Molecular Pathways of Cardiometabolic Residual Risk in Type 2 Diabetes: Insulin Resistance, Metaflammation, and Liver–Kidney–Vascular Crosstalk

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses a highly timely and important topic, summarizing the molecular pathways of cardiometabolic risk in type 2 diabetes mellitus (T2DM) from the perspective of renal, hepatic, and cardiac comorbidities. The relevance of this review is further highlighted by the recent publication of the new joint consensus document focusing on the complex management of these patients. The overall structure of the paper is logical, and the table is particularly valuable, offering a well-organized and concise summary of the main points. However, in its current form, the manuscript remains somewhat superficial regarding the molecular mechanisms. The description of complex metabolic pathways is occasionally confusing, making it difficult to follow the precise causal relationships. To enhance the scientific value and impact of the paper, I suggest the following revisions: Major Revisions:

1. Elaboration on Molecular Mechanisms: The description of the key metabolic and signaling pathways is currently too brief. I recommend that the authors provide a more in-depth and detailed explanation of the core pathomechanisms within each section.
2. Inclusion of Pathway Diagrams: The current figure functions more as a graphical abstract rather than a detailed scientific guide. To improve clarity, it is highly recommended to include specific, detailed molecular pathway diagrams for each section/organ system to clarify the pathological links between the organs.
3. Integration of the Newest Clinical Guidelines: The contemporary relevance of the paper would be significantly strengthened if the authors explicitly integrated the newly released 2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome< !--TgQPHd||[]--> into their review, with a particular focus on complex, interdisciplinary therapeutic approaches. (https://doi.org/10.1161/CIR.0000000000001453)

Minor Revisions:

1. Abbreviation Consistency: Several professional abbreviations are used throughout the text without being defined upon first mention. Please systematically check and define all acronyms when they first appear, or provide a comprehensive list of abbreviations.

Author Response

We sincerely thank Reviewer 1 for the careful and constructive evaluation of our manuscript. We are grateful for the positive assessment of the clinical relevance, logical structure, and value of the summary table. In response to each comment, we have made substantive revisions to the text, figures, and abbreviation framework. Point-by-point responses are provided below, with explicit references to the modified sections so that changes can be easily located in the revised manuscript.

 

 

Reviewer 1 – General Comment

"The manuscript addresses a highly timely and important topic, summarizing the molecular pathways of cardiometabolic risk in type 2 diabetes mellitus (T2DM) from the perspective of renal, hepatic, and cardiac comorbidities. The relevance of this review is further highlighted by the recent publication of the new joint consensus document focusing on the complex management of these patients. The overall structure of the paper is logical, and the table is particularly valuable, offering a well-organized and concise summary of the main points. However, in its current form, the manuscript remains somewhat superficial regarding the molecular mechanisms. The description of complex metabolic pathways is occasionally confusing, making it difficult to follow the precise causal relationships. To enhance the scientific value and impact of the paper, I suggest the following revisions."

Response:

We thank the reviewer for this balanced assessment and for the positive comments regarding clinical relevance, structure, and the summary table. We fully agree that a review centred on cardiometabolic residual risk must clearly separate clinical associations from molecular causal links. The revised manuscript explicitly restructures each major section to present metabolic stress and insulin resistance, adipose tissue dysfunction, metaflammation, hepatic lipotoxicity and fibrogenesis, diabetic kidney disease, endothelial dysfunction, and thrombo-inflammatory vascular injury as interconnected but anatomically and mechanistically distinct axes, with a defined causal direction at each step.

 

Major Revisions

Reviewer 1 – Major Comment 1: Elaboration on Molecular Mechanisms

"The description of the key metabolic and signaling pathways is currently too brief. I recommend that the authors provide a more in-depth and detailed explanation of the core pathomechanisms within each section."

