Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity
Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity
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DOI：
10.2337/db14-1945
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发表时间：
2015-10-01
期刊：
影响因子：
7.7
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
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作者：
Ozcan, Lale;Xu, Xiaoming;Tabas, Ira
肥胖引起的 2 型糖尿病 (T2D) 的患病率在全球范围内不断增加，需要新的治疗策略。我们最近发现，肥胖激活了一种以前未知的途径，该途径促进肝脏葡萄糖产生过多（HGP）和肝细胞中胰岛素信号传导缺陷，从而导致肥胖症中高血糖和胰岛素抵抗的加剧。这条新途径的核心是激酶级联，涉及钙/钙调蛋白依赖性蛋白激酶 II (CaMKII)、p38 α 丝裂原激活蛋白激酶 (MAPK) 和 MAPKAPK2/3 (MK2/3)。对这些激酶进行基因抑制可改善肥胖小鼠的新陈代谢。在此，我们报告用变构 MK2/3 抑制剂化合物 (cmpd) 28 治疗肥胖胰岛素抵抗小鼠，可通过抑制过量的 HGP 和增强胰岛素信号传导来改善葡萄糖稳态。 cmpd 28 所见的代谢改善与领先的 T2D 药物二甲双胍相加，但与显性失活 MK2 没有相加，这表明其作用机制是靶向的。变构 MK2/3 抑制剂代表了一种潜在的治疗 T2D 的新方法，该方法高度基于机制，与人类 T2D 相关，并且预计可以避免当前 T2D 药物出现的某些不良反应。
The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide, and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway that promotes both excessive hepatic glucose production (HGP) and defective insulin signaling in hepatocytes, leading to exacerbation of hyperglycemia and insulin resistance in obesity. At the hub of this new pathway is a kinase cascade involving calcium/calmodulin-dependent protein kinase II (CaMKII), p38 alpha mitogen-activated protein kinase (MAPK), and MAPKAPK2/3 (MK2/3). Genetic-based inhibition of these kinases improves metabolism in obese mice. Here, we report that treatment of obese insulin-resistant mice with an allosteric MK2/3 inhibitor, compound (cmpd) 28, ameliorates glucose homeostasis by suppressing excessive HGP and enhancing insulin signaling. The metabolic improvement seen with cmpd 28 is additive with the leading T2D drug, metformin, but it is not additive with dominant-negative MK2, suggesting an on-target mechanism of action. Allosteric MK2/3 inhibitors represent a potentially new approach to T2D that is highly mechanism based, has links to human T2D, and is predicted to avoid certain adverse effects seen with current T2D drugs.