Changes in whole blood gene expression in obese subjects with type 2 diabetes following bariatric surgery: a pilot study

Abstract

Background: A pilot study was performed in order to investigate the effects of bariatric surgery on whole blood gene expression profiles in obese subjects with type 2 diabetes.

Methodology/principal findings: Whole blood from eleven obese subjects with type 2 diabetes was collected in PAXgene tubes prior to and 6-12 months after bariatric surgery. Total RNA was isolated, amplified, labeled and hybridized to Illumina gene expression microarrays. Clinical and expression data were analyzed using a paired t-test, and correlations between changes in clinical trait and transcript levels were calculated. Pathways were identified using Ingenuity Pathway Analysis and DAVID gene ontology software. Overall, bariatric surgery resulted in significant reduction of body mass index, fasting plasma glucose, fasting plasma insulin, and normalization of glycosylated hemoglobin levels. The expression levels of 204 transcripts, representing 200 unique genes, were significantly altered after bariatric surgery. Among the significantly regulated genes were GGT1, CAMP, DEFA1, LCN2, TP53, PDSS1, OLR1, CNTNAP5, DHCR24, HHAT and SARDH, which have been previously implicated in lipid metabolism, obesity and/or type 2 diabetes. Selected findings were replicated by quantitative real-time-PCR. The changes in expression of seven transcripts, WDR35, FLF45244, DHCR24, TIGD7, TOPBP1, TSHZ1, and FAM8A1 were strongly correlated with the changes in body weight, fasting plasma glucose and glycosylated hemoglobin content. The top pathways associated with gene expression changes after bariatric surgery was lipid metabolism, small molecule biochemistry and gene expression. Two antimicrobial peptides were among the transcripts with the largest changes in gene expression after bariatric surgery.

Conclusions/significance: Data from this pilot study suggest that whole blood expression levels of specific transcripts may be useful as biomarkers associated with susceptibility for type 2 diabetes and/or therapeutic response.

Figure 1. Lipid metabolism, small molecule biochemistry, free radical scavenging network.

The straight lines represent direct relationships and the dotted lines represent indirect relationships. Up regulated and down regulated genes that meet the P-value cutoff of <0.01 are shown in red and green shading respectively, with color intensity related to the fold change in expression. The molecules that do not meet the abovementioned P-value cutoff are shown in gray, while the molecules that are incorporated in the network through relationships with other molecules and are not user specified are shown in white. Symbols used in the figure represent: trapezoid, transporter; circle, other; concentric circles, complex/group; dotted square, growth factor; vertical rhombus, enzyme; horizontal rhombus, peptidase; vertical oval, transmembrane receptor; horizontal oval, transcription regulation.

Figure 2. Venn diagram representing the number of transcripts whose change in expression after bariatric surgery were highly correlated with percent changes in weight loss, fasting plasma glucose, and HbA_1C content.

Seven transcripts were highly correlated with changes in all three of these clinical characteristics.