Impact of Roux-em-Y gastric bypass on metabolomic profile of obese women with type 2 diabetes

Author(s)

Natasha Mendonça Machado

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2019-01-23

Examining board members

Dan Linetzky Waitzberg; Elinton Adami Chaim; Roberto de Cleva; Bayardo Baptista Torres

• Advisor: Dan Linetzky Waitzberg

Abstract

In recent years, much has been learned about the metabolic role of Rouxem- Y gastric bypass (RYGB), although there are still important questions to be answered. Obese metabolically decompensated patients present fast improvement of type 2 diabetes (T2D) in the early RYGB postoperative. T2D remission rates reach up to 89% after a year, but the precise mechanisms and determinant factors of this improvement are still unknown. To the best of our knowledge, there is no clinical study that fully explains the phenomena in humans. Post-genomic era has substantially changed the way science and medicine are practiced, making it possible to investigate diseases at molecular level. Obesity and T2D result from systemic metabolic alterations and, in this context, metabolomics appears as a promising approach to investigate changes induced by RYGB, as is focused on dynamic fluctuations of the molecules that translate metabolism, the metabolites. These molecules reflect the ultimate response of biological systems to metabolic, genetic and environmental changes, representing an important source of cellular and systemic information. In this research, we considered that the mechanisms of RYGB action includes systemic and gastrointestinal metabolomic alterations, which modulate several metabolic pathways, and that may lead out T2D improvement in obese patients. In this perspective, we developed a prospective clinical study, self-controlled (paired), in which 23 obese patients with T2D submitted RYGB were investigated. Metabolomic analysis were performed in a multi-compartmental approach, analyzing plasma, urine and gastrointestinal biopisies before and after 3 months of surgery. Analysis were performed at an international reference metabolomics center, located at University of California, United States of America (NIH West Coast Metabolomics Center), by using liquid and gas chromatography, coupled to mass spectrometry. Patients were analyzed together, and to determine the relationship of glycemic control with RYGB, we also analyzed patients divided by groups, classified according T2D remission, following the American Diabetes Association criteria. All patients presented body composition and clinical improvements, showing no difference from the clinical perspective. On the other hand, metabolomic profile exhibited a discriminatory pattern of alterations, suggesting important differences between patients with and without T2D remission. On plasma, 235 metabolites were significantly changed, while urine 113 and 106, 0, 82, 146 and 60 at stomach upper body, stomach median body, duodenum, jejunum and ileum, respectively. The principal metabolites involved in these alterations includes bile acids, uremic toxins produced by microbiota, dicarboxylic acids, and different lipid classes. Several hypotheses were generated from our results, indicating that RYGB deeply changes metabolomic profile and that T2D remission seems to be associated with metabolic flexibility improvement, stimulated by increased omega oxidation and nuclear receptors activation, modifying lipid and glucose metabolism. In contrast, non-remission of T2D seems to be related to changes of microbiota, associated with subclinic kidney dysfunction, that impairs the metabolic adaptation in which RYGB occurs. Thus, we suppose that RYGB develops a functional role, including - but not limited to - regulation in the substrate flux and utilization, microbiota composition and activity, and activation of nuclear receptors. These metabolic alterations seem to act together to form a circuit of alterations that activate triggers that lead to T2D improvement (AU)

• FAPESP's process: 13/23355-9 - Metabolomics profile of patients with type 2 diabetes and obesity after Roux en Y gastric bypass
• Grantee: Natasha Mendonça Machado
• Support Opportunities: Scholarships in Brazil - Doctorate