Genomic and epigenetic factors associated with Diabetes resolution after Roux-en-Y gastric bypass and with the pathogenesis of Diabetes secondary to pancreatic adenocarcinoma

Abstract

Bariatric surgery in the treatment of obesity determines sustained weight loss and improves metabolic outcomes, including remission of type 2 diabetes mellitus (T2D). Roux-en-Y gastric bypass (RYGB) is one of the most frequently employed modalities and the mechanisms suggested to explain its beneficial effects on glucose tolerance include a negative energy balance with weight loss and consequent improvement in insulin sensitivity and an increase on secretion of prandial insulin secondary to an exacerbated secretion of glucagon-like peptide-1 (GLP1). The reasons why a portion of the patients does not reach remission of T2D remain little known. In the study SURgically induced Metabolic effects on the Human GastroIntestinal Tract (SURMetaGIT), samples of gastrointestinal segments were collected by double balloon enteroscopy, before, after 3 months and after 24 months of RYGB in 20 women with body mass index ³ 35 kg/m2 and T2D. The first objective of this project is to investigate whether the remission of T2D after RYGB is related to postoperative alterations in gastrointestinal "omic" functions. To do so, we will evaluate: (1) the duodenal transcriptomic changes after 24 months of surgery, comparing them with those found at baseline and after 3 months of surgery; (2) the duodenal methylation profile in the three periods (baseline and 3 and 24 months postoperative) and (3) the duodenal miRNA profile in the three periods. These findings will be compared among groups of patients with different responses related to glycemic homeostasis (remission or not of T2D). The second problem that will be addressed in this project is the relationship between ductal pancreatic adenocarcinoma and diabetes; a very high relative risk (5.4) of ductal pancreatic adenocarcinoma was reported in individuals with diabetes < 1year of duration, making newly-onset diabetes a marker of this neoplasm. The suspicion that a newly-onset diabetes is not T2D, but diabetes secondary to ductal pancreatic adenocarcinoma, has important clinical implications, since it may allow the early detection of this neoplasia, because diabetes arises between 24 and 36 months before the diagnosis of the pancreatic adenocarcinoma. Thus, the second objective of the present project is to try to identify, in individuals with pancreatic adenocarcinoma and newly-onset diabetes, serum biomarkers which could facilitate the screening of this neoplasm. (AU)