The Intricate Relationship Between Thyroid Disorders and Type 2 Diabetes—A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper explores the literature to offer an overview of the epidemiological, pathophysiological, and clinical dimensions of the relationship between thyroid dysfunction and type 2 diabetes mellitus. It is well organized to lead the reader through the intricate mechanisms underlying diseases and their potential interplay.  Due to the conflicting results of the papers published so far, especially due to difficulties in homogenizing daily iodine intake (for proper thyroid function definition) and diet/therapy and complications (for proper diabetes control), they cannot go further than just suggesting the need for early detection and appropriate management of thyroid dysfunction in the case of diabetes to optimize therapeutic outcomes and mitigate potential complications.

Author Response

Dear Reviewer,

We are deeply honored and sincerely grateful for your thorough and generous evaluation of our manuscript.

Your kind acknowledgment of the organization, scientific rigor, and clarity with which we endeavored to present the intricate interplay between thyroid dysfunction and type 2 diabetes mellitus is profoundly appreciated. It is particularly gratifying to know that our effort to systematically guide the reader through the complex epidemiological, pathophysiological, and clinical dimensions of this relationship has resonated with your esteemed expertise.

We wholeheartedly concur with your insightful observations regarding the inherent challenges that persist in this field, notably the variability in iodine intake, diet, therapy, and the heterogeneity of diabetes-related complications. These confounding factors, as you aptly noted, preclude the possibility of drawing absolute conclusions, reinforcing instead the critical importance of early detection and vigilant management of thyroid dysfunction in patients with diabetes to optimize therapeutic outcomes. We have been mindful to reflect these limitations faithfully in the final form of the manuscript.

We wish to express once again our deepest appreciation for your invaluable feedback, which has undoubtedly elevated the scientific merit of our work. It has been a distinct privilege to benefit from your discerning review, and we are truly grateful for your contribution to the refinement and enhancement of our manuscript.

With highest respect and sincere gratitude,
On behalf of all co-authors

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript offers a review examining the link between thyroid dysfunction and type 2 diabetes mellitus (T2DM). It covers reported prevalence rates, underlying physiological processes, metabolic connections, and genetic factors associated with this relationship. The authors consolidate findings from studies across various regions to highlight the reciprocal influence between thyroid health and T2DM, advocating for routine thyroid screening in individuals with diabetes.

Please find below my questions and suggestions-

1. The authors state a critical review of studies over the past 20 years but do not detail the criteria used for including or excluding studies, methods for assessing study quality, or adherence to established guidelines like PRISMA. Could the authors please clarify if this review followed a specific systematic framework, and if not, explain the rationale?
2. The description of the search strategy (lines 66–72) lacks detail. Information on the initial number of studies retrieved, how duplicates were handled, and the final count of included studies is missing. Providing a detailed flowchart illustrating the study selection process would significantly improve transparency.
3. In Table 1, some studies presented do not include data on hyperthyroidism or differentiate between overt and subclinical cases. How was this missing information managed during comparative analysis? Were attempts made to contact the original study authors for additional details?
4. Several studies cited in Table 2, such as those by Biju Shrestha and Imam Subekti, employ a cross-sectional design, which inherently limits the ability to infer cause and effect. However, the manuscript frequently implies a directional influence (e.g., suggesting thyroid dysfunction leads to T2DM). Could the authors rephrase these statements or provide stronger evidence that supports claims of causality?
5. There appears to be inconsistency in citations and repetition of studies (e.g., Biju Shrestha's study is listed in both Table 1 and Table 2). Please ensure consistent citation practices throughout the manuscript and avoid referencing the same study multiple times across tables or text without a clear purpose.
6. section discussing GLUT transporter regulation (lines 153–159) lacks direct citations to primary experimental studies on GLUT2 and GLUT3 in the context of thyroid dysfunction. Could the authors provide direct mechanistic evidence or specify if these claims are based on preclinical models?
7. The review acknowledges conflicting findings regarding the association between TSH/FT4 levels and T2DM risk but does not offer a meta-analytical synthesis or use forest plots to visually represent and analyze heterogeneity across studies. Have the authors considered conducting a quantitative meta-analysis or, at minimum, providing a more in-depth discussion of the variations in study design, populations, or assay methodologies that might contribute to this heterogeneity?
8. A critical inconsistency exists in the statistical reporting. The authors use specific p-values from original studies (e.g., in the summary of SU Ogbonna’s study) but do not clarify if these were recalculated or interpreted independently. Furthermore, while some results include clear p-values (e.g., p=0.03, p=0.001), others are presented with less clear thresholds (e.g., "hazard ratio = 1.23" on line 255). Could the authors clarify if a consistent statistical significance threshold was applied throughout the review, and how borderline or unclear statistical outcomes were interpreted?