Response:

We agree with this comment. The revised manuscript provides substantially expanded mechanistic descriptions in each organ-specific section. To help the reviewer locate each addition, we list the specific new or substantially modified passages below:

Section 2 – Insulin Resistance (new paragraph beginning "A useful way to follow this pathway is to start from substrate overload…"): we added a step-by-step causal sequence from excess fatty-acid delivery to DAG and ceramide accumulation, PKCε and novel PKC isoform activation, IRS-1 serine phosphorylation, impaired PI3K/Akt activity, and the tissue-specific downstream consequences (impaired GLUT4 translocation, incomplete suppression of hepatic gluconeogenesis, reduced eNOS phosphorylation, persistent adipose lipolysis, and beta-cell stress).

Section 3 – Metaflammation / NLRP3 (new paragraph beginning "This two-signal model is clinically important because…"): we explicitly explain why the priming signal (TLR4 → NF-κB → NLRP3 transcription and pro-IL-1β upregulation) and the activation signal (K⁺ efflux, lysosomal destabilisation, mtROS and mtDNA release → NLRP3–ASC–pro-caspase-1 assembly → IL-1β/IL-18 maturation) together create a durable inflammatory loop driven by endogenous metabolic danger signals.

Section 4 – Liver / MASLD (new paragraph beginning "The paradox of selective hepatic insulin resistance is particularly relevant…"): we elaborated the FoxO1/SREBP-1c/ChREBP imbalance, explaining how impaired Akt-mediated FoxO1 nuclear exclusion maintains gluconeogenic transcription while hyperinsulinemia simultaneously activates SREBP-1c and ChREBP, resulting in coexisting hyperglycaemia and de novo lipogenesis.

Section 5 – Kidney / DKD (new paragraph beginning "The causal pathway from renal metabolic stress to systemic risk can therefore be summarised as follows…"): we describe glomerular hyperfiltration and RAAS activation, podocyte slit-diaphragm disruption and albuminuria, tubular glucose–sodium overload with hypoxia, and TGF-β/Smad–driven extracellular-matrix deposition as a sequential chain.

Section 6 – Vascular / Endothelial (new paragraph beginning "These biochemical changes create a self-reinforcing endothelial loop…"): we explain eNOS uncoupling (BH4 oxidation to BH2, ADMA accumulation), the resulting superoxide generation and peroxynitrite formation, and the feed-forward cycle between nitric oxide deficiency and oxidative stress.

 

Reviewer 1 – Major Comment 2: Inclusion of Pathway Diagrams

"The current figure functions more as a graphical abstract rather than a detailed scientific guide. To improve clarity, it is highly recommended to include specific, detailed molecular pathway diagrams for each section/organ system to clarify the pathological links between the organs." (https://doi.org/10.1161/CIR.0000000000001453)

Response:

We agree that the original Figure 1 served primarily as a high-level overview and did not fulfil the function of a mechanistic guide. We have therefore added a completely new Figure 2, dedicated entirely to organ-specific molecular pathway diagrams. Figure 1 is retained as the integrative network map; Figure 2 is a six-panel figure (Panels A–F) with the following structure:

Panel A – Adipose tissue / insulin-resistance axis: substrate overload → DAG (PKCε) and ceramide (PP2A) accumulation → IRS-1/IRS-2 serine phosphorylation via JNK and IKKβ → PI3K/Akt inhibition → impaired GLUT4, eNOS, and FoxO1 suppression; preserved MAPK → endothelin-1 and VSMC proliferation; mitochondrial dysfunction and ER stress.

Panel B – Metaflammation / NLRP3 inflammasome axis: Signal 1 (TLR4/NF-κB priming) and Signal 2 (K⁺ efflux, mtROS, mtDNA) → NLRP3–ASC–pro-caspase-1 complex → IL-1β and IL-18 → TNF-α–mediated JNK/IKKβ activation → IRS inhibition → feed-forward metabolic memory loop.

Panel C – Liver / MASLD axis: selective hepatic insulin resistance → FoxO1 nuclear retention (gluconeogenesis ↑) and SREBP-1c/ChREBP activation (DNL ↑) → DAG/ceramide lipotoxicity → ER stress, mitochondrial injury, TLR4/Kupffer cell activation → TGF-β/Smad → hepatic stellate cell activation → MASH/fibrosis; hepatokines (fetuin-A, FGF21) → systemic vascular risk.

