doesn’t contain them in depth. 2) It was mentioned that the expression of ARG2 in human beta cell and its possible relationship with beta cell function. However, there were no evidences to support this sentence. So it is hard to understand why the authors consist like that and what they want to say. 3) Please explain in depth relationship between Arginase2 and polyamines at first. There is no organic combination of elements in body contexts. 4) Please organize the order of the contents. Main body should be numbers as 2. Also please check numbering. There was two '1.3' 
4. Result: In review paper, result section is not necessary. Please switch to 'conclusion'.  Result section is too short to contain summary of this review manuscript. 
5. Figures: 1) Figure 7 is consisted of unpublished data set?? In review article, unpublished experimental data sets are not necessary. 2) Please combine figure 2A and 2B. 

Author Response

We thank this Reviewer for the useful comments, that have been addressed as follows.

1. The title has been changed to better explain the content of the manuscript.
2. The abstract has been implemented as requested.
3. 1: sorry for not having been sufficiently clear; ARG1 is localized in the cytosol of hepatocytes, where it participates in the urea cycle; instead, ARG2 is localized in the mitochondria, where it converts arginine to ornithine; this is now better described. 2: This point has been now better explained in the text. 3: The content of the manuscript has been organized as suggested.
4. The last part of the manuscript has been organized as indicated, and Figure 7 has been removed.

Round 2

Reviewer 1 Report