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  • Effect of pioglitazone trea...
    Das, Swapan K; Chu, Winston S; Mondal, Ashis K; Sharma, Neeraj K; Kern, Philip A; Rasouli, Neda; Elbein, Steven C

    American journal of physiology: endocrinology and metabolism, 08/2008, Letnik: 295, Številka: 2
    Journal Article

    1 Endocrinology Section, Medicine and Research Services, Central Arkansas Veterans Healthcare System, Little Rock; and 2 Division of Endocrinology and Metabolism, Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas Submitted 10 April 2008 ; accepted in final form 6 June 2008 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 eIF2 , 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. insulin sensitivity; fatty acid; thiazolidinediones; type 2 diabetes; obesity Address for reprint requests and other correspondence: S. C. Elbein or Swapan K. Das, Univ. of Arkansas for Medical Sciences, Endocrinology 111J-1/LR, John L. McClellan Memorial Veterans Hospital, 4300 W. 7th St., Little Rock, AR 72205 (e-mail: elbeinstevenc{at}uams.edu )