Panel D – Kidney / DKD axis: glomerular hyperfiltration → podocyte injury (nephrin/podocin ↓, TRPC6 ↑) → albuminuria; RAAS activation → NADPH oxidase → ROS; tubular glucose–Na overload → hypoxia → senescence-associated secretory phenotype; NLRP3 and TGF-β/Smad → tubulointerstitial fibrosis; MR activation (finerenone target).

Panel E – Vascular / endothelial dysfunction axis: PI3K/Akt/eNOS ↓ (NO ↓) + MAPK preserved (endothelin-1 ↑) → eNOS uncoupling (BH4 → BH2/ADMA) → superoxide → self-reinforcing loop; AGE–RAGE → NF-κB, ROS, permeability ↑; atherogenic dyslipidaemia → platelet hyperreactivity and plaque vulnerability → ASCVD and microvascular disease.

Panel F – Clinical translation: side-by-side alignment of translational biomarkers (TyG/TyG-BMI, VAI/LAP, AIP, HSI/FIB-4, albuminuria/eGFR, hs-CRP) with the corresponding pathway-targeted therapies (SGLT2i, GLP-1/GIP-GLP-1 RA, finerenone, statin/ezetimibe, RAAS blockade, lifestyle), anchored to the 2026 AHA/ACC/ADA/ASN CKM Guideline framework.

Figure 2 is provided as a separate high-resolution file (PNG, 300 dpi; PDF vector format) for editorial review and production. We believe this new figure directly addresses the reviewer's request for detailed, organ-specific molecular pathway diagrams that function as scientific guides rather than visual summaries.

 

Reviewer 1 – Major Comment 3: Integration of the Newest Clinical Guidelines

"The contemporary relevance of the paper would be significantly strengthened if the authors explicitly integrated the newly released 2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome into their review, with a particular focus on complex, interdisciplinary therapeutic approaches. (https://doi.org/10.1161/CIR.0000000000001453)"

Response:

We fully agree. The 2026 AHA/ACC/ADA/ASN CKM Guideline (Circulation, doi:10.1161/CIR.0000000000001453) has been incorporated as Reference 91 and is now cited in three strategically relevant locations:

Introduction (second paragraph, beginning "This integrated interpretation has been further reinforced by the 2026 AHA/ACC/ADA/ASN Guideline…"): the guideline is introduced as the contemporary clinical framework that operationalises the organ-crosstalk concept, emphasising that obesity, dysglycaemia, CKD, hypertension, dyslipidaemia, and cardiovascular disease should be detected and managed as interdependent components of a single CKM continuum.

Section 8 – Therapeutic Modulation (second paragraph, beginning "In line with the 2026 AHA/ACC/ADA/ASN CKM guideline…"): we connect the pathway-oriented therapeutic view to the guideline's recommendation for coordinated, risk-based treatment intensification across the CKM continuum, including simultaneous targeting of lifestyle, adiposity, blood pressure, atherogenic lipoproteins, kidney protection, and glucose-lowering strategies with proven organ benefit.

Section 9 – Future Perspectives (first paragraph, beginning "The 2026 CKM guideline provides a clinical counterpart to this biological model…"): the guideline is used to frame the proposal that future molecular staging should be aligned with CKM clinical categories, linking dominant pathway signatures (adipose-insulin-resistant, liver-lipotoxic, kidney-fibrotic, vascular-oxidative, inflammatory-thrombotic) to the guideline's staged management algorithm.

 

Minor Revisions

Reviewer 1 – Minor Comment 1: Abbreviation Consistency

"Several professional abbreviations are used throughout the text without being defined upon first mention. Please systematically check and define all acronyms when they first appear, or provide a comprehensive list of abbreviations."

