TY - JOUR
T1 - Gene expression in peripheral blood mononuclear cells from children with diabetes
AU - Kaizer, Ellen C.
AU - Glaser, Casey L.
AU - Chaussabel, Damien
AU - Banchereau, Jacques
AU - Pascual, Virginia
AU - White, Perrin C.
N1 - Funding Information:
This work was supported by the Children's Medical Center Foundation, Baylor Research Foundation, Mary Celestia Fisher Fund, and Grants U19AIO57234, P50AIO54083, and T32DK007307 from the National Institutes of Health. P.C.W. holds the Audre Newman Rapoport Distinguished Chair in Pediatric Endocrinology at the University of Texas Southwestern Medical Center. J.B. holds the Caruth Chair in Transplantation at Baylor Institute for Immunology Research.
PY - 2007/9
Y1 - 2007/9
N2 - 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 β-cell dysfunction that includes secretion of IL-1β and prostaglandins by immune effector cells, exacerbating existing β-cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy.
AB - 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 β-cell dysfunction that includes secretion of IL-1β and prostaglandins by immune effector cells, exacerbating existing β-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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U2 - 10.1210/jc.2007-0979
DO - 10.1210/jc.2007-0979
M3 - Article
C2 - 17595242
AN - SCOPUS:34548786857
SN - 0021-972X
VL - 92
SP - 3705
EP - 3711
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 9
ER -