Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes
Round 1
Reviewer 1 Report
I cannot see the novelty of this study. There are dozens of articles on B12 deficiency on metformin. Thus authors should emphasise the novelty (if any) in the introduction. The discussion is poorly written. It describes the results and provides only a few comparisons with the literature. The introduction is too short. The gap of knowledge was not shown. The aim of the study was not presented.
- I do not understand what is in Table 1 a and b, what is the difference? The number of patients. is different, but the means and standard deviations are the same.
- Figure 1. There is no linear correlaion. Please remove the trend line and add the Spearman correlation coefficient.
- Table 2. What is compared in Table 2? It is not clear. Table 2 should be merged with Table 1.
- Table 4. Could you present the results of post-hoc test?
- Please perform the multiple regression.
- Table 6. Please provide p-value of metformin dose and the duration of diabetes. Why only these variables were included? What about e.g. the age?
- I cannot agree that” with an increase in the cumulative dose of metformin, vitamin B12 levels decreased linearly”
- I do not understand the sentence “The evident discrepancy of the prevalence of neuropathy by the above two methods is due to differences in sensitivity, specificity between the two tools.” Which two methods?
- The results should be presented in Results section, not a discussion
- “The HbA1c levels in patients with and without clinical neuropathy were 8.7±1.27 and 7.92±0.88 respectively (P-value <.001) showing that HbA1c levels in the clinical neuropathy group were higher by a mean of 0.78% than in patients without neuropathy suggesting that poor glycemic control is associated worse status of diabetic neuropathy.” How was it discovered that diabetic neuropathy is not caused by vitamin B12 deficiency?
Author Response
I am very grateful that you have reviewed my work. Thank you very much.
I cannot see the novelty of this study. There are dozens of articles on B12 deficiency on metformin. Thus authors should emphasise the novelty (if any) in the introduction. The discussion is poorly written. It describes the results and provides only a few comparisons with the literature. The introduction is too short. The gap of knowledge was not shown. The aim of the study was not presented.
Answer: - Yes, you are right there is not any originality in my work, but we have added positive correlation between metformin use, Vit B 12 deficiency and clinical neuropathy in large number of patients. I have added aim of my study also. Also tried to modify my discussion.
1. I do not understand what is in Table 1 a and b, what is the difference? The number of patients. is different, but the means and standard deviations are the same.
Answer: - Table 2b has been deleted as it was an error.
2. Figure 1. There is no linear correlaion. Please remove the trend line and add the Spearman correlation coefficient.
Answer : - Yes, you are right the relationship is not linear and figure has been modified.
3. Table 2. What is compared in Table 2? It is not clear. Table 2 should be merged with Table 1.
Answer: - Table 2 & 4 was wrongly written, hence deleted. New tables has been added.
4. Table 4. Could you present the results of post-hoc test?
Answer: - Table 2 & 4 was wrongly written, hence deleted. New tables has been added.
5. Please perform the multiple regression.
Answer: - I am not able to perform multiple regression from my results. I am sorry for that.
6. Table 6. Please provide p-value of metformin dose and the duration of diabetes. Why only these variables were included? What about e.g. the age?
Answer: - p valve has been added. We did not compared age and other parameters in our study.
7. I cannot agree that” with an increase in the cumulative dose of metformin, vitamin B12 levels decreased linearly”
Answer: - Yes, i have changed that statement. Thank you.
8. I do not understand the sentence “The evident discrepancy of the prevalence of neuropathy by the above two methods is due to differences in sensitivity, specificity between the two tools.” Which two methods?
Answer: - Again it was printing error and has been modified. Sorry!
9. The results should be presented in Results section, not a discussion
Answer: - Yes, i have changed it.
10. “The HbA1c levels in patients with and without clinical neuropathy were 8.7±1.27 and 7.92±0.88 respectively (P-value <.001) showing that HbA1c levels in the clinical neuropathy group were higher by a mean of 0.78% than in patients without neuropathy suggesting that poor glycemic control is associated worse status of diabetic neuropathy.” How was it discovered that diabetic neuropathy is not caused by vitamin B12 deficiency?
Answer: - Our study showed that metformin use leads to vit B 12 deficiency which can cause neuropathy in addition to clinical neuropathy of uncontrolled diabetes.
Reviewer 2 Report
These data demonstrate a relationship between metformin use, vitamin B12 deficiency, and neuropathy in individuals with type 2 diabetes. Given the prevalence of type 2 diabetes and metformin use, these are important data; however, these relationships have been well documented in the literature. Hence, this report adds to the available evidence but does not contribute new information. The purpose of the study is not presented – the authors need to state the study purpose to orient the reader. That is, what were the authors hoping to contribute to this discussion in the literature? The manuscript requires careful editing for grammar. Throughout the text, participants should not be referred to as ‘diabetic’ rather as ‘individuals with type 2 diabetes’. Consistent abbreviations need to be used for vitamin B12 and type 2 diabetes throughout the text. Specific comments are listed below.
Abstract: a results section is missing. Line 8 of the methods section of the abstract repeats information.
Introduction:
The second sentence needs editing for clarity ‘….more common in approximately more than 90% of all diabetes cases….’
Methods:
A consort flow chart for participants needs to be provided. How many patients were excluded per the criteria? Clarify that written consent was obtained from all participants. Please state the ADA criteria for type 2 diabetes and reference (or WHO criteria – it is unclear as in the Discussion it states ADA criteria were used). Did the authors collect B12 supplement use? If not, this needs to be added as a study limitation.