Response:

We thank the reviewer for this observation. We have addressed abbreviation consistency through two complementary actions:

First, the legend of Table 1 has been substantially expanded. In the original submission, the table legend listed only 13 abbreviations; the revised version contains a comprehensive list of more than 50 terms, including all pathway-level and therapeutic abbreviations used in the table (e.g., ACC, ADA, AGE, AHA, AIP, ALT, AMPK, ApoB, ASN, ASCVD, AST, BH2, BH4, ChREBP, CKM, DAMP, EPAC, FGF21, FoxO1, GGT, GIP, GLUT4, HbA1c, HOMA-IR, hs-CRP, IKKβ, MCP-1, MR, NLRP3, PGC-1α, PKC, RAGE, SIRT1, SREBP-1c, TLR4, TNF-α, TRPC6, VLDL, and others).

Second, first-use definitions in the running text have been verified. Key acronyms introduced in the expanded mechanistic sections — including JNK (Section 2), IKKβ (Section 2), PKCε (Section 2), NLRP3 and ASC (Section 3), FoxO1, SREBP-1c and ChREBP (Section 4), TRPC6 (Section 5), eNOS and BH4/BH2 (Section 6) — are defined at first mention in the main text. A comprehensive abbreviation list covering the principal terms used throughout the manuscript is also provided at the end of the document.

 

 

 

We again thank Reviewer 1 for the constructive and detailed assessment. We believe the revised manuscript is now substantially more mechanistically detailed, clearer in its causal pathway organisation, better illustrated with organ-specific molecular diagrams (new Figure 2), more closely aligned with the 2026 CKM framework, and more consistent in abbreviation use throughout. We hope the revised version meets the standards of the journal and look forward to the editorial decision.

 

Sincerely,

 

The Authors

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript provides a timely, well-structured, and clinically relevant narrative review of cardiometabolic residual risk in type 2 diabetes. The authors successfully integrate several interconnected molecular and organ-specific pathways, including insulin resistance, metaflammation, MASLD, diabetic kidney disease, endothelial dysfunction, oxidative stress, thrombo-inflammation, and fibrosis. The pathway-centered approach is valuable because it moves the discussion beyond isolated therapeutic targets and emphasizes persistent biological vulnerability despite apparent clinical control.

The manuscript is generally comprehensive and scientifically sound. The figure and table are useful additions and help synthesize the complex interaction between molecular mechanisms, clinical proxies, and therapeutic modulation. The therapeutic section is also relevant, particularly in relation to SGLT2 inhibitors, GLP-1 receptor agonists, dual incretin-based therapies, RAAS blockade, lipid-lowering therapy, and finerenone.

I recommend minor revision before acceptance. The following points should be addressed:

1. The authors should add a brief methodological statement describing how the literature was selected, even if this is a narrative review. For example, they could briefly mention the databases consulted, the approximate time frame, the main keywords, and the rationale for prioritizing mechanistic, translational, guideline-based, and clinical outcome evidence.

2. The concept of “cardiometabolic residual risk” should be defined even more explicitly at the beginning of the manuscript. It would be useful to distinguish it from classical cardiovascular residual risk and clarify how the term is being expanded here to include liver, kidney, vascular, inflammatory, metabolic, and fibrotic dimensions.

3. Some mechanistic claims should be slightly tempered when the evidence is derived mainly from experimental, translational, or indirect clinical data. This is particularly relevant for proposed mechanisms involving AMPK, SIRT1, PGC-1alpha, sodium-hydrogen exchanger modulation, inflammasome activity, hepatokines, and endothelial dysfunction. The manuscript would benefit from clearer differentiation between established clinical outcome evidence and plausible mechanistic interpretation.

4. A short limitations section should be added. This section may acknowledge that the review is narrative rather than systematic, that many biomarkers and indices are indirect proxies rather than direct molecular measurements, and that pathway-centered phenotyping remains an emerging rather than fully validated clinical strategy.

5. The authors should verify the consistency and completeness of the reference list, especially very recent references and guideline citations. Please ensure that all cited references are published, correctly formatted, and fully traceable.

6. The manuscript contains some incomplete administrative statements, including the APC funding statement and the acknowledgments section. These should be completed or removed before publication.

