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

Abstract

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-α remained higher 1 year postpartum compared to women with NGT studied previously. Skeletal muscle TNF-α mRNA was elevated 5 to 6-fold in GDM women, and remained higher 1 year postpartum. While levels of IR, IRS-1 and p85α 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-α 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.