Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects
Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects
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DOI：
10.1007/s00125-004-1612-3
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发表时间：
2005-01-01
期刊：
影响因子：
8.2
通讯作者：
Smith, U
中科院分区：
文献类型：
--
作者：
Hammarstedt, A;Sopasakis, VR;Smith, U
目的/假设：我们研究了噻唑烷二酮的短期治疗是否可以改善非肥胖但胰岛素抵抗受试者的胰岛素敏感性，以及这是否与我们之前记录的与胰岛素抵抗相关的脂肪组织失调（IRS-1、GLUT4、PPAR、共激活剂 1 和终末分化标记物的表达减少）的改善有关。方法：10 名非糖尿病受试者接受了为期 3 周的吡格列酮治疗，这些受试者被确定脂肪细胞中 IRS-1 和 GLUT-4 蛋白含量较低（作为胰岛素抵抗的标志物）。使用正常血糖-高胰岛素钳夹技术来测量治疗前后的胰岛素敏感性。分析血清样本的葡萄糖、胰岛素、脂质、总脂联素和高分子量（HMW）脂联素水平。对腹部皮下脂肪组织进行活检，测量细胞大小，提取 mRNA 和蛋白质，并使用实时 RT-PCR 和蛋白质印迹进行定量。结果：治疗 3 周后，胰岛素敏感性得到改善，所有受试者的循环脂联素总量和 HMW 脂联素均有所增加，但对血脂没有影响。在脂肪细胞中，IRS-1和PPAR的基因和蛋白表达。共激活因子1保持不变，而脂联素、脂肪细胞P 2、解偶联蛋白2、GLUT4和肝X受体-α增加。胰岛素刺激的酪氨酸磷酸化和 p-ser-PKB/Akt 增加，而噻唑烷二酮治疗对这些非肥胖受试者的脂肪组织炎症状态没有显着影响。结论/解释：在循环 NEFA 或血脂水平没有任何变化的情况下，吡格列酮短期治疗可改善胰岛素敏感性。先前显示胰岛素抵抗会降低的几种脂肪细胞分化标志物得到增强，支持了这些个体的胰岛素抵抗与脂肪细胞终末分化受损相关的概念。
Aims/hypothesis: We examined whether shortterm treatment with a thiazolidinedione improves insulin sensitivity in non-obese but insulin-resistant subjects and whether this is associated with an improvement in dysregulated adipose tissue ( reduced expression of IRS-1, GLUT4, PPAR. co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance. Methods: Ten nondiabetic subjects, identified as having low IRS-1 and GLUT-4 protein in adipose cells as markers of insulin resistance, underwent 3 weeks of treatment with pioglitazone. The euglycaemic - hyperinsulinaemic clamp technique was used to measure insulin sensitivity before and after treatment. Serum samples were analysed for glucose, insulin, lipids, total and high-molecular-weight (HMW) adiponectin levels. Biopsies from abdominal subcutaneous adipose tissue were taken, cell size measured, mRNA and protein extracted and quantified using real-time RT-PCR and Western blot. Results: Insulin sensitivity was improved after 3 weeks treatment and circulating total as well as HMW adiponectin increased in all subjects, while no effect was seen on serum lipids. In the adipose cells, gene and protein expression of IRS-1 and PPAR. co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor-alpha increased. Insulin-stimulated tyrosine phosphorylation and p-ser-PKB/Akt increased, while no significant effect of thiazolidinedione treatment was seen on the inflammatory status of the adipose tissue in these non-obese subjects. Conclusions/interpretation: Short-term treatment with pioglitazone improved insulin sensitivity in the absence of any changes in circulating NEFA or lipid levels. Several markers of adipose cell differentiation, previously shown to be reduced in insulin resistance, were augmented, supporting the concept that insulin resistance in these individuals is associated with impaired terminal differentiation of the adipose cells.