J Biol Chem：研究者开发出治疗II型糖尿病的新药

治疗II型糖尿病的药物可以促使体重增加、骨折以及心血管疾病，但是近日，来自美国华盛顿大学医学院的研究者研究表明，一种研究药物的使用可以导致小鼠增加对胰岛素的敏感性，而没有任何副作用。这项研究刊登在了国际杂志Journal of Biological Chemistry上，新研究将为治疗胰岛素耐受性以及糖尿病提供新的分子靶点。

当前的糖尿病用药可以激活一种受体，进而提高对胰岛素的敏感性，但是也会有一些副作用，比如可以使部分人产生别的健康问题从而中断治疗。研究者Finck表示，尽管这些药物很有效，我们也会寻找一些新的胰岛素敏感疗法以避免产生相同的受体。

这种药物可以改善小鼠的血糖水平以及胰岛素的耐受性，市场上的药物罗格列酮和吡格列酮也可以达到这样的疗效，三种药物的效果看似一样，但是MSD-0602并不会结合并且激活受体PPARγ。这种新药可以仅仅附着在线粒体上，影响其发挥细胞能量工厂的功能，而且这种药物也有抗炎的效果，研究者发现这种药物也可以改善包括肌肉细胞、肝脏等细胞在内的细胞对胰岛素的敏感性。

下一步，研究者将试图去识别结合到线粒体膜上的蛋白质，更为深入的治疗方法将会使得新药只是结合到细胞线粒体的蛋白质上，而避免激活PPARγ途径。目前研究者正在使用此种新药进行II期临床试验，并且深入研究这种药物如何更好地控制血糖的水平。

编译自：Investigational Diabetes Drug May Have Fewer Side Effects

编译者：T.Shen

doi:10.1074/jbc.M112.363960
PMC:
PMID:

Insulin Resistance and Metabolic Derangements in Obese Mice are Ameliorated by a Novel Peroxisome Proliferator-Activated Receptor γ-sparing Thiazolidinedione

Zhouji Chen1, Patrick A. Vigueira1, Kari T. Chambers1, Angela M. Hall1, Mayurranjan S. Mitra1, Nathan Qi2, William G. McDonald3, Jerry R. Colca3, Rolf F. Kletzien3 and Brian N. Finck4,*

Currently-approved thiazolidinediones (TZDs) are effective insulin-sensitizing drugs that may have efficacy for treatment of a variety of metabolic and inflammatory diseases, but their use is limited by side effects that are mediated through ectopic activation of the peroxisome proliferator-activated receptor γ (PPARγ). Emerging evidence suggests that the potent anti-diabetic efficacy of TZDs can be separated from the ability to serve as ligands for PPARγ. A novel TZD analog (MSDC-0602) with very low affinity for binding and activation of PPARγ was evaluated for its effects on insulin resistance in obese mice. MSDC-0602 treatment markedly improved several measures of multi-organ insulin sensitivity, adipose tissue inflammation, and hepatic metabolic derangements, including suppressing hepatic lipogenesis and gluconeogenesis. These beneficial effects were mediated, at least in part, via direct actions on hepatocytes and were preserved in hepatocytes from liver-specific PPARγ-/- mice, indicating that PPARγ was not required to suppress these pathways. In conclusion, the beneficial pharmacology exhibited by MSDC-0602 on insulin sensitivity suggests that PPARγ-sparing TZDs are effective for treatment of type 2 diabetes with reduced risk of PPARγ-mediated side effects.