Das Swapan K, Chu Winston S, Mondal Ashis K, Sharma Neeraj K, Kern Philip A, Rasouli Neda, Elbein Steven C
Endocrinology Section, Medicine and Research Services, Central Arkansas Veterans Healthcare System, John L. McClellan Memorial Veterans Hospital, 4300 W. 7th St., Little Rock, AR 72205, USA.
Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E393-400. doi: 10.1152/ajpendo.90355.2008. Epub 2008 Jun 10.
Obesity and elevated cytokine secretion result in a chronic inflammatory state and may cause the insulin resistance observed in type 2 diabetes. Recent studies suggest a key role for endoplasmic reticulum stress in hepatocytes and adipocytes from obese mice, resulting in reduced insulin sensitivity. To address the hypothesis that thiazolidinediones, which improve peripheral insulin sensitivity, act in part by reducing the endoplasmic reticulum stress response, we tested subcutaneous adipose tissue from 20 obese volunteers treated with pioglitazone for 10 wk. We also experimentally induced endoplasmic reticulum stress using palmitate, tunicamycin, and thapsigargin in the human HepG2 liver cell line with or without pioglitazone pretreatment. We quantified endoplasmic reticulum stress response by measuring both gene expression and phosphorylation. Pioglitazone significantly improved insulin sensitivity in human volunteers (P = 0.002) but did not alter markers of endoplasmic reticulum stress. Differences in pre- and posttreatment endoplasmic reticulum stress levels were not correlated with changes in insulin sensitivity or body mass index. In vitro, palmitate, thapsigargin, and tunicamycin but not oleate induced endoplasmic reticulum stress in HepG2 cells, including increased transcripts CHOP, ERN1, GADD34, and PERK, and increased XBP1 splicing along with phosphorylation of eukaryotic initiation factor eIF2alpha, JNK1, and c-jun. Although patterns of endoplasmic reticulum stress response differed among palmitate, tunicamycin, and thapsigargin, pioglitazone pretreatment had no significant effect on any measure of endoplasmic reticulum stress, regardless of the inducer. Together, our data suggest that improved insulin sensitivity with pioglitazone is not mediated by a reduction in endoplasmic reticulum stress.
肥胖和细胞因子分泌增加会导致慢性炎症状态，并可能引发2型糖尿病中出现的胰岛素抵抗。最近的研究表明，内质网应激在肥胖小鼠的肝细胞和脂肪细胞中起关键作用，导致胰岛素敏感性降低。为了验证噻唑烷二酮类药物可通过部分降低内质网应激反应来改善外周胰岛素敏感性这一假说，我们检测了20名接受吡格列酮治疗10周的肥胖志愿者的皮下脂肪组织。我们还在人肝癌细胞系HepG2中，使用棕榈酸、衣霉素和毒胡萝卜素，在有或没有吡格列酮预处理的情况下，通过实验诱导内质网应激。我们通过测量基因表达和磷酸化来量化内质网应激反应。吡格列酮显著改善了人类志愿者的胰岛素敏感性（P = 0.002），但并未改变内质网应激标志物。治疗前后内质网应激水平的差异与胰岛素敏感性或体重指数的变化无关。在体外，棕榈酸、毒胡萝卜素和衣霉素而非油酸诱导了HepG2细胞中的内质网应激，包括CHOP、ERN1、GADD34和PERK转录本增加，XBP1剪接增加以及真核起始因子eIF2α、JNK1和c-jun磷酸化增加。尽管棕榈酸、衣霉素和毒胡萝卜素的内质网应激反应模式不同，但无论诱导剂如何，吡格列酮预处理对任何内质网应激指标均无显著影响。总之，我们的数据表明，吡格列酮改善胰岛素敏感性并非通过降低内质网应激介导。
