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Gene Expression in Peripheral Blood Mononuclear Cells from Children with Diabetes

Department of Pediatrics (E.C.K., P.C.W.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Baylor Institute for Immunology Research (C.L.G., D.C., J.B., V.P.), Dallas, Texas 75204

Address all correspondence and requests for reprints to: Perrin C. White, M.D., University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063. E-mail: Perrin.White{at}utsouthwestern.edu.

Objective: 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.

Research Design and Methods: 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.

Results: 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.

Conclusion: T1D and T2D likely share a final common pathway for ß-cell dysfunction that includes secretion of IL-1ß and prostaglandins by immune effector cells, exacerbating existing ß-cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy.

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