Park K S, Ciaraldi T P, Lindgren K, Abrams-Carter L, Mudaliar S, Nikoulina S E, Tufari S R, Veerkamp J H, Vidal-Puig A, Henry R R
Department of Medicine, University of California, San Diego, La Jolla 92093, USA.
J Clin Endocrinol Metab. 1998 Aug;83(8):2830-5. doi: 10.1210/jcem.83.8.5034.
Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). To determine whether troglitazone might enhance insulin action by stimulation of PPARgamma gene expression in muscle, total PPARgamma messenger RNA (mRNA), and protein were determined in skeletal muscle cultures from nondiabetic control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days +/- troglitazone, 11.5 microM). Troglitazone treatment increased PPARgamma mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 +/- 63 to 630 +/- 100 x 10(3) copies/microg total RNA, P = 0.003) and in nondiabetic control subjects (200 +/- 42 to 490 +/- 81, P = 0.003). PPARgamma protein levels in both diabetic (4.7 +/- 1.6 to 13.6 +/- 3.0 AU/10 microg protein, P < 0.02) and nondiabetic cells (7.4 +/- 1.0 to 12.7 +/- 1.8, P < 0.05) were also upregulated by troglitazone treatment. Increased PPARgamma was associated with stimulation of human adipocyte lipid binding protein (ALBP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPARdelta, myogenin, uncoupling protein-2, or sarcomeric alpha-actin protein. In summary, we showed that troglitazone markedly induces PPARgamma, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPARgamma protein and other genes involved in glucose and lipid metabolism in skeletal muscle may account, in part, for the insulin sensitizing effects of troglitazone in type II diabetes.
除了能改善胰岛素抵抗患者的胰岛素作用外，曲格列酮还是核受体过氧化物酶体增殖物激活受体γ（PPARγ）的特异性配体。为了确定曲格列酮是否可能通过刺激肌肉中PPARγ基因表达来增强胰岛素作用，在非糖尿病对照者和II型糖尿病患者的骨骼肌培养物中，于用曲格列酮（4天，±曲格列酮，11.5微摩尔）处理培养物之前和之后，测定了总的PPARγ信使核糖核酸（mRNA）和蛋白质。曲格列酮处理使II型糖尿病患者肌肉培养物中的PPARγ mRNA水平增加高达3倍（从277±63增至630±100×10³拷贝/微克总RNA，P = 0.003），在非糖尿病对照者中也是如此（从200±42增至490±81，P = 0.003）。曲格列酮处理还上调了糖尿病（从4.7±1.6增至13.6±3.0 AU/10微克蛋白质，P < 0.02）和非糖尿病细胞（从7.4±1.0增至12.7±1.8，P < 0.05）中的PPARγ蛋白质水平。PPARγ增加与人类脂肪细胞脂质结合蛋白（ALBP）和肌肉脂肪酸结合蛋白（mFABP）mRNA的刺激有关，而甘油-3-磷酸脱氢酶、PPARδ、生肌调节因子、解偶联蛋白-2或肌节α-肌动蛋白蛋白质的mRNA没有变化。总之，我们表明曲格列酮显著诱导非糖尿病和II型糖尿病患者肌肉培养物中的PPARγ、ALBP和mFABP mRNA丰度。骨骼肌中PPARγ蛋白质和其他参与葡萄糖及脂质代谢的基因表达增加可能部分解释了曲格列酮在II型糖尿病中的胰岛素增敏作用。
