Keller Mark P, Choi YounJeong, Wang Ping, Davis Dawn Belt, Rabaglia Mary E, Oler Angie T, Stapleton Donald S, Argmann Carmen, Schueler Kathy L, Edwards Steve, Steinberg H Adam, Chaibub Neto Elias, Kleinhanz Robert, Turner Scott, Hellerstein Marc K, Schadt Eric E, Yandell Brian S, Kendziorski Christina, Attie Alan D
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53076, USA.
Genome Res. 2008 May;18(5):706-16. doi: 10.1101/gr.074914.107. Epub 2008 Mar 17.
Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 wk of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between (2)H(2)O incorporation into islet DNA in vivo and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including Igf2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation.
胰岛素抵抗是2型糖尿病发生所必需的，但并不充分。当胰腺β细胞无法通过增加β细胞量或增加胰岛素分泌来增加胰岛素产生以补偿胰岛素抵抗时，糖尿病就会发生。胰岛素靶组织与β细胞之间的通讯可能启动这种代偿反应。组织间基因表达的相关变化可为这种细胞间通讯提供证据。我们分析了肥胖诱导的糖尿病抵抗和糖尿病易感品系小鼠在糖尿病发病前后六个组织中的基因表达。我们研究了mRNA丰度的相关结构，确定了105个共表达基因模块。我们提供了一个交互式基因网络模型，展示了六个组织内和组织间表达模块之间的相关结构。该资源还提供了一个可搜索的数据库，包含瘦素和肥胖的糖尿病抵抗和糖尿病易感小鼠在4周龄和10周龄时六个组织中所有基因的基因表达谱。胰岛中的一个细胞周期调节模块可预测糖尿病易感性。该模块可预测胰岛复制；我们发现体内（2）H（2）O掺入胰岛DNA与细胞周期模块的表达模式之间存在很强的相关性。这种模式与胰岛素靶组织中几个单个基因的模式高度相关，包括已被证明可促进β细胞增殖的Igf2，这表明这些基因可能在胰岛素抵抗和β细胞增殖之间提供联系。
