Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle.
Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle.
复制标题
DOI：
10.1371/journal.pone.0019878
复制
发表时间：
2011-05-11
期刊：
影响因子：
3.7
通讯作者：
Youngren JF
中科院分区：
文献类型：
--
作者：
Masharani UB;Maddux BA;Li X;Sakkas GK;Mulligan K;Schambelan M;Goldfine ID;Youngren JF
在没有肥胖的情况下，胰岛素抵抗的发病机制尚不清楚。在肥胖中，已经发现多种应激激酶通过关键第二信使蛋白的丝氨酸磷酸化损害胰岛素信号通路。这些应激激酶通过多种机制被激活，这些机制与胰岛素靶组织和各种脂肪库的局部脂质供应过剩有关。为了探索与肥胖胰岛素抵抗有关的特定应激激酶是否可能导致非肥胖者的胰岛素抵抗，我们研究了20名健康、非肥胖、血糖正常、胰岛素敏感或胰岛素抵抗的受试者。在正血糖和高胰岛素钳夹期间获得股外侧肌活检，评估胰岛素信号和应激激酶途径的激活。通过DXA、MRI和1H-MRS评估总脂肪和局部脂肪储存和细胞内脂质（IMCL）。在耐药组肌肉中，JNK磷酸化升高（1.36±0.23 OD单位比0.78±0.10 OD单位，P<0.05），而p38 MAPK或IKKβ未被激活。胰岛素刺激后，IRS-1丝氨酸磷酸化升高（1.30±0.09比0.22±0.03 OD单位，P<0.005），酪氨酸磷酸化降低（10.97±0.95比0.89±0.50 OD单位，P<0.005）。胰岛素抵抗组的IMCL水平是胰岛素敏感组的两倍（3.26±0.48 vs 1.58±0.35% H2O峰值，P<0.05），总脂肪和腹部脂肪也比胰岛素敏感组增加。这是第一个证明非肥胖、血糖正常受试者的胰岛素抵抗与JNK通路激活相关的报告，JNK通路与IMCL增加和全身和腹部脂肪储存增加有关。虽然JNK激活与肌脂积累对代谢应激的主要影响是一致的，但需要进一步的工作来确定各种介质在该人群中胰岛素信号受损的相对贡献。
The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots. To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and 1H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKβ. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H2O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls. This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population.
登录
查看更多内容
影响因子：
8.2
作者：
Krssak, M;Petersen, KF;Roden, M
通讯作者：
Roden, M
影响因子：
15.9
作者：
Morino, K;Petersen, KF;Shulman, GI
通讯作者：
Shulman, GI
DOI：
10.1038/oby.2003.176
发表时间：
2003-11-01
期刊：
OBESITY RESEARCH
影响因子：
--
作者：
Gan, SK;Kriketos, AD;Chisholm, DJ
通讯作者：
Chisholm, DJ
影响因子：
19.6
作者：
Johansen, KL;Shubert, T;Kent-Braun, JA
通讯作者：
Kent-Braun, JA
影响因子：
15.9
作者：
Folli, F;Kahn, CR;Feener, EP
通讯作者：
Feener, EP