Association Between Diabetes Mellitus–Tuberculosis and the Generation of Drug Resistance
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear authors, thank you for your interesting review on the study of the association between diabetes mellitus - tuberculosis and generation drug resistance. After reading it, I have some suggestions and comments to improve your manuscript:
1. In the review devoted to bacterial resistance to antibiotics, the authors pay much attention to the immunological reactions that occur in human tuberculosis and type 2 diabetes mellitus, but almost nothing is said about the peculiarities of the tuberculosis pathogen Mycobacterium tuberculosis, its characteristics as a pathogen in terms of the microorganism's ability to adapt:
· Markova N, Slavchev G, Michailova L. Unique biological properties of Mycobacterium tuberculosis L-form variants: impact for survival under stress. Int Microbiol. 2012 Jun;15(2):61-8. doi: 10.2436/20.1501.01.159. PMID: 22847267.
· Orgeur M, Sous C, Madacki J, Brosch R. Evolution and emergence of Mycobacterium tuberculosis. FEMS Microbiol Rev. 2024 Mar 1;48(2):fuae006. doi: 10.1093/femsre/fuae006. PMID: 38365982; PMCID: PMC10906988.
· Alame Emane AK, Guo X, Takiff HE, Liu S. Drug resistance, fitness and compensatory mutations in Mycobacterium tuberculosis. Tuberculosis (Edinb). 2021 Jul;129:102091. doi: 10.1016/j.tube.2021.102091. Epub 2021 May 21. PMID: 34090078.
· Goossens SN, Sampson SL, Van Rie A. Mechanisms of Drug-Induced Tolerance in Mycobacterium tuberculosis. Clin Microbiol Rev. 2020 Oct 14;34(1):e00141-20. doi: 10.1128/CMR.00141-20. PMID: 33055230; PMCID: PMC7566895.
2. The purpose of the study is not clear and needs to be stated.
How does the novelty of this review differ from Huang D et.al (2020) and Restrepo BI et.al (2013) from a microbiological perspective, as the authors plan to publish in Microorganisms? Novelty needs to be explained.
· Huang D, Wang Y, Wang Y, Liang Z. The impact of diabetes mellitus on drug resistance in patients with newly diagnosed tuberculosis: a systematic review and meta-analysis. Ann Palliat Med. 2020 Mar;9(2):152-162. doi: 10.21037/apm.2020.02.16. PMID: 32268768.
· Restrepo BI, Schlesinger LS. Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus. Tuberculosis (Edinb). 2013 Dec;93 Suppl(0):S10-4. doi: 10.1016/S1472-9792(13)70004-0. PMID: 24388642; PMCID: PMC4019931.
3. It is necessary to mention the difficulties of phenotypic drug susceptibility testing and the existence of a database of mutations associated with antibiotic resistance in Mycobacterium tuberculosis.
· Flandrois, JP., Lina, G. & Dumitrescu, O. MUBII-TB-DB: a database of mutations associated with antibiotic resistance in Mycobacterium tuberculosis. BMC Bioinformatics 15, 107 (2014). https://doi.org/10.1186/1471-2105-15-107
4. The authors did not mention the role of TB vaccination, which is an important component of TB control:
· Radhakrishnan RK, Thandi RS, Tripathi D, Paidipally P, McAllister MK, Mulik S, Samten B, Vankayalapati R. BCG vaccination reduces the mortality of Mycobacterium tuberculosis-infected type 2 diabetes mellitus mice. JCI Insight. 2020 Mar 12;5(5):e133788. doi: 10.1172/jci.insight.133788. PMID: 32161191; PMCID: PMC7141407.
· Bouzeyen R, Javid B. Therapeutic Vaccines for Tuberculosis: An Overview. Front Immunol. 2022 Jun 24;13:878471. doi: 10.3389/fimmu.2022.878471. PMID: 35812462; PMCID: PMC9263712.
Comments on the Quality of English LanguageThe English could be improved.
Author Response
Please see attached file.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThe review by Cornejo-Báez et al. is focused on the relationship between type 2 diabetes mellitus (T2DM) and tuberculosis (TB), particularly how T2DM influences susceptibility to TB, its impact on the immune response, and the development of drug resistance. The text explores epidemiological data, the physiological relationship between T2DM and TB, immune responses, and the influence of T2DM on drug resistance mechanisms of TB. It also highlights the potential of metformin in treating TB among patients with diabetes. Although the text is rich in information and research findings, it faces challenges in language clarity, grammar, and readability, which could affect its overall clarity and effectiveness in communicating key messages. The manuscript needs major revisions:
Major comments by sections:
Introduction: While the global burden of each disease is well presented, the connection between DM and TB, specifically the increased susceptibility of individuals with DM to TB, could be more explicitly articulated early on. The objective of the review is only stated in the abstract and could also be included at the end of the introduction. There is a lack of text explaining the methodology used in the survey and criteria for selecting references.
