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Clinical Research

Capturing metabolic syndrome: new thresholds for insulin resistance and novel body composition indices

International Journal of Obesity (2026)Cite this article

Subjects

Abstract

Background

Despite being a defining feature of metabolic syndrome (MetS), clinical assessment of IR remains challenging, due to the costs of reference methods and the numerosity of IR indices. Furthermore, to which extent IR contributes to MetS, while controlling for altered body composition, is still largely unexplored.

Objectives

The present work aims at proposing new cut points for IR among people with overweight and obesity, assessing the concordance of different IR definitions and investigating how IR interacts with body composition in predicting MetS status.

Subjects

665 patients were assessed for potential enrolment, using a cross-sectional design. The following inclusion criteria were applied: age ≥18 years, body mass index ≥25 kg/m2, White European, no fulfilled criterion for diabetes mellitus, no current pregnancy.

Methods

Concordance of previously validated IR definitions was assessed by Cohen’s κ. ROC curve analysis with 5-fold cross-validation was used to determine novel cut points for IR indices based on MetS presence. Finally, mediation analysis was employed to test whether IR mediates the relationship between body composition indices (i.e., fat mass-to-fat-free mass ratio, FM:FFM and appendicular lean soft tissue-to-visceral fat area ratio, ALST:VFA) and MetS.

Results

A total of 515 patients were included in the final analysis (females: 80.9%; MetS prevalence: 40%). Overall, IR definitions which previously validated against the hyperinsulinemic-euglycemic clamp displayed the highest level of agreement. The following cut-points were identified from ROC curve analysis: ISI-Matsuda<3.33 (AUROC = 0.675, p < 0.001), HOMA-IR > 2.93 (AUROC = 0.663 p < 0.001), HOMA2-IR > 1.67 (AUROC = 0.651 p < 0.001). Finally, ALST:VFA but not FM:FFM significantly predicted MetS status independent of age, with the mediating role of ISI-Matsuda, HOMA-IR and HOMA2-IR.

Conclusions

IR indices mediated the effect of altered body composition (i.e., reduced appendicular muscularity and increased visceral adiposity) on MetS. Newly proposed diagnostic thresholds can aid in the identification of IR among patients at increased cardio-metabolic risk.

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Fig. 1: Predictive ability of insulin resistance on metabolic syndrome.
Fig. 2: Correlation between insulin resistance, anthropometry and body composition.
Fig. 3: Relationship between ISI-Matsuda and body composition indices.
Fig. 4: Relationship between HOMA-IR and body composition indices.
Fig. 5: Relationship between HOMA2-IR and body composition indices.

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Data availability

Data supporting the findings of the present study are available upon reasonable request from the corresponding author.

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Acknowledgements

We acknowledge the role of the nursing personnel represented by Cinzia Estivi, Rossana Principato, Antonella Anzuini, Francesco Impelliccieri, Anna Ruggeri, Antonella Bellissari, Lidia Pawlowska, Roberto Ferri, in the assistance to patients and collection of biological samples.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Author notes

  1. Francesco Frigerio

    Present address: Department for the Promotion of Human Sciences and Quality of Life, San Raffaele Open University, Rome, Italy

Authors and Affiliations

  1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Francesco Frigerio, Claudia Piciocchi, Federico Ricci, Valeria Galfano, Carla Lubrano, Stefania Mariani, Elena Gangitano, Marianna Minnetti, Luca Muzzioli, Andrea Lenzi, Andrea M Isidori, Lucio Gnessi, Silvia Migliaccio, Lorenzo Maria Donini & Eleonora Poggiogalle

  2. Department of Statistical Sciences, Sapienza University of Rome, Rome, Italy

    Alessia Vitozzi

  3. Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy

    Maria De Marinis

  4. Unicamillus, Saint Camillus International University of Health Sciences, Rome, Italy

    Elena Gangitano

  5. Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele, Rome, Italy

    Massimiliano Caprio

  6. Department for the Promotion of Human Sciences and Quality of Life, San Raffaele Open University, Rome, Italy

    Massimiliano Caprio

  7. School of Population Health, Curtin University, Perth, WA, Australia

    Mario Siervo

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Contributions

Conceptualization: EP, LMD, MS; Methodology: FF, EP, LMD, MS; Data curation FF, CP, FR, MDM, VG, EG, MM. Formal analysis: FF, AV, EP; Visualization: FF, AV, LM, CP; Investigation and resources: LMD, S.Mariani, AL, AI, LG, CL, MC; Writing–original draft preparation: all authors. Writing—review and editing: all authors. Supervision: EP, LMD, MS, S.Migliaccio; Project administration: LMD, S.Migliaccio, AL, AMI, LG, CL.

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Correspondence to Francesco Frigerio.

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The authors declare no competing interests.

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The study was conducted according to the declarations of Helsinki; protocol was approved by the Ethical Committee of the Sapienza University of Rome, Rome, Italy. Written informed consent was obtained from all the participants.

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Frigerio, F., Vitozzi, A., Piciocchi, C. et al. Capturing metabolic syndrome: new thresholds for insulin resistance and novel body composition indices. Int J Obes (2026). https://doi.org/10.1038/s41366-025-01993-1

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