Title: Associations between non-insulin-based insulin resistance surrogate markers and liver-
related outcomes in metabolic dysfunction-associated steatotic liver disease: a nationwide cohort
study in South Korea
Version: 5 Date: 13 Mar 2025
Reviewer:  Kyoko Sakai
Reviewer's report:
I agree to  rereview the article and access the review cite , read authors' response.I noticed that
the authors did not read the word file I attached and did not respond to my 7 comments.
Their response is needed to make my final decision.
Could you please  open the file of comments, read it all the way through, and respond ?
I note my all contents below, just in case.
##Review Comments 02/03/2025#
#1 This article is a valuable long-term follow-up study of the association between MASLD and
insulin resistance in national data from South Korea. Furthermore, the results are interesting
because they differ from the positive correlation between insulin resistance and the occurrence
of liver disease events in previous studies.
#2 The attempt to assess insulin resistance using surrogate markers without using insulin
measurements is a promising method, if validated, for examining the association between insulin
resistance and various diseases in big data.
On the other hand, if these surrogate markers do not correlate well enough to substitute for IR,
the present argument does not hold. However, the authors do not state with sufficient clarity
whether there is or is not a high correlation and the scientific basis for this.
#3 Of the three alternative markers, the association between TyG index and IR has been
examined in the literature10 Systematic Review, but the quality of evidence seems to be low
due to the high risk of bias of the inclusion studies and their large heterogeneity. AUROC is
also not high enough at 0.6-0.8. The literature on TG/HDL ratios in reference 11 and METSIR
in reference 12 does not directly examine the correlation between alternative markers and
HOMAIR or IR.
Therefore, if the authors believe that the correlation between surrogate markers and IR is high
enough, they need to provide more scientifically valid evidence.
#4 If there is not sufficient evidence, do the authors still consider and conclude that the decrease
in surrogate markers in the liver-related disease group of MASLD is a decrease in IR? Or do they
consider the three surrogate markers in the present study to be useful as independent indicators,
although it is unclear whether they are sufficiently correlated with IR? The authors should state
which view they take. This would make the direction of the implications for practice of the
results from these valuable data more plausible and clear.
#5 What is the rationale for using the AST/ALT ratio indicator for advanced fibrosis among the
many liver fibrosis indicators?  For this indicator as well, isn’t it necessary to state the rationale
for its validity, rather than just because it was possible to obtain data?
#6 Deterioration in nutritional status due to the progression of liver disease may temporarily
give the appearance of improved indices of glucose tolerance. Which of the following do the
authors consider to be associated with the lower IR index group and higher incidence of liver-
related events in the present cohort study? Please explain their rationale for this consideration.
(i) The low IR surrogate index group is involved in the occurrence of liver-related events.
(ii) The low IR surrogate index group is originally mixed with a large number of patients with
progressive liver disease, and the progression of liver disease contributes to the high incidence
of liver-related events.
#7 As the authors state in their limitations, the causal relationship between the two is unknown
due to the lack of a planned inclusion cohort, and in this case an association can simply be stated.
The authors would like to explain how they infer a causal relationship between low alternative
indicators and high incidence of liver disease, taking into account the above-mentioned mix of
patient groups, including their rationale.
Title: Associations between non-insulin-based insulin resistance surrogate markers and liver-
related outcomes in metabolic dysfunction-associated steatotic liver disease: a nationwide cohort
study in South Korea
Version: 5 Date: 13 Mar 2025
Reviewer:  Kyoko Sakai
Reviewer's report:
I agree to  rereview the article and access the review cite , read authors' response.I noticed that
the authors did not read the word file I attached and did not respond to my 7 comments.
Their response is needed to make my final decision.
Could you please  open the file of comments, read it all the way through, and respond ?
I note my all contents below, just in case.
##Review Comments 02/03/2025#
#1 This article is a valuable long-term follow-up study of the association between MASLD and
insulin resistance in national data from South Korea. Furthermore, the results are interesting
because they differ from the positive correlation between insulin resistance and the occurrence
of liver disease events in previous studies.
#2 The attempt to assess insulin resistance using surrogate markers without using insulin
measurements is a promising method, if validated, for examining the association between insulin
resistance and various diseases in big data.
On the other hand, if these surrogate markers do not correlate well enough to substitute for IR,
the present argument does not hold. However, the authors do not state with sufficient clarity
whether there is or is not a high correlation and the scientific basis for this.
#3 Of the three alternative markers, the association between TyG index and IR has been
examined in the literature10 Systematic Review, but the quality of evidence seems to be low
due to the high risk of bias of the inclusion studies and their large heterogeneity. AUROC is
also not high enough at 0.6-0.8. The literature on TG/HDL ratios in reference 11 and METSIR
in reference 12 does not directly examine the correlation between alternative markers and
HOMAIR or IR.
