Increased Skeletal Muscle Tumor Necrosis Factor-α and Impaired Insulin Signaling Persist in Obese Women With Gestational Diabetes Mellitus 1 Year Postpartum
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OBJECTIVE: Women with gestational diabetes mellitus (GDM) demonstrate chronic and progressive insulin resistance and a markedly increased risk of converting to type 2 diabetes after pregnancy. However, the cellular mechanisms underlying this insulin resistance are unknown. RESEARCH DESIGN AND METHODS: We investigated the progression of insulin resistance in nine obese women with GDM during late pregnancy (30-36 weeks) and 1 year postpartum. Skeletal muscle biopsies were obtained at each visit, and insulin resistance was determined by the hyperinsulinemic-euglycemic clamp technique. RESULTS: Insulin resistance was not significantly improved in GDM women (4.1 +/- 0.4 vs. 5.8 +/- 1.1 10(-2) mg x kg FFM x min(-1)/microU x ml(-1)). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose, and plasma tumor necrosis factor (TNF)-alpha remained higher 1 year postpartum than seen in previously studied normal glucose-tolerant women. Skeletal muscle TNF-alpha mRNA was elevated five- to sixfold in GDM women and remained higher 1 year postpartum. While levels of insulin receptor (IR), IR substrate (IRS)-1, and p85 alpha improved postpartum, insulin-stimulated IR tyrosine phosphorylation and receptor tyrosine kinase activity did not significantly improve postpartum in GDM. The levels of (312)Ser-IRS-1 also did not improve postpartum and correlated with TNF-alpha mRNA (r(2) = 0.19, P < 0.03), consistent with a state of subclinical inflammation and chronic skeletal muscle insulin resistance. CONCLUSIONS: These results suggest the mechanisms underlying chronic insulin resistance in GDM women may be driven by increased inflammation that impinges on the IR and IRS-1 signaling cascade in skeletal muscle. These findings have important implications for the health of GDM women during subsequent pregnancies and their risk for progression to type 2 diabetes.
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Many molecular changes in insulin signaling in GDM persist beyond pregnancy.
“Many of these molecular changes persist beyond pregnancy [86].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [86]
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- Authors
- Friedman, J. E., Kirwan, J. P., Jing, M., Presley, L., & Catalano, P. M.
- Affiliations
- University of Colorado Denver (US)
- Cleveland Clinic (US)
- Case Western Reserve University (US)
- MetroHealth Medical Center (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-03-01
- Volume
- 57
- Issue
- 3
- Pages
- 606-613
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4697130
- OpenAlex
- W2103887497
- Cited by
- 98
- References
- 68
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 1 · 2023: 8 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 9
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (KL2TR000440)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK048520, DK-62115)
- National Center for Research Resources (M01RR000080, RR 00080)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD11089, R01HD022965)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- gestational diabetes mellitus, insulin resistance, TNF-α, skeletal muscle, postpartum period, obesity, type 2 diabetes risk, insulin receptor tyrosine phosphorylation, IRS-1 serine phosphorylation, insulin receptor substrate, subclinical inflammation, hyperinsulinemic-euglycemic clamp
- MeSH terms
- Adult, Female, Humans, Inflammation, Insulin, Insulin Resistance, Obesity, Pregnancy, Risk Factors, Time Factors, Tumor Necrosis Factor-alpha, Signal Transduction, Diabetes, Gestational, Muscle, Skeletal, Postpartum Period
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