Epidemiology of the T2DM-TB Binomial: The section lacks detailed epidemiological data to support the claim of a syndemic. Including specific incidence rates, prevalence, or studies that directly compare regions with high T2DM prevalence and TB rates would strengthen this argument.The discussion on the challenges of establishing a clear association at the national level due to confounding factors is mentioned but not elaborated on. Examples of these confounding factors and how they complicate the analysis would be beneficial.
Physiology of the T2DM-TB Binomial: The presentation of evidence linking hyperglycemia to increased TB growth and spread is somewhat disjointed. More direct evidence or studies linking T2DM physiological effects to specific TB outcomes would improve clarity. The discussion on the impact of T2DM on TB treatment outcomes, such as treatment failure and relapse, is valuable, but lacks depth regarding the underlying physiological mechanisms.
Innate immune response to Mycobacterium tuberculosis: A detailed description of the immune mechanisms is a strong point of the manuscript. However, the link between T2DM's impact on these immune responses and the consequent increased susceptibility to TB is not clearly made. For instance, how T2DM specifically alters these responses could be better highlighted. In line 120, a reference number should be used in the citation instead of (Natarajan et al. 2011).
T2DM Promotes Chronic Inflammation: There is a missed opportunity to directly link the specific inflammatory markers and pathways elevated in T2DM to their roles in TB susceptibility and progression. In line 229, reference numbers should be used in the citations instead of (Michailidou et al., 2022; Sabio et al., 2008).
Influence of T2DM on the Modification of M. tuberculosis Genomes Drug Resistance Generation: The evidence that T2DM directly impacts the genetic evolution of M. tuberculosis towards drug resistance is intriguing but speculative. More robust data or studies that directly demonstrate this relationship would strengthen this argument.
Metformin in Prevention and Treating TB: This section introduces an interesting perspective on how common T2DM treatment could influence TB treatment outcomes, highlighting the potential for cross-disease therapeutic strategies. However, evidence linking metformin use to improved TB outcomes has not been convincingly presented. More direct evidence, possibly from large-scale studies or clinical trials, would be beneficial.
Conclusion: The conclusion could be strengthened by summarizing key findings from the manuscript more explicitly, particularly regarding novel insights into T2DM's impact on TB drug resistance and the potential role of metformin.
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Authors,
Thank you for the quality revision of the publication. In this form, the manuscript looks more complete and finished.
Author Response
Comments: Dear Authors, Thank you for the quality revision of the publication. In this form, the manuscript looks more complete and finished.
Response: Dear Reviewer, Thank you for your positive feedback and kind words regarding our revised manuscript. We greatly appreciate the opportunity to improve our work and are pleased to hear that the manuscript now meets the expectations of the journal.
Additionally, we would like to inform you that we included a brief paragraph in the manuscript detailing the databases consulted and the keywords used during the literature search. Specifically:
"To form this review, we conducted comprehensive searches in databases such as PubMed, ScienceDirect, and Google Scholar, without imposing any restrictions on language or date of publication. The search included keywords such as 'Type 2 Diabetes Mellitus, Tuberculosis, Mycobacterium tuberculosis, T2DM-TB binomial, innate immune response, macrophages, drug resistance, efflux pumps, and BCG,' with no restrictions on region or language."
We hope this addition further enhances the clarity and rigor of the review. If there are any further suggestions or requirements, we will be happy to address them promptly.
Best regards,
Dra. Axhell Aleid Cornejo Báez
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript has undergone significant improvements and the authors have done an excellent job. Nevertheless, they failed to address the initial comments regarding the review methodology. Specifically, information is still lacking on the databases utilized for reference searches, the keywords employed, language restrictions (if any), and other selection criteria. Once these details have been incorporated, the manuscript is ready for publication.
Author Response
Comments: The manuscript has undergone significant improvements and the authors have done an excellent job. Nevertheless, they failed to address the initial comments regarding the review methodology. Specifically, information is still lacking on the databases utilized for reference searches, the keywords employed, language restrictions (if any), and other selection criteria. Once these details have been incorporated, the manuscript is ready for publication.
Response: Dear Reviewer, thank you for your constructive feedback and for acknowledging the improvements in our manuscript. We appreciate your thorough review and valuable comments.
In response to your specific concern regarding the review methodology, we have addressed your suggestions by including a paragraph detailing the databases consulted, the keywords used, and the inclusion criteria for our literature search. This paragraph can be found on line 74 of the revised manuscript, highlighted in yellow for ease of reference.
The text reads as follows:
"To form this review, we conducted comprehensive searches in databases such as PubMed, ScienceDirect, and Google Scholar, without imposing any restrictions on language or date of publication. The search included keywords such as 'Type 2 Diabetes Mellitus, Tuberculosis, Mycobacterium tuberculosis, T2DM-TB binomial, innate immune response, macrophages, drug resistance, efflux pumps, and BCG,' with no restrictions on region or language."
We hope this addition addresses your concerns and meets the journal's standards. Please do not hesitate to let us know if further adjustments are required.
Thank you once again for your guidance throughout this process.
Best regards,
Dra. Axhell Aleid Cornejo Báez
