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Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy

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Abstract

Aims/hypothesis

Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk.

Methods

In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index [IGI]/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models.

Results

Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (p=0.03) and 2 h glucose (p<0.0001) than non-progressors, coupled with higher BMI (p=0.001), greater insulin resistance (both Matsuda index and HOMA-IR, p≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR, p≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both p<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance.

Conclusion/interpretation

Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy.

Graphical Abstract

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Abbreviations

CCI:

Concordance index

GCT:

Glucose challenge test

GDM:

Gestational diabetes mellitus

GIGT:

Gestational impaired glucose tolerance

IFG:

Impaired fasting glucose tolerance

IGI:

Insulinogenic index

IGT:

Impaired glucose tolerance

ISSI-2:

Insulin secretion-sensitivity index-2

NGT:

Normal glucose tolerance

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Author information

Authors and Affiliations

  1. Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, ON, Canada

    Ravi Retnakaran, Chang Ye, Caroline K. Kramer, Anthony J. Hanley & Bernard Zinman

  2. Division of Endocrinology, University of Toronto, Toronto, ON, Canada

    Ravi Retnakaran, Caroline K. Kramer, Anthony J. Hanley, Philip W. Connelly & Bernard Zinman

  3. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Ravi Retnakaran, Caroline K. Kramer & Bernard Zinman

  4. Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada

    Anthony J. Hanley

  5. Keenan Research Centre for Biomedical Science of St Michael’s Hospital, Toronto, ON, Canada

    Philip W. Connelly

  6. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Philip W. Connelly

  7. Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON, Canada

    Mathew Sermer

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  1. Ravi Retnakaran
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Corresponding author

Correspondence to Ravi Retnakaran.

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Acknowledgements

RR holds the Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at Mount Sinai Hospital and his research programme is supported by the Sun Life Financial Program to Prevent Diabetes in Women.

Data availability

De-identified data can be made available under restricted access from the corresponding author, for academic purposes, subject to a material transfer agreement and approval of the Mount Sinai Hospital Research Ethics Board.

Funding

This study was supported by operating grants from the Canadian Institutes of Health Research (CIHR) (MOP-84206 and PJT-156286).

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

RR, CKK, AJH, PWC, MS and BZ designed and implemented the study. CY performed the statistical analyses. RR wrote the manuscript. RR and CY verified the data. All authors critically revised the manuscript for important intellectual content. All authors approved the final manuscript. RR is guarantor, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Retnakaran, R., Ye, C., Kramer, C.K. et al. Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy. Diabetologia 66, 2154–2163 (2023). https://doi.org/10.1007/s00125-023-05994-5

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