7. Minor editorial harmonization is recommended. For example, the authors should standardize terminology and symbols throughout the manuscript, including beta/β, kappaB/κB, TGF-beta/TGF-β, GLP-1 RA/GLP-1 receptor agonist, SGLT2i/SGLT2 inhibitor, and other abbreviations.

Overall, this is a strong and useful review that requires only minor revisions to improve transparency, precision, and editorial completeness.

Author Response

We sincerely thank Reviewer 2 for the careful, constructive, and encouraging evaluation of our manuscript. We are grateful for the positive assessment of the review as timely, clinically relevant, comprehensive, and scientifically sound. Each comment is quoted verbatim below, followed by our point-by-point response and explicit reference to the location of changes in the revised manuscript.

 

REVIEWER 2

 

General Comment

"The manuscript provides a timely, well-structured, and clinically relevant narrative review of cardiometabolic residual risk in type 2 diabetes. The authors successfully integrate several interconnected molecular and organ-specific pathways, including insulin resistance, metaflammation, MASLD, diabetic kidney disease, endothelial dysfunction, oxidative stress, thrombo-inflammation, and fibrosis. The pathway-centered approach is valuable because it moves the discussion beyond isolated therapeutic targets and emphasizes persistent biological vulnerability despite apparent clinical control. The manuscript is generally comprehensive and scientifically sound. The figure and table are useful additions and help synthesize the complex interaction between molecular mechanisms, clinical proxies, and therapeutic modulation. The therapeutic section is relevant, particularly in relation to SGLT2 inhibitors, GLP-1 receptor agonists, dual incretin-based therapies, RAAS blockade, lipid-lowering therapy, and finerenone. I recommend minor revision before acceptance."

Response:

We thank the reviewer for this highly positive overall assessment and for the recognition of the clinical relevance, mechanistic integration, and translational value of the review. All minor revision points have been addressed through targeted additions and editorial harmonisation, as detailed below.

 

Minor Revisions

Comment 1 – Methodological Statement for Literature Selection

"The authors should add a brief methodological statement describing how the literature was selected, even if this is a narrative review. For example, they could briefly mention the databases consulted, the approximate time frame, the main keywords, and the rationale for prioritizing mechanistic, translational, guideline-based, and clinical outcome evidence."

Response:

We agree. A short "Literature selection" paragraph has been added at the end of the Introduction (new paragraph beginning "Literature selection was performed as a targeted narrative review…"). It specifies that the literature was identified through PubMed/MEDLINE and Google Scholar, supplemented by major guideline documents and reference lists of relevant reviews and clinical trials. The search focused primarily on evidence published from 2010 to 2026, retaining older landmark mechanistic studies when necessary. Key search terms included type 2 diabetes, cardiometabolic residual risk, insulin resistance, metaflammation, MASLD, diabetic kidney disease, endothelial dysfunction, oxidative stress, fibrosis, CKM syndrome, SGLT2 inhibitors, GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonism, finerenone, and translational biomarkers. We further clarified that studies were prioritised when they provided mechanistic insight, translational relevance, guideline support, or clinically validated outcome evidence.

 

Comment 2 – Definition of Cardiometabolic Residual Risk

"The concept of "cardiometabolic residual risk" should be defined even more explicitly at the beginning of the manuscript. It would be useful to distinguish it from classical cardiovascular residual risk and clarify how the term is being expanded here to include liver, kidney, vascular, inflammatory, metabolic, and fibrotic dimensions."

Response:

We agree. An explicit definition has been added in the Introduction. The revised text distinguishes classical cardiovascular residual risk — which generally refers to the persistence of atherosclerotic or cardiovascular events despite treatment of traditional risk factors (principally LDL cholesterol) — from the broader CKM-oriented concept used in the present review. Cardiometabolic residual risk is now defined as the persistent multi-organ biological vulnerability that remains despite apparent control of HbA1c, LDL cholesterol, blood pressure, body weight, and renal markers, and that involves metabolic, hepatic, renal, vascular, inflammatory, thrombo-inflammatory, and fibrotic pathways. This clarification explicitly justifies why the liver-kidney-vascular and inflammatory-fibrotic axes are discussed alongside classical cardiovascular risk pathways.

