title: Assessment of DNA damage and mRNA/miRNA transcriptional expression profiles in hyperglycemic versus non-hyperglycemic patients with type 2 diabetes mellitus.
abstract: The development of type 2 diabetes mellitus (T2D) is associated with a number of genetic and environmental factors. Hyperglycemia, a T2D hallmark, is related to several metabolic complications, comorbidities and increased DNA damage. However, the molecular alterations of a proper glucose control are still unclarified. In this study, we aimed to evaluate DNA damage (comet assay), as well as to compare the transcriptional expression (mRNA and miRNA analyzed by the microarray technique) displayed by peripheral blood mononuclear cells (PBMCs) from three distinct groups: hyperglycemic T2D patients (T2D-H, n=14), non-hyperglycemic T2D patients (T2D-N, n=15), and healthy non-diabetic individuals (n=16). The comet assay revealed significantly (p<0.05) higher levels of DNA damage in T2D-H group compared to both T2D-N and control groups, while a significant difference was not observed between the control and T2D-N groups. After bioinformatics analysis, the differentially expressed mRNAs were subjected to functional enrichment analysis (DAVID) and inflammatory response was among the enriched terms found when comparing T2D-N with controls and T2D-H with T2D-N. Concerning the gene set enrichment and gene set analyses, among the differentially expressed gene sets, three were of interest: regulation of DNA repair (T2D-H versus T2D-N), superoxide response (T2D-H versus control group), and response to endoplasmic reticulum stress (T2D-H versus control group). We also identified miRNAs related with T2D and hyperglycemia not yet associated with these conditions in the literature. Some of the differentially expressed mRNAs were among the predicted targets of the differentially expressed miRNAs. Our results showed the association of hyperglycemia with increased DNA damage and aberrant expression of miRNAs and genes related to several biological processes, such as inflammation, DNA repair, ROS production and antioxidant defense, highlighting the importance of proper glycemic control. Moreover, the transcriptional expression of miRNAs provided novel information for understanding the regulatory mechanisms involved in the T2D progression.
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Danilo J
authors.initials: DJ
authors.lastname: Xavier
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Paula
authors.initials: P
authors.lastname: Takahashi
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Adriane F
authors.initials: AF
authors.lastname: Evangelista
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14048-900 Ribeirão Preto, SP, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Foss-Freitas
authors.affiliation: Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14048-900 Ribeirão Preto, SP, Brazil.
authors.forename: Milton C
authors.initials: MC
authors.lastname: Foss
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14048-900 Ribeirão Preto, SP, Brazil.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Donadi
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil; Disciplines of Genetics and Molecular Biology, Department of Morphology, Faculty of Dentistry of Ribeirão Preto, University of São Paulo - USP, Av. Do Café, s/n, Monte Alegre, 14040-904 Ribeirão Preto, SP, Brazil.
authors.forename: Geraldo A
authors.initials: GA
authors.lastname: Passos
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil; Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo - USP, Av. Bandeirantes, 3900 - Monte Alegre, 14040-901 Ribeirão Preto, SP, Brazil. Electronic address: etshojo@usp.br.
authors.forename: Elza T
authors.initials: ET
authors.lastname: Sakamoto-Hojo
mesh_terms: D000328:Adult; D000368:Aged; D004249:DNA Damage; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis*; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger
keywords: DNA damage; Hyperglycemia; MicroRNA; Microarrays; Type 2 diabetes mellitus