Identification and function analysis of risk pathways in subjects with a family history of type 2 diabetes

doi:10.16150/j.1671-2870.2016.05.009

Abstract

Abstract: Objective: To investigate the relationship between family history of type 2 diabetes (T2D) and insulin resistance. Bioinformatic approach was used to identify the risk pathways in subjects with a family history (FH) of T2D, and then functions of key driver genes were analyzed using gene expression profiles from Gene Expression Omnibus (GEO). Methods: Gene expression data set was retrieved using GSE 25462 at NCBI GEO. The data set contained 26 normoglycemic individuals with 1 or both parents having T2D (FH⁺) and 15 normoglycemic individuals with no one having diabetes in first-degree relatives(FH^-). Insulin sensitivity was assessed by the Bergman minimal model from intravenous glucose tolerance test. Gene expression in quadriceps muscle biopsies was analyzed to identify the differentially expressed genes associated with insulin resistance. Gene set enrichment analysis and identification of risk pathways were used to explore the pathogenesis of T2D at molecular level. Results: Compared with FH^- subjects, FH⁺ subjects were insulin resistant as demonstrated by a 41% reduction in insulin sensitivity(P<0.05). A total of 202 genes showed differential expression in our analysis. Five biological pathways of gene set enrichment in FH⁺ were identified, including hematopoiesis from multipotent stem cells, hematopoiesis from pluripotent stem cells, role of JAK1 and JAK3 in c-cytokine signaling, antiproliferative role of TOB in T cell signaling, and B cell development. Conclusions: Family history of T2D in normal subjects is associated with insulin resistance. Significantly enriched pathways identified by gene set enrichment analysis reveale that pathogenesis of T2D is associated with function of multipotent stem cells and immune status.

Key words: Diabetes, type 2, Diabetes family history, Risk pathways, Functional enrichment analysis

CLC Number:

R587.1

WANG Wei, WU Liping, ZHAO Yongju, CAO Jiumei. Identification and function analysis of risk pathways in subjects with a family history of type 2 diabetes[J]. Journal of Diagnostics Concepts & Practice, 2016, 15(05): 477-481.

References

[1] Chen GY, Li L, Dai F, et al.Prevalence of and risk factors for type 2 diabetes mellitus in hyperlipidemia in China[J]. Med Sci Monit,2015,21:2476-2484.
[2] Yang SH, Dou KF, Song WJ.Prevalence of diabetes among men and women in China[J]. N Engl J Med,2010, 362(25):2425-2426.
[3] Cornelis MC, Zaitlen N, Hu FB, et al.Genetic and environmental components of family history in type 2 diabetes[J]. Hum Genet,2015,134(2):259-267.
[4] Greig SL, Scott LJ.Insulin degludec/liraglutide: A review in type 2 diabetes[J]. Drugs,2015,75(13):1523-1534.
[5] Jin W, Goldfine AB, Boes T, et al.Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance[J]. J Clin Invest,2011, 121(3):918-929.
[6] Diboun I, Wernisch L, Orengo CA, et al.Microarray analysis after RNA amplification can detect pronounced differences in gene expression using limma[J]. BMC Genomics,2006,7:252.
[7] Papazafiropoulou AK, Papanas N, Melidonis A, et al. Family history of type 2 diabetes: does having a diabetic parent increase the risk?[J/OL]. Curr Diabetes Rev,2015-10-22[2016-06-20].http://www.ncbi.nlm.nih.gov/pubmed/26490432.
[8] Himsworth HP.Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types. 1936[J]. Int J Epidemiol,2013,42(6):1594-1598.
[9] Karnieli O, Izhar-Prato Y, Bulvik S, et al.Generation of insulin-producing cells from human bone marrow mesen-chymal stem cells by genetic manipulation[J]. Stem Cells,2007,25(11):2837-2844.
[10] Ding Y, Xu D, Feng G, et al.Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and-9[J]. Diabetes,2009,58(8):1797-1806.
[11] Lee RH, Seo MJ, Reger RL, et al.Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice[J]. Proc Natl Acad Sci U S A,2006,103(46):17438-17443.
[12] Duran-Salgado MB, Rubio-Guerra AF.Diabetic nephropathy and inflammation[J]. World J Diabetes,2014, 5(3):393-398.
[13] Wu CC, Sytwu HK, Lu KC, et al.Role of T cells in type 2 diabetic nephropathy[J]. Exp Diabetes Res,2011,2011:514738.
[14] Abouzeid S, Sherif N.Role of alteration in Treg/Th17 cells' balance in nephropathic patients with Type 2 diabetes mellitus[J]. Electron Physician,2015,7(8):1613-1618.
[15] Zhai X, Qian G, Wang Y, et al.Elevated B cell activation is associated with type 2 diabetes development in obese subjects[J]. Cell Physiol Biochem,2016,38(3):1257-1266.
[16] Li D, Lu Z, Jia J, et al.MiR-124 is related to podocytic adhesive capacity damage in STZ-induced uninephrectomized diabetic rats[J]. Kidney Blood Press Res,2013, 37(4-5):422-431.
[17] Li D, Lu Z, Jia J, et al.Curcumin ameliorates podocytic adhesive capacity damage under mechanical stress by inhibiting miR-124 expression[J]. Kidney Blood Press Res,2013,38(1):61-71.