 

Author Response

Dear Reviewer,

We would like to express our deepest gratitude for your time, careful attention, and invaluable insights in reviewing our manuscript. It is truly an honor to have our work scrutinized by someone with such expertise, and we are incredibly fortunate to have received feedback from a reviewer with such a keen eye for detail.
We humbly ask for the opportunity to revise and resubmit our manuscript in accordance with your thoughtful suggestions. We fully recognize that your comments have highlighted important areas for improvement, and we are eager to ensure that our work aligns with the highest standards of scientific quality.
Your guidance is an immense privilege, and we genuinely hope that you will consider granting us the chance to make these revisions. We sincerely appreciate your patience and the invaluable role you are playing in helping us improve this manuscript.

We sincerely hope that with these revisions, the manuscript will now meet the level of quality expected for publication. We are deeply hopeful that the changes made will be to your satisfaction and that the manuscript will be accepted.

Please find below our responses to each of your comments, and we look forward to your opinion:

1. The authors state a critical review of studies over the past 20 years but do not detail the criteria used for including or excluding studies, methods for assessing study quality, or adherence to established guidelines like PRISMA. Could the authors please clarify if this review followed a specific systematic framework, and if not, explain the rationale?

Response: We followed a systematic approach but did not strictly adhere to PRISMA guidelines due to the limited availability of studies that met all the criteria for systematic inclusion. The criteria for including studies were based on their relevance to thyroid dysfunction and type 2 diabetes, their study design, and the availability of data. However, we did not explicitly outline the assessment of study quality or inclusion/exclusion criteria in the manuscript. We revised the Methods section provided a more transparent explanation of our inclusion criteria, the exclusion of non-relevant studies, and the methods used for assessing study quality.

2. The description of the search strategy (lines 66–72) lacks detail. Information on the initial number of studies retrieved, how duplicates were handled, and the final count of included studies is missing. Providing a detailed flowchart illustrating the study selection process would significantly improve transparency.

Response: Thank you for your comment. The search strategy section was expanded to include specific details on the number of studies retrieved during our initial search, how duplicates were identified and handled, and the final number of studies included after applying the inclusion/exclusion criteria. A flowchart of the study selection process was also added to improve clarity and for transparency. The Search Strategy section was rewritten to include the missing details.

 

3. In Table 1, some studies presented do not include data on hyperthyroidism or differentiate between overt and subclinical cases. How was this missing information managed during comparative analysis? Were attempts made to contact the original study authors for additional details?

Response: We acknowledge that some studies in Table 1 lack data on hyperthyroidism or do not differentiate between overt and subclinical cases of thyroid dysfunction. For studies without this information, we focused on the data that was available and indicated in the manuscript where these limitations were present. We did not attempt to contact the original authors for additional details, but we will mention this limitation in the manuscript to avoid any confusion.

 

4. Several studies cited in Table 2, such as those by Biju Shrestha and Imam Subekti, employ a cross-sectional design, which inherently limits the ability to infer cause and effect. However, the manuscript frequently implies a directional influence (e.g., suggesting thyroid dysfunction leads to T2DM). Could the authors rephrase these statements or provide stronger evidence that supports claims of causality?

Response: We appreciate this observation. We revised the manuscript to better clarify that the studies cited in Table 2 that are cross-sectional and, therefore, cannot definitively establish causality. Any statements implying causality was rephrased to reflect the observational nature of the studies.

We emphasize the need for further longitudinal studies to confirm any causal relationships.

 

5. There appears to be inconsistency in citations and repetition of studies (e.g., Biju Shrestha's study is listed in both Table 1 and Table 2). Please ensure consistent citation practices throughout the manuscript and avoid referencing the same study multiple times across tables or text without a clear purpose.