Therefore, if the authors believe that the correlation between surrogate markers and IR is high
enough, they need to provide more scientifically valid evidence.
#4 If there is not sufficient evidence, do the authors still consider and conclude that the decrease
in surrogate markers in the liver-related disease group of MASLD is a decrease in IR? Or do they
consider the three surrogate markers in the present study to be useful as independent indicators,
although it is unclear whether they are sufficiently correlated with IR? The authors should state
which view they take. This would make the direction of the implications for practice of the
results from these valuable data more plausible and clear.
#5 What is the rationale for using the AST/ALT ratio indicator for advanced fibrosis among the
many liver fibrosis indicators?  For this indicator as well, isn’t it necessary to state the rationale
for its validity, rather than just because it was possible to obtain data?
#6 Deterioration in nutritional status due to the progression of liver disease may temporarily
give the appearance of improved indices of glucose tolerance. Which of the following do the
authors consider to be associated with the lower IR index group and higher incidence of liver-
related events in the present cohort study? Please explain their rationale for this consideration.
(i) The low IR surrogate index group is involved in the occurrence of liver-related events.
(ii) The low IR surrogate index group is originally mixed with a large number of patients with
progressive liver disease, and the progression of liver disease contributes to the high incidence
of liver-related events.
#7 As the authors state in their limitations, the causal relationship between the two is unknown
due to the lack of a planned inclusion cohort, and in this case an association can simply be stated.
The authors would like to explain how they infer a causal relationship between low alternative
indicators and high incidence of liver disease, taking into account the above-mentioned mix of
patient groups, including their rationale.
Please review this paper.
user
Title: Associations between non-insulin-based insulin resistance surrogate markers and liver-
related outcomes in metabolic dysfunction-associated steatotic liver disease: a nationwide cohort
study in South Korea
Version: 5 Date: 13 Mar 2025
Reviewer:  Kyoko Sakai
Reviewer's report:
I agree to  rereview the article and access the review cite , read authors' response.I noticed that
the authors did not read the word file I attached and did not respond to my 7 comments.
Their response is needed to make my final decision.
Could you please  open the file of comments, read it all the way through, and respond ?
I note my all contents below, just in case.
##Review Comments 02/03/2025#
#1 This article is a valuable long-term follow-up study of the association between MASLD and
insulin resistance in national data from South Korea. Furthermore, the results are interesting
because they differ from the positive correlation between insulin resistance and the occurrence
of liver disease events in previous studies.
#2 The attempt to assess insulin resistance using surrogate markers without using insulin
measurements is a promising method, if validated, for examining the association between insulin
resistance and various diseases in big data.
On the other hand, if these surrogate markers do not correlate well enough to substitute for IR,
the present argument does not hold. However, the authors do not state with sufficient clarity
whether there is or is not a high correlation and the scientific basis for this.
#3 Of the three alternative markers, the association between TyG index and IR has been
examined in the literature10 Systematic Review, but the quality of evidence seems to be low
due to the high risk of bias of the inclusion studies and their large heterogeneity. AUROC is
also not high enough at 0.6-0.8. The literature on TG/HDL ratios in reference 11 and METSIR
in reference 12 does not directly examine the correlation between alternative markers and
HOMAIR or IR.
Therefore, if the authors believe that the correlation between surrogate markers and IR is high
enough, they need to provide more scientifically valid evidence.
#4 If there is not sufficient evidence, do the authors still consider and conclude that the decrease
in surrogate markers in the liver-related disease group of MASLD is a decrease in IR? Or do they
consider the three surrogate markers in the present study to be useful as independent indicators,
although it is unclear whether they are sufficiently correlated with IR? The authors should state
which view they take. This would make the direction of the implications for practice of the
results from these valuable data more plausible and clear.
#5 What is the rationale for using the AST/ALT ratio indicator for advanced fibrosis among the
many liver fibrosis indicators?  For this indicator as well, isn’t it necessary to state the rationale
for its validity, rather than just because it was possible to obtain data?
#6 Deterioration in nutritional status due to the progression of liver disease may temporarily
give the appearance of improved indices of glucose tolerance. Which of the following do the
authors consider to be associated with the lower IR index group and higher incidence of liver-
related events in the present cohort study? Please explain their rationale for this consideration.
(i) The low IR surrogate index group is involved in the occurrence of liver-related events.
(ii) The low IR surrogate index group is originally mixed with a large number of patients with
progressive liver disease, and the progression of liver disease contributes to the high incidence
of liver-related events.
#7 As the authors state in their limitations, the causal relationship between the two is unknown
due to the lack of a planned inclusion cohort, and in this case an association can simply be stated.
The authors would like to explain how they infer a causal relationship between low alternative
indicators and high incidence of liver disease, taking into account the above-mentioned mix of
patient groups, including their rationale.
assistant