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Increased Skeletal Muscle TNF- and Impaired Insulin Signaling Persists in Obese GDM Women 1 Year Postpartum

¹Departments of Pediatrics and Biochemistry & Molecular Genetics, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045
²Departments of Pathobiology and Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, OH 44195
³Department of Reproductive Biology and
⁴Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland OH 44106; and
⁵Schwartz Center for Metabolism and Nutrition, MetroHealth Medical Center, Cleveland, OH 44109

Objective.: Women with 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 is 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 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·kgFFM·min^–1/µU·ml^–1). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose and plasma TNF- remained higher 1 year postpartum compared to women with NGT studied previously. Skeletal muscle TNF- mRNA was elevated 5 to 6-fold in GDM women, and remained higher 1 year postpartum. While levels of IR, 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 sub-clinical 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 as well as the risk for progression to type 2 diabetes.

Key Words: insulin sensitivity • signal transduction • diabetes • obesity • inflammation

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