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Cited by 738Gestational Diabetes Research and ManagementPregnancy and preeclampsia studiesAdipokines, Inflammation, and Metabolic Diseases

TNF-α Is a Predictor of Insulin Resistance in Human Pregnancy

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Kirwan, John P., Hauguel-De Mouzon, Sylvie, Lepercq, Jacques, Challier, Jean-Claude, Huston-Presley, Larraine, Friedman, Jacob E., Kalhan, Satish C., Catalano, Patrick M.·2002·Diabetes
DOI 10.2337/diabetes.51.7.2207
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Abstract

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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  • Placental gene expression of TNF-α, IL-1β and their receptors has been reported to be increased in GDM.

    “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]

    The Discussion reports that placentas from women with GDM released more TNF-α than those from women with normal glucose tolerance in response to glucose. That supports an increase in placental TNF-α release, but not the claimed increase in placental gene expression of TNF-α, IL-1β, or their receptors; the cited passages do not report those gene-expression measurements. Page numbers were not available in our copy. (LLM, conf=0.82)

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  • Excess visceral adiposity does not merely represent a passive energy reserve; rather, it acts as an active immunometabolic organ.

    “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]

    The Discussion (page unavailable) says fat cells secrete TNF-α and leptin, supporting the point that adipose tissue is metabolically active rather than merely an energy reserve. It does not examine visceral adiposity specifically or establish that excess visceral fat acts as an immunometabolic organ; for the pregnancy-related TNF-α increase studied here, it identifies the placenta as the apparent primary source. (LLM, conf=0.86)

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  • Plasma TNF-α is strongly correlated with insulin resistance.

    “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]

  • Kirwan et al. stated that an increase in insulin resistance characteristic of pregnancy most strongly correlates with the increase in TNF-α concentration.

    “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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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)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2002-07-01
Volume
51
Issue
7
Pages
2207-2213
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.51.7.2207
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
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 › Epidemiology › 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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