Shah Ravi, Murthy Venkatesh, Pacold Michael, Danielson Kirsty, Tanriverdi Kahraman, Larson Martin G, Hanspers Kristina, Pico Alexander, Mick Eric, Reis Jared, de Ferranti Sarah, Freinkman Elizaveta, Levy Daniel, Hoffmann Udo, Osganian Stavroula, Das Saumya, Freedman Jane E
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
Department of Medicine and Radiology, University of Michigan-Ann Arbor, Ann Arbor, MI
Diabetes Care. 2017 Apr;40(4):546-553. doi: 10.2337/dc16-1354. Epub 2017 Feb 9.
Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort.
We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level). We measured association between candidate ex-RNAs and markers of adiposity. Sensitivity analyses included individuals with diabetes. In a separate cohort of 90 overweight/obese youth, we measured selected ex-RNAs and metabolites. Biology of candidate microRNAs was investigated in silico.
The mean age of FHS participants was 65.8 years (56% female), with average BMI 27.7 kg/m; participants in the youth cohort had a mean age of 15.5 years (60% female), with mean BMI 33.8 kg/m. In age-, sex-, and BMI-adjusted models across 391 ex-RNAs in FHS, 18 ex-RNAs were associated with IR (of which 16 were microRNAs). miR-122 was associated with IR and regional adiposity in adults and IR in children (independent of metabolites). Pathway analysis revealed metabolic regulatory roles for miR-122, including regulation of IR pathways (AMPK, target of rapamycin signaling, and mitogen-activated protein kinase).
These results provide translational evidence in support of an important role of ex-RNAs as novel circulating factors implicated in IR.
胰岛素抵抗（IR）是肥胖和代谢性疾病的一个标志。循环细胞外RNA（ex-RNA），即血浆中的稳定RNA分子，可能在IR中发挥作用，不过大多数关于IR中ex-RNA的研究规模较小。我们试图在一个大型社区人群队列中描述ex-RNA与代谢表型之间的关系。
我们在弗雷明汉心脏研究（FHS）后代队列第8周期的2317名无糖尿病参与者中测量了循环血浆ex-RNA，并确定ex-RNA与IR（通过循环胰岛素水平测量）之间的关联。我们测量了候选ex-RNA与肥胖标志物之间的关联。敏感性分析纳入了糖尿病患者。在一个由90名超重/肥胖青年组成的独立队列中，我们测量了选定的ex-RNA和代谢物。对候选微小RNA的生物学特性进行了计算机模拟研究。
FHS参与者的平均年龄为65.8岁（56%为女性），平均体重指数为27.7kg/m²；青年队列参与者的平均年龄为15.5岁（60%为女性），平均体重指数为33.8kg/m²。在FHS中对391种ex-RNA进行年龄、性别和体重指数调整的模型中，18种ex-RNA与IR相关（其中16种为微小RNA）。miR-122与成人的IR和局部肥胖以及儿童的IR相关（独立于代谢物）。通路分析揭示了miR-122的代谢调节作用，包括对IR通路（AMPK、雷帕霉素信号靶点和丝裂原活化蛋白激酶）的调节。
这些结果提供了转化证据，支持ex-RNA作为与IR相关的新型循环因子发挥重要作用。
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