 

Comment 3 – Tempering Mechanistic Claims from Indirect Evidence

"Some mechanistic claims should be slightly tempered when the evidence is derived mainly from experimental, translational, or indirect clinical data. This is particularly relevant for proposed mechanisms involving AMPK, SIRT1, PGC-1alpha, sodium-hydrogen exchanger modulation, inflammasome activity, hepatokines, and endothelial dysfunction. The manuscript would benefit from clearer differentiation between established clinical outcome evidence and plausible mechanistic interpretation."

Response:

We agree. In the therapeutic and mechanistic sections, a clarifying statement has been added specifying that, while the clinical benefits of selected drug classes are supported by randomised outcome trials, proposed mechanisms involving AMPK, SIRT1, PGC-1α, sodium-hydrogen exchanger modulation, inflammasome activity, hepatokines, and endothelial dysfunction remain incompletely proven in humans and should be interpreted as biological plausibility rather than definitively causal pathways.

Throughout the relevant sections, overly definitive wording for these pathways has been replaced with more cautious language. Examples of revised phrasing include: "may contribute" (in reference to AMPK/SIRT1/PGC-1α activation), "has been proposed" (for sodium-hydrogen exchanger modulation), "is supported by mechanistic and translational evidence" (for inflammasome activity in the vasculature), "provides a plausible biological link" (for hepatokine-mediated organ crosstalk). A general caveat sentence has also been added to the Introduction, noting that the mechanistic interpretation below is intended to connect biological plausibility with clinical evidence without implying that all molecular pathways have been directly validated in human trials.

 

Comment 4 – Addition of a Limitations Section

"A short limitations section should be added. This section may acknowledge that the review is narrative rather than systematic, that many biomarkers and indices are indirect proxies rather than direct molecular measurements, and that pathway-centered phenotyping remains an emerging rather than fully validated clinical strategy."

Response:

A dedicated Limitations section has been added immediately before the Conclusions. It explicitly acknowledges three points:

(1) Narrative rather than systematic design: the review is narrative and not systematic; the literature selection was designed to provide a clinically and mechanistically coherent synthesis rather than a formally exhaustive or PRISMA-based evidence map.

(2) Indirect clinical proxies: several biomarkers and composite indices discussed in the manuscript — including TyG-derived indices, VAI, LAP, AIP, HSI, FIB-4, albuminuria, and eGFR — are indirect clinical proxies rather than direct molecular measurements of intracellular kinase activation, inflammasome assembly, eNOS coupling, hepatocyte lipotoxicity, podocyte stress, or tissue fibrosis.

(3) Emerging clinical strategy: pathway-centred phenotyping is a promising interpretative framework but remains an emerging strategy that requires prospective validation before it can be considered a fully established tool for individualised treatment allocation.

 

Comment 5 – Reference-List Consistency and Recent Guidelines

"The authors should verify the consistency and completeness of the reference list, especially very recent references and guideline citations. Please ensure that all cited references are published, correctly formatted, and fully traceable."

Response:

The reference list has been checked for consistency, completeness, and traceability. Particular attention was given to the following documents: the 2026 AHA/ACC/ADA/ASN CKM Guideline (Circulation, doi:10.1161/CIR.0000000000001453, added as ref. 91), the ADA Standards of Care 2026, KDIGO 2024 CKD Clinical Practice Guideline, MASLD clinical practice guidance, and recent clinical outcome trials for SGLT2 inhibitors, GLP-1/GIP-GLP-1 receptor agonists, and finerenone. All cited references are published and fully traceable. Formatting has been harmonised in accordance with journal style.

 

Comment 6 – Administrative Statements

"The manuscript contains some incomplete administrative statements, including the APC funding statement and the acknowledgments section. These should be completed or removed before publication."

