Increased skeletal muscle tumor necrosis factor-α and impaired insulin signaling persist in obese women with gestational diabetes Mellitus 1 year postpartum
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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DOI：
10.2337/db07-1356
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发表时间：
2008-03-01
期刊：
影响因子：
7.7
通讯作者：
Catalano, Patrick M.
中科院分区：
文献类型：
--
作者：
Friedman, Jacob E.;Kirwan, John P.;Catalano, Patrick M.
妊娠期糖尿病（GDM）妇女表现出慢性进行性胰岛素抵抗，妊娠后转化为2型糖尿病的风险显著增加。然而，这种胰岛素抵抗的细胞机制尚不清楚。研究设计和方法：我们研究了9例妊娠晚期（30-36周）和产后1年伴有GDM的肥胖妇女胰岛素抵抗的进展情况。每次就诊时进行骨骼肌活检，并通过高胰岛素-正血糖钳夹技术测定胰岛素抵抗。结果：GDM女性胰岛素抵抗无明显改善(4.1 +/- 0.4 vs. 5.8 +/- 1.1 10(-2) mg中心点kg FFM中心点min（-1)/mu U中心点ml(-1)）。受试者在产后没有明显的体重减轻。体重、脂肪量、空腹血糖和血浆肿瘤坏死因子(TNF)- α在产后1年仍高于先前研究的正常血糖耐受妇女。骨骼肌tnf - α mRNA在GDM妇女中升高5 - 6倍，并在产后1年保持较高水平。虽然产后胰岛素受体（IR）、IR底物(IRS)-1和p85 α的水平有所改善，但胰岛素刺激的IR酪氨酸磷酸化和受体酪氨酸激酶活性并没有显著改善产后GDM。产后（312）Ser-IRS-1水平也没有改善，且与tnf - α mRNA相关（r(2) = 0.19, P < 0.03），与亚临床炎症和慢性骨骼肌胰岛素抵抗状态一致。结论：这些结果表明GDM女性慢性胰岛素抵抗的机制可能是由骨骼肌中IR和IRS-1信号级联的炎症增加所驱动的。这些发现对GDM妇女在随后怀孕期间的健康及其进展为2型糖尿病的风险具有重要意义。
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 I 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 center dot kg FFM center dot min(-1)/mu U center dot 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.