Potential Molecular Pathways involving the Resolution of Type II Diabetes following RYGB

Background: Following Roux-en-Y gastric bypass (RYGB), hyperglycemia dramatically improves in obese patients with Type II diabetes (T2D). For many patients, hypoglycemic agents and insulin are discontinued after RYGB. However, the exact mechanisms of this process are unknown. This unique study attempts to identify differences in gene expression profiles between pre- and post-operative T2D patients following RYGB.

Methods: Non-diabetic and T2D obese patients undergoing RYGB were included in this study. Pre- and post-operative (3-6 months) blood samples were stabilized in PaxGene tubes (PreAnalytiX) and total RNA was extracted. 100ng of the total RNA was amplified and labeled using the Ovation RNA Amplification System V2 with the Ovation Whole Blood Reagent (NuGen) before hybridizing to an Affymetrix Focus Array containing over 8500 verified genes. Microarray results were analyzed using GeneSpring and Ingenuity analyses to identify a list of genes that were significantly changed (p < 0.05). Real-time quantitative (QPCR) was used to verify the genes of interest from the microarray study.

Results: A list of genes related to metabolism was identified by microarray studies comparing obese T2D and non-diabetic patients. A total of 112 genes were upregulated and 151 were down-regulated in the obese T2D versus non-diabetic patients. Ingenuity analysis identified molecular pathways involving energy metabolism such as beta-catenin like 1 (CTNNBL1) and Insulin-like growth factor binding protein 4 (IGFRBP4). Using QPCR analyses in post-op T2D patients, CTNNBL1 and IGFRBP4 were upregulated 4.6 X and 3.8 X, respectively.

Conclusions: This pilot data is one of the first studies to document that blood gene expression profiles are altered after RYGB surgery. Among the genes identified, CTNNBL1 expression was increased after surgery. Although the function of CTNNBL1 has not been fully elucidated, it shows homology to beta-catenin, which binds to TCF/LEF transcription factor to promote glucose metabolism. Also, the significant upregulation of IGFRBP4 in T2D patients after RYGB is notable as IGFRBP4 is decreased in animal models with diabetes. Thus, upregulation of these genes may help explain the resolution of T2D in obese patients after RYGB.

Session: Podium Presentation

Program Number: S022

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