Results:
Please add a descriptives table for participants with and without metformin use. Please add vitamin B12 concentrations to table 1. Units need to be added to tables as well as footnotes under the tables to define groupings and statistical analyses. Data should be presented to one decimal place only. The number of tables should be reduced by condensing the data presentation.
Discussion:
The third paragraph should be moved to the results section. In the methods a 2% B12 deficiency was anticipated – however, the study reported that 29% were B12 deficient. Can the authors discuss this much higher that anticipated deficiency rate and compare to rates reported by others in this population. Please compare to the B12 deficiency for Indian populations at large.
The authors compare their results to that of others (ref. 25-29, 32) but they do not provide the specific data from the other studies. Please add these data points to allow the reader to compare. In the 6th paragraph, the authors discuss a discrepancy between two methods, yet it is not clear to the reader what the 2 methods are. These methods need to be clearly outlined in the Methods section.
A limitations section needs to be added to the discussion.
Author Response
I am very grateful that you have reviewed my work. Thank you very much.
These data demonstrate a relationship between metformin use, vitamin B12 deficiency, and neuropathy in individuals with type 2 diabetes. Given the prevalence of type 2 diabetes and metformin use, these are important data; however, these relationships have been well documented in the literature. Hence, this report adds to the available evidence but does not contribute new information. The purpose of the study is not presented – the authors need to state the study purpose to orient the reader. That is, what were the authors hoping to contribute to this discussion in the literature? The manuscript requires careful editing for grammar. Throughout the text, participants should not be referred to as ‘diabetic’ rather as ‘individuals with type 2 diabetes’. Consistent abbreviations need to be used for vitamin B12 and type 2 diabetes throughout the text. Specific comments are listed below.
Answer: - I have done modification accordingly. Thanks.
Abstract: a results section is missing. Line 8 of the methods section of the abstract repeats information.
Answer: I have done modification accordingly. Thanks.
Introduction:
The second sentence needs editing for clarity ‘….more common in approximately more than 90% of all diabetes cases….’
Answer: I have done modification accordingly. Thanks.
Methods:
A consort flow chart for participants needs to be provided. How many patients were excluded per the criteria? Clarify that written consent was obtained from all participants. Please state the ADA criteria for type 2 diabetes and reference (or WHO criteria – it is unclear as in the Discussion it states ADA criteria were used). Did the authors collect B12 supplement use? If not, this needs to be added as a study limitation.
Answer: I have added some more tables to the literature and have modified according your suggestions.
Results:
Please add a descriptives table for participants with and without metformin use. Please add vitamin B12 concentrations to table 1. Units need to be added to tables as well as footnotes under the tables to define groupings and statistical analyses. Data should be presented to one decimal place only. The number of tables should be reduced by condensing the data presentation.
Answer : - Done
Discussion:
The third paragraph should be moved to the results section. In the methods a 2% B12 deficiency was anticipated – however, the study reported that 29% were B12 deficient. Can the authors discuss this much higher that anticipated deficiency rate and compare to rates reported by others in this population. Please compare to the B12 deficiency for Indian populations at large.
The authors compare their results to that of others (ref. 25-29, 32) but they do not provide the specific data from the other studies. Please add these data points to allow the reader to compare. In the 6th paragraph, the authors discuss a discrepancy between two methods, yet it is not clear to the reader what the 2 methods are. These methods need to be clearly outlined in the Methods section.
Answer: - There was some printing error in the 6th para and it has been changed.
A limitations section needs to be added to the discussion.
Answer : - Done
Thank you.
Author Response File: 
Author Response.pdf
Round 2
Reviewer 1 Report
1. In my opinion, the article has not improved significantly. Authors need to find a justification for the absence of certain statistical analyses other than: "We did not do that in this study".
2. I cannot see some tables because the figures cover them.
3. Please correct the description of the figures with correlations as it can be understood that the Pearson correlation is negative. Please provide p-values for correlations
4. Please provide the results of the post hoc analysis when more than two comparisons are included.
5. table 1. please include these results in the text.
6. the results are not adequately commented. Please explain what can be seen in the tables
Author Response
Thank you very much for correcting my work and providing me with this amazing guidance.
- In my opinion, the article has not improved significantly. Authors need to find a justification for the absence of certain statistical analyses other than: "We did not do that in this study". Answer: - I am sorry i have not provided multiple regression because the time limit to resubmit is 5 days only.
- I cannot see some tables because the figures cover them. Answer: - I have corrected it.
- Please correct the description of the figures with correlations as it can be understood that the Pearson correlation is negative. Please provide p-values for correlations. Answer: - I have corrected it and p valve is provided now.
- Please provide the results of the post hoc analysis when more than two comparisons are included. Answer: - It has been provided in Table 2b.
- 5. table 1. please include these results in the text. Answer: - I have included it in the discussion section ( paragraph 2 )
- the results are not adequately commented. Please explain what can be seen in the tables. Answer: - I have done it
Author Response File: Author Response.pdf
Reviewer 2 Report
The manuscript is improved and reads better. However, data need to consistently be reported to tenths only. There is much inconsistency in the data reporting in terms of decimal use. Also the study purpose is not clearly stated at the end of the introduction: what new concept/data were the authors hoping to contribute the literature? That is, what is novel in this research?
Author Response
thank you very much for providing me guidance and appraising my manuscript.
- I have tried to give all data in the tenth decimal
- I have provided the aim of the research in the introduction section. Thank you.
Author Response File: Author Response.pdf
