Synthalin, Buformin, Phenformin, and Metformin: A Century of Intestinal “Glucose Excretion” as Oral Antidiabetic Strategy in Overweight/Obese Patients

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript provides a thoroughly documented historical analysis and proposes a novel reinterpretation of the mechanism of action of biguanides, particularly metformin. The hypothesis that the glucose-lowering effect of these agents is mediated not only through reduced intestinal glucose absorption but also via an active secretion mechanism into the intestinal lumen is both innovative and supported by relevant clinical and imaging data.

The discussion is comprehensive and well-articulated, with the historical perspective enhancing the scientific discourse and contextualizing the findings. The author effectively addresses key clinical concerns, including nutritional deficiencies and chronic adverse effects, which are particularly important in the long-term management of type 2 diabetes in elderly and overweight populations.

The manuscript now demonstrates clarity, coherence, and solid scientific rigor. However, certain minor but important issues remain, primarily related to grammar, formatting, and stylistic consistency. These do not compromise the scientific merit of the work but must be resolved to ensure the manuscript meets the highest standards of academic presentation.

Therefore, I recommend minor editorial revisions focused on language polishing, citation formatting, and typographical correction. 

 

The man

Comments for author File: Comments.pdf

Author Response

Replay to reviewer 1

Thank you for the very constructive criticisms.

The manuscript has been critically reviewed and several

messages should now be more understandable.Redundancies have been

reduced.Mispellings and mistakes and typos have now been eliminated.

I hope that the manuscript is now more readable and more attractive for the readers of the journal.

Thank you very much again.

Warmest regards

Giuliano Ramadori MD

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript explores the history, pharmacokinetics, mechanisms of action, and side effects of biguanide drugs used for the treatment of type 2 diabetes. The theme is interesting and appropriate for the journal. However, the manuscript is not well structured and needs major changes.

 

Comments:

It seems the main thesis that biguanides primarily act by enhancing intestinal glucose excretion is presented in Secton 3 of the manuscrpt. I recommend the authors to introduce this hypothesis clearly in the abstract and introduction.  

Sections related to the historical development are unnecesary detailed in contrast to Section 3 (mechanism of action) and Section 4 (side effects), which are comparatively brief. The manuscript should focus on a deeper analysis of recent investigations and clinical data.

Some animal studies are cited in the text without a critique of their methodological limitations. A more critical approach is needed and will improve the review.

The UKPDS and DeFronzo trials are mentioned in the manuscript but not analysed. A discussion summarising their primary endpoints, patient populations, and outcomes would be valuable for the review.

Discussion of Alternative Mechanisms (e.g., microbiome modulation, AMPK activation) is briefly noted but lacks synthesis. A comparison of proposed mechanisms, with supporting data, would clarify the gut-excretion model.

The tables presented are practically meaningless, since they are essentially not tables (they consist of only one column).

The emphasis in the literature used should be on research from recent years, although part of the manuscript examines historical aspects.

Author Response

Re:manuscript ID livers-3694067

 

 

Dear Reviewer

Thank you very much for your very constructive criticisms and suggestions.

The criticisms were justified and the suggestions very helpful.

I hope that the changes introduced into the manuscript contributed to

make the review more understandable and more attractive.

1.the word excretion for intestinal elimination of glucose has now been introduced into the abstract,into the introduction and into the text.

2.the historical background has now been shortened as has been done for the description of several experiments.The long description of the work of Sombol NC et al.(127)

has been cancelled (pages 11-13)

3.Since the review focuses on the discussion of the old and new publications  showing that biguanides lack the characteristics of a classical drug, several publications have been discussed in more detail.

3.The two main prospective trials, namely the UKPDS (1977-1997) and the De Fronzo trial (1995) are the two pivotal clinical studies, which have been the basis for the FDA-release of metformin in USA 1995. The review  therefore critically analyzes this aspect in detail, reporting the concerns of several scientists about the UKPS (234,235) and the De Fronzo publication (122,123,211,212).Table 1 also underlines the discrepancies between the particular trial conditions (healthy, yuonger diabetics) and the real-world patients (older and with comorbidities) treated with metformin.The review also tries to underline the fact that there is only one long-term prospective trial,namely the UKPDS,where a subgroup of patients were first treated with metformin as a single drug.The review discusses

the clinical results also taking into account  the data published by Holman et al (233 pages 23-24) (10 years follow-up after the end oft he UKPDS)

4.the suggestion about the possible changes of the intestinal  microbiota induced by metformin is well taken.Two publications (reviewes 166,167,page 15),which critically discuss the hypothesis of the possible involvementof the changes of the microbial populations in the gut as a factor contributing to glucose excretion through the action of metformin,have now been introduced (page 15).

5.Thank you for this suggestion;5 tables have been now taken out.

6.Latest publications supporting the original report of Werner and Bell (93,94) about the strong capacity of metformin to attract water have now been discussed :a)to increase renal elimination of sodium and water (207,page 19) ,b) attraction of water into the gut are now mentioned,c) influence of protein digestion and d) increase of intestinal production of appetite inhibiting peptides in page 15 (163,164,165) and in page 16 (190,191,192).

I am thankful for the work the reviewer invested in the manuscript.

Warmest regards

G.Ramadori MD

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have responded to all my comments, and I sincerely thank them for that. After reviewing their replies, I can confirm that I do not have any additional comments or suggestions.