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

Abstract

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. 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 312 Ser-IRS-1 also did not improve postpartum and correlated with TNF-␣ mRNA (r 2 ϭ 0.19, P Ͻ 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. Diabetes 57:606-613, 2008

Cytokine Levels in Gestational Diabetes Mellitus: a Systematic Review of the Literature

“…After screening titles and abstracts, 31 references were selected for full-text reading [16][17][18][19][20][21][22][23][24][25][26][27][28][29][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] and 23 citations reporting on 22 studies were included in this review (Fig. 2).…”

Living in a Box or Call of the Wild? Revisiting Lifetime Inactivity and Sarcopenia

“…In addition, caloric restriction (CR) reversed age-related increases in pro-inflammatory mediators in the kidney, heart, and brain (22). TNF-a contributes to IRS-1 phosphorylation and insulin resistance, possibly via AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase signaling (24, 35,129). Chronic inflammation also increased tissue damage, and has been noted with disuse and aging (71).…”

“…By the year 2040 up to 15 million Americans will be age 85 or older (117). Indeed, the number of persons aged > 65 years is expected to double from approximately 35 Sarcopenia is traditionally defined as a degenerative loss of muscle mass and strength. Muscle atrophy is considered a central part of an age-related process of remodeling in skeletal muscle, whereby changes in muscle architecture occur.…”

ENDOCRINOLOGY OF PREGNANCY: Gestational diabetes mellitus: definition, aetiological and clinical aspects

“…However, a direct effect of hPL on mother insulin sensitivity has not been demonstrated. In addition, changes in inflammatory circulating factors such as tumour necrosis factor alpha (TNFa) may also be involved in pregnancy-associated insulin resistance (25). Kirwan et al reported that the level of placental TNFa is the most important determinant of insulin resistance during pregnancy independently from fat mass changes (26).…”