HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-1356v1 57/3/606    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Friedman, J. E. Articles by Catalano, P. M. PubMed PubMed Citation Articles by Friedman, J. E. Articles by Catalano, P. M. Social Bookmarking                What's this?

Increased Skeletal Muscle Tumor Necrosis Factor- and Impaired Insulin Signaling Persist in Obese Women With Gestational Diabetes Mellitus 1 Year Postpartum

¹ Departments of Pediatrics and Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, Colorado
² Departments of Pathobiology and Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio
³ Department of Reproductive Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio
⁴ Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio
⁵ Schwartz Center for Metabolism and Nutrition, MetroHealth Medical Center, Cleveland, Ohio

Address correspondence and reprint requests to Jacob E. Friedman, PhD, Departments of Pediatrics and Biochemistry & Molecular Genetics, University of Colorado Denver, P.O. Box 6511, MS-8106, Aurora, CO 80045. E-mail: jed.friedman{at}uchsc.edu

Key Words: ELISA, enzyme-linked immunosorbent assay • FFA, free fatty acid • GDM, gestational diabetes mellitus • IR, insulin receptor • IRS, insulin receptor substrate • IRTK, insulin receptor tyrosine kinase • ISI, insulin sensitivity index • NGT, normal glucose tolerance • OGTT, oral glucose tolerance test • PI3K, phosphoinositide 3-kinase

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 · kg FFM · min^–1/µU · ml^–1). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose, and plasma tumor necrosis factor (TNF)- remained higher 1 year postpartum than seen in previously studied normal glucose-tolerant women. Skeletal muscle TNF- 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 improved postpartum, insulin-stimulated IR tyrosine phosphorylation and receptor tyrosine kinase activity did not significantly improve postpartum in GDM. The levels of ³¹²Ser-IRS-1 also did not improve postpartum and correlated with TNF- mRNA (r² = 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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?