Del Aguila L F, Krishnan R K, Ulbrecht J S, Farrell P A, Correll P H, Lang C H, Zierath J R, Kirwan J P
Noll Physiological Research Center, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Am J Physiol Endocrinol Metab. 2000 Jul;279(1):E206-12. doi: 10.1152/ajpendo.2000.279.1.E206.
Physiological stress associated with muscle damage results in systemic insulin resistance. However, the mechanisms responsible for the insulin resistance are not known; therefore, the present study was conducted to elucidate the molecular mechanisms associated with insulin resistance after muscle damage. Muscle biopsies were obtained before (base) and at 1 h during a hyperinsulinemic-euglycemic clamp (40 mU x kg(-1) x min(-1)) in eight young (age 24+/-1 yr) healthy sedentary (maximal O(2) consumption, 49.7+/-2.4 ml x kg(-1) x min(-1)) males before and 24 h after eccentric exercise (ECC)-induced muscle damage. To determine the role of cytokines in ECC-induced insulin resistance, venous blood samples were obtained before (control) and 24 h after ECC to evaluate ex vivo endotoxin-induced mononuclear cell secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. Glucose disposal was 19% lower after ECC (P<0.05). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation was 45% lower after ECC (P<0.05). Insulin-stimulated phosphatidylinositol (PI) 3-kinase, Akt (protein kinase B) serine phosphorylation, and Akt activity were reduced 34, 65, and 20%, respectively, after ECC (P < 0.05). TNF-alpha, but not IL-6 or IL-1beta production, increased 2.4-fold 24 h after ECC (P<0.05). TNF-alpha production was positively correlated with reduced insulin action on PI 3-kinase (r = 0.77, P = 0.04). In summary, the physiological stress associated with muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase, presumably leading to decreased insulin-mediated glucose uptake. Although more research is needed on the potential role for TNF-alpha inhibition of insulin action, elevated TNF-alpha production after muscle damage may impair insulin signal transduction.
与肌肉损伤相关的生理应激会导致全身胰岛素抵抗。然而，导致胰岛素抵抗的机制尚不清楚；因此，本研究旨在阐明肌肉损伤后与胰岛素抵抗相关的分子机制。在8名年轻（24±1岁）健康久坐（最大耗氧量，49.7±2.4 ml·kg⁻¹·min⁻¹）男性进行离心运动（ECC）诱导的肌肉损伤之前（基础状态）和损伤后24小时，在高胰岛素-正常血糖钳夹（40 mU·kg⁻¹·min⁻¹）期间的1小时采集肌肉活检样本。为了确定细胞因子在ECC诱导的胰岛素抵抗中的作用，在ECC之前（对照）和之后24小时采集静脉血样本，以评估内毒素诱导的单核细胞体外分泌肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和IL-1β的情况。ECC后葡萄糖处置降低了19%（P<0.05）。ECC后胰岛素刺激的胰岛素受体底物（IRS）-1酪氨酸磷酸化降低了45%（P<0.05）。ECC后胰岛素刺激的磷脂酰肌醇（PI）3-激酶、Akt（蛋白激酶B）丝氨酸磷酸化和Akt活性分别降低了34%、65%和20%（P<0.05）。ECC后24小时，TNF-α而非IL-6或IL-1β的产生增加了2.4倍（P<0.05）。TNF-α的产生与胰岛素对PI 3-激酶的作用降低呈正相关（r = 0.77，P = 0.04）。总之，与肌肉损伤相关的生理应激损害了胰岛素对IRS-1、PI 3-激酶和Akt激酶的刺激，可能导致胰岛素介导的葡萄糖摄取减少。尽管需要对TNF-α抑制胰岛素作用的潜在作用进行更多研究，但肌肉损伤后TNF-α产生升高可能会损害胰岛素信号转导。