Response:

The incomplete APC funding placeholder ("The APC funding statement should be completed before submission") and the unresolved acknowledgments text ("To be completed, if applicable") have been removed from the manuscript. The funding and acknowledgments sections now contain only final, completed text with no residual placeholder wording.

 

Comment 7 – Editorial Harmonisation of Terminology and Symbols

"Minor editorial harmonization is recommended. For example, the authors should standardize terminology and symbols throughout the manuscript, including beta/β, kappaB/κB, TGF-beta/TGF-β, GLP-1 RA/GLP-1 receptor agonist, SGLT2i/SGLT2 inhibitor, and other abbreviations."

Response:

A full harmonisation pass has been performed across the main text, table, figure legends, and abbreviation list. Specific corrections include:

TGF-beta → TGF-β (7 occurrences corrected throughout text and table legend).

Greek symbols (β, κ, α): consistently rendered as Unicode characters throughout all sections.

GLP-1 receptor agonist / GLP-1 RA: full term used at first mention with abbreviation defined; GLP-1 RA applied consistently thereafter.

SGLT2 inhibitor / SGLT2i, RAAS, MASLD, DKD, CKM, eNOS, NLRP3, AGE-RAGE, TyG, VAI, LAP, AIP, HSI, FIB-4: terminology verified and applied consistently across all sections, figure legends, table, and abbreviation list.

 

Final Comment

"Overall, this is a strong and useful review that requires only minor revisions to improve transparency, precision, and editorial completeness."

Response:

We thank the reviewer for this positive conclusion. The revisions described above improve the transparency of the literature-selection process, clarify the conceptual definition of cardiometabolic residual risk, appropriately temper mechanistic interpretation, acknowledge the limitations of the narrative and translational framework, complete all administrative sections, and harmonise terminology and symbols throughout the manuscript.

 

 

 

We sincerely thank Reviewer 2 and the Editor for the constructive and rigorous evaluation. We believe the revised version fully addresses all comments and meets the scientific and editorial standards of the journal. We look forward to the editorial decision.

 

Sincerely,

 

the autors

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for carefully addressing my previous comments. The manuscript has improved substantially, and I appreciate the authors' efforts in revising it. I have only a few minor comments remaining before the manuscript is suitable for publication:

1. The abstract should be self-contained; therefore, it should not refer to figures in the main text. Please remove the reference to Figure 2 from the abstract.
2. Please use abbreviations only where they are truly necessary. Excessive use of abbreviations may reduce readability.
3. The quality of Figure 2 is very poor. The labels and text are difficult to read, so I recommend replacing it with a higher-resolution version.

Author Response

We sincerely thank the reviewer for the positive reassessment of our revised manuscript and for acknowledging that the manuscript has improved substantially. We have carefully addressed the remaining minor comments. The manuscript has been revised accordingly, with changes highlighted in the revised file.

Reviewer Comment 1

The abstract should be self-contained; therefore, it should not refer to figures in the main text. Please remove the reference to Figure 2 from the abstract.

Response: We agree. The reference to Figure 2 has been removed from the abstract so that the abstract remains fully self-contained. The abstract now summarizes the scope and key message of the review without referring to any figure in the main text.

Reviewer Comment 2

Please use abbreviations only where they are truly necessary. Excessive use of abbreviations may reduce readability.

Response: We agree with the reviewer. We re-checked the manuscript and reduced unnecessary abbreviation density where possible, especially in explanatory sentences where the full term improves readability. Essential and standard abbreviations were retained only when repeatedly used or widely recognized in the field. We also maintained the abbreviation list to support clarity for readers.

Reviewer Comment 3

The quality of Figure 2 is very poor. The labels and text are difficult to read, so I recommend replacing it with a higher-resolution version.

Response: We agree. Figure 2 has been replaced with a higher-resolution version to improve readability of the labels, panel headings, and pathway annotations. The revised figure is also provided as a separate high-resolution figure file for editorial review and production.

Closing statement

We again thank the reviewer for the constructive final comments. We believe that these minor revisions improve the clarity, readability, and presentation quality of the manuscript, and we hope that the revised version is now suitable for publication.

Sincerely,

The Authors