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TNF-α Is a Predictor of Insulin Resistance in Human Pregnancy
Open accessAbstract
Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-α. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12–14 weeks) and late (34–36 weeks) gestation. Body composition, plasma TNF-α, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-α was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 ± 1.2 vs. 8.1 ± 0.8 10−2 mg · kg−1 fat-free mass · min−1 · μU−1 · ml−1). TNF-α, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-α (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-α was inversely correlated with insulin sensitivity (r = −0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF-α from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r = −0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF-α was the most significant independent predictor of insulin sensitivity (r = −0.67, P < 0.0001), even after adjustment for fat mass by covariance (r = 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF-α in a new paradigm to explain insulin resistance in pregnancy.
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“Similarly, placental gene expression of TNF-α, IL-1β and their receptors has been reported to be increased in GDM [118,119].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [118]
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“Excess visceral adiposity does not merely represent a passive energy reserve; rather, it acts as an active immunometabolic organ [8-10].”
From Trimester-Specific Bioelectrical Impedance Reference Curves in Physiological Pregnancy: Mapping Maternal Body Composition and Hydration Trajectories (2026) · cites this paper as [10]
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“Plasma TNF-α, in particular, is strongly correlated with insulin resistance [118].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [118]
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“Kirwan et al. stated that an increase in insulin resistance, which is characteristic of pregnancy, most strongly correlates with the increase in TNF-α concentration, considering that TNF-α as a marker of insulin resistance during pregnancy [45].”
From Gestational Diabetes Mellitus—Recent Literature Review (2022) · cites this paper as [45]
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Citations
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Cited by
Sorted by citations
Weight Gain During Pregnancy: Reexamining the Guidelines
Rasmussen, K. M., & Yaktine, A. L. (2009) · Cited by 4,052
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Houstis, N., Rosen, E. D., & Lander, E. S. (2006) · Nature · doi:10.1038/nature04634 · Cited by 2,525
Host Remodeling of the Gut Microbiome and Metabolic Changes during Pregnancy
Koren, O., Goodrich, J. K., Cullender, T. C., Spor, A., Laitinen, K., Kling Bäckhed, H., Gonzalez, A., Werner, J. J., Angenent, L. T., Knight, R., et al. (2012) · Cell · doi:10.1016/j.cell.2012.07.008 · Cited by 2,165
The Pathophysiology of Gestational Diabetes Mellitus
Plows, J. F., Stanley, J. L., Baker, P. N., Reynolds, C. M., & Vickers, M. H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113342 · Cited by 1,874
Catalano, P. M., & Shankar, K. (2017) · BMJ · doi:10.1136/bmj.j1 · Cited by 1,306
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Metadata
- Authors
- Kirwan, J. P., Hauguel-De Mouzon, S., Lepercq, J., Challier, J.-C., Huston-Presley, L., Friedman, J. E., Kalhan, S. C., & Catalano, P. M.
- Affiliations
- MetroHealth (US)
- Département d’Endocrinologie, Institut Cochin de Génétique Moléculaire, Paris, France
- Institut Cochin (FR)
- Hôpital Cochin (FR)
- University of Colorado Health (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-07-01
- Volume
- 51
- Issue
- 7
- Pages
- 2207-2213
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2130148279
- Cited by
- 738
- References
- 46
- Citations by year
- 2026: 22 · 2025: 26 · 2024: 24 · 2023: 33 · 2022: 36 · 2021: 34 · 2020: 36 · 2019: 47 · 2018: 37 · 2017: 34 · 2016: 38 · 2015: 37 · 2014: 40 · 2013: 38 · 2012: 33
- FWCI
- 19.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (11089, HD-22965, HD-11089)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD11089, HD-22965)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin resistance, pregnancy, TNF-α, gestational diabetes mellitus, insulin sensitivity, placental hormones, cortisol, leptin, human placental lactogen, human chorionic gonadotropin, hyperinsulinemic-euglycemic clamp, fat mass, reproductive hormones, body composition, estradiol
- MeSH terms
- Adult, Blood Glucose, Body Composition, Female, Gestational Age, Chorionic Gonadotropin, Humans, Hydrocortisone, Infusions, Intravenous, Insulin, Insulin Resistance, Placenta, Placental Lactogen, Predictive Value of Tests, Pregnancy, Prolactin, Reference Values, Regression Analysis, Tumor Necrosis Factor-alpha, Glucose Clamp Technique, Diabetes, Gestational, Glucose Intolerance, Leptin
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