Oral Elif A, Reilly Shannon M, Gomez Andrew V, Meral Rasimcan, Butz Laura, Ajluni Nevin, Chenevert Thomas L, Korytnaya Evgenia, Neidert Adam H, Hench Rita, Rus Diana, Horowitz Jeffrey F, Poirier BreAnne, Zhao Peng, Lehmann Kim, Jain Mohit, Yu Ruth, Liddle Christopher, Ahmadian Maryam, Downes Michael, Evans Ronald M, Saltiel Alan R
Division of Metabolism, Endocrinology, and Diabetes, Department of Medicine, and Brehm Center for Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Departments of Medicine and Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
Cell Metab. 2017 Jul 5;26(1):157-170.e7. doi: 10.1016/j.cmet.2017.06.006.
Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.
大量研究表明肥胖与2型糖尿病之间存在炎症关联。炎症激酶IKKɛ和TBK1在肥胖状态下会升高；在肥胖小鼠中抑制它们可减轻体重、改善胰岛素抵抗、缓解脂肪肝和炎症。在此，我们在一项概念验证性随机、双盲、安慰剂对照研究中，对42名患有2型糖尿病和非酒精性脂肪肝病的肥胖患者使用了IKKɛ和TBK1的抑制剂氨来呫诺进行研究。用氨来呫诺治疗患者后，糖化血红蛋白和果糖胺有统计学意义的显著降低。有趣的是，一部分药物反应者在胰岛素敏感性和肝脂肪变性方面也有所改善。该亚组在基线时活检的皮下脂肪中有独特的炎症基因表达特征。他们对氨来呫诺的反应还呈现出独特的基因表达变化模式，这与能量消耗增加一致。这些数据共同表明，IKKɛ和TBK1的双特异性抑制剂可能是特定亚组患者代谢疾病的有效治疗方法。