Response: Thank you for pointing this out. We will ensure that each study is referenced consistently and avoid unnecessary repetition of studies across tables and the text.  After reviewing the manuscript, we have removed the repetition and ensured that each study is referenced only once per table. Additionally, we have reviewed all other citations to ensure consistency and clarity. We sincerely thank the reviewer for their valuable observation. We deeply regret the oversight regarding the inconsistency in citations and the unintentional repetition of studies, including the duplication of Biju Shrestha's study across Tables 1 and 2. Upon receiving this feedback, we conducted a thorough and careful review of the entire manuscript, with particular attention to Tables 1 and 2, as well as the References section.

All citation inconsistencies have been addressed, and we have ensured that each study is referenced in a consistent manner throughout the manuscript. Redundant references—particularly those appearing in multiple tables without justified rationale—have been removed or appropriately clarified. We have also taken additional steps to cross-check all other references to maintain clarity and coherence across the text and tables.

We truly appreciate the reviewer’s attention to detail, which has helped improve the overall quality and precision of our work.

6. The section discussing GLUT transporter regulation (lines 153–159) lacks direct citations to primary experimental studies on GLUT2 and GLUT3 in the context of thyroid dysfunction. Could the authors provide direct mechanistic evidence or specify if these claims are based on preclinical models?

Response: We sincerely thank the reviewer for this valuable observation and for the careful attention given to our manuscript. We acknowledge the lack of direct citations to primary experimental studies in the section discussing GLUT transporter regulation. In response to this comment, we have revised the section accordingly to include relevant mechanistic evidence from primary studies and clarified where the claims are supported by preclinical models. We truly appreciate this insightful feedback, which has helped us improve the clarity and scientific rigor of our work.

 

7. The review acknowledges conflicting findings regarding the association between TSH/FT4 levels and T2DM risk but does not offer a meta-analytical synthesis or use forest plots to visually represent and analyze heterogeneity across studies. Have the authors considered conducting a quantitative meta-analysis or, at minimum, providing a more in-depth discussion of the variations in study design, populations, or assay methodologies that might contribute to this heterogeneity?

 

Response: We are deeply grateful to the reviewer for this insightful and constructive suggestion, which we highly appreciate. The observation regarding the absence of a quantitative meta-analytical synthesis and the potential utility of forest plots to represent heterogeneity is both thoughtful and valuable. We fully acknowledge the conflicting findings in the current literature concerning the association between TSH/FT4 levels and type 2 diabetes risk.

Although we did not perform a meta-analysis in the present manuscript due to substantial heterogeneity in study designs, populations, and assay methodologies, we have now expanded the Discussion section to provide a more detailed analysis of these sources of variability.

Moreover, we sincerely thank the reviewer for highlighting the potential of a meta-analytical approach, and we will most certainly consider conducting such an analysis in a future dedicated manuscript. This thoughtful recommendation has given us valuable direction for ongoing and future research efforts.

 

8. A critical inconsistency exists in the statistical reporting. The authors use specific p-values from original studies (e.g., in the summary of SU Ogbonna’s study) but do not clarify if these were recalculated or interpreted independently. Furthermore, while some results include clear p-values (e.g., p=0.03, p=0.001), others are presented with less clear thresholds (e.g., "hazard ratio = 1.23" on line 255). Could the authors clarify if a consistent statistical significance threshold was applied throughout the review, and how borderline or unclear statistical outcomes were interpreted?

Response: We would like to express our deepest apologies for the inconsistencies observed in the statistical reporting. It was our genuine intention to interpret the p-values directly from the original studies; however, we acknowledge that we did not sufficiently clarify whether these values had been recalculated or independently interpreted. We sincerely regret any confusion or inconvenience this may have caused.

Following your insightful and meticulous feedback, we have undertaken a thorough revision of the manuscript. We have now consistently applied clear statistical significance thresholds and have carefully removed less precisely reported measures, such as hazard ratios without associated p-values, to enhance clarity and transparency.

We are truly grateful for your attentive and detailed review, which has been invaluable in guiding us toward improving the manuscript. Thank you profoundly for giving us the opportunity to revise and resubmit our work. We genuinely appreciate your dedication, patience, and commitment to maintaining the highest standards of scientific rigor.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have replied to my question and suggestions satisfactorily.