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Discovery and validation of plasma, saliva and multi-fluid plasma–saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults

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Abstract

Aims/hypothesis

Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites.

Methods

We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma–saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors.

Results

Plasma, saliva and multi-fluid plasma–saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures.

Conclusions/interpretation

The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

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Abbreviations

CRP:

C-reactive protein

FDR:

False discovery rate

FPG:

Fasting plasma glucose

HDL-C:

HDL-cholesterol

LDL-C:

LDL-cholesterol

MET-h/week:

Metabolic equivalent hours per week

SOALS:

San Juan Overweight Adults Longitudinal Study

TC:

Total cholesterol

TG:

Triglyceride

WC:

Waist circumference

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Authors and Affiliations

  1. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Danielle E. Haslam, JoAnn E. Manson, Frank B. Hu, Meir J. Stampfer & Shilpa N. Bhupathiraju

  2. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Danielle E. Haslam, Frank B. Hu, Meir J. Stampfer & Shilpa N. Bhupathiraju

  3. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Liming Liang, JoAnn E. Manson, Frank B. Hu, Meir J. Stampfer & Kaumudi Joshipura

  4. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Liming Liang

  5. Center for Clinical Research and Health Promotion, Graduate School of Public Health, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico

    Kai Guo, Marijulie Martínez-Lozano & Kaumudi Joshipura

  6. Department of Biostatistics and Epidemiology, Graduate School of Public Health, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico

    Cynthia M. Pérez

  7. Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Chih-Hao Lee

  8. School of Dental Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico

    Evangelia Morou-Bermudez

  9. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA

    Clary Clish

  10. Center for Oral/Head and Neck Oncology Research, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA

    David T. W. Wong

  11. Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    JoAnn E. Manson

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  1. Danielle E. Haslam
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Corresponding author

Correspondence to Shilpa N. Bhupathiraju.

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Acknowledgements

The authors thank all SOALS participants and staff for their contribution to this study. Part of this study was presented as an abstract at the virtual Metabolomics Society 2021 conference, 22–24 June 2021.

Data availability

Data are available upon reasonable request. Information on requesting data from SOALS can be found on their website: http://soals.rcm.upr.edu/.

Funding

This work was supported by the National Institutes of Health: T32CA009001 (DEH), 1K01DK136968 (DEH) and R01DK120560-01 (DEH, LL, C-HL, DTWW, FBH, MJS, KJ and SNB) and the National Institute of General Medical Sciences [U54GM133807 (KG, CMP, EM-B, KJ)].

Authors’ relationships and activities

DTWW is a consultant to AIONCO and has equity in Liquid Diagnostics LLC. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

DEH performed the statistical analyses. DEH and SNB drafted the manuscript. DEH, LL, KG, MM-L, CMP, C-HL, EM-B, CC, DTWW, JEM, FBH, MJS, KJ and SNB contributed to interpretation of the data and revised the article critically for important intellectual content. All authors approved the final version of the manuscript. DEH and SNB are guarantors of the work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Haslam, D.E., Liang, L., Guo, K. et al. Discovery and validation of plasma, saliva and multi-fluid plasma–saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults. Diabetologia (2024). https://doi.org/10.1007/s00125-024-06169-6

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