Kaizer Ellen C, Glaser Casey L, Chaussabel Damien, Banchereau Jacques, Pascual Virginia, White Perrin C
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA.
J Clin Endocrinol Metab. 2007 Sep;92(9):3705-11. doi: 10.1210/jc.2007-0979. Epub 2007 Jun 26.
We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency, and hyperglycemia.
Microarray analysis was performed on peripheral blood mononuclear cells from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D), and 24 healthy controls. One- and 4-month follow-up samples were obtained from 20 of the T1D patients.
Microarray analysis identified 282 genes differing in expression between newly diagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of IL1B, early growth response gene 3, and prostaglandin-endoperoxide synthase 2 resolved within 4 months of insulin therapy and were also observed in T2D, suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81 of 282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D.
T1D and T2D likely share a final common pathway for beta-cell dysfunction that includes secretion of IL-1beta and prostaglandins by immune effector cells, exacerbating existing beta-cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy.
我们推测1型糖尿病（T1D）伴有外周血单个核细胞基因表达的变化，这是由于适应性和先天性免疫失调、对免疫失调的反调节反应、胰岛素缺乏和高血糖所致。
对43例新诊断的T1D患者、12例新诊断的2型糖尿病（T2D）患者和24名健康对照者的外周血单个核细胞进行微阵列分析。从20例T1D患者中获取1个月和4个月的随访样本。
微阵列分析确定，在错误发现率为0.05时，新诊断的T1D患者与对照者之间有282个基因的表达存在差异。胰岛素治疗4个月内，白细胞介素1β（IL1B）、早期生长反应基因3和前列腺素内过氧化物合酶2的表达变化得到解决，且在T2D中也观察到这些变化，这表明它们是由高血糖引起的。利用一个知识库，282个基因中的81个可被置于一个相互关联基因的网络中，这些基因的预测功能包括细胞凋亡和细胞增殖。IL1B和MYC癌基因是该网络中连接性最高的基因。IL1B在T1D和T2D中均高度过表达，而MYC仅在T1D中表达失调。
T1D和T2D可能共享β细胞功能障碍的最终共同途径，包括免疫效应细胞分泌IL-1β和前列腺素，加剧现有的β细胞功能障碍，并导致进一步的高血糖。这些结果确定了糖尿病疾病修饰治疗的几个靶点以及监测治疗效果的潜在生物标志物。
