A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

Abstract

Background Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. Methods We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca 2+ -imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. Findings EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca 2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. Interpretation Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. Funding European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Société Francophone du Diabète, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030–188447), Fondation de l'Avenir.

Intravital imaging of islet Ca2+ dynamics reveals enhanced β cell connectivity after bariatric surgery in mice

“…Our data with this approach did not, however, provide compelling evidence for such changes after surgery, though our sample size was relatively small. It is conceivable, therefore, that changes in the expression of genes more directly associated with the control of Ca 2+ dynamics and connectivity in and between β-cells, including Trpm2 and Gjd2 (Cx36) 69 and others associated with insulin secretion 44 , play a role in the improvements observed postsurgery.…”

“…Changes in metabolic signalling by glucose, particularly changes in the glycolytic and oxidative metabolism of the sugar by mitochondria, are observed in islets from human subjects with T2D 68 and are implicated in the recovery of glucose tolerance after Roux-en-Y-like gastric surgery in the mouse 69 . In the former case, this is likely to involve decreases in the expression of the critical β-cell glucose transporter, GLUT2/SLC2A2, and in the low affinity glucose phosphorylating enzyme glucokinase (GCK) 70 .…”

Homocysteine Metabolism Pathway Is Involved in the Control of Glucose Homeostasis: A Cystathionine Beta Synthase Deficiency Study in Mouse

“…The supernatant (500 µL) was immediately collected and stored at −20 °C until being assayed for insulin by ELISA (ultra-sensitive mouse insulin ELISA Kit; Crystal Chem, #90080, the Netherland). The islets were homogenized in protein extraction buffer and stored until insulin content determination by ELISA (ultra-sensitive mouse insulin ELISA Kit; Crystal Chem, #90080, Netherland), as previously described [ 17 ].…”

Intestinal alteration of α-gustducin and sweet taste signaling pathway in metabolic diseases is partly rescued after weight loss and diabetes remission

“…To evaluate if the altered sweet taste transduction pathway gene expression within EECs could be corrected after weight loss and diabetes remission, we used EGA surgery in mice (a surrogate of the RYGB in humans), as described before (20,28). EGA surgery forms a loop that excludes the duodenum and proximal jejunum from alimentary tract.…”

“…The rise of postprandial GLP-1 secretion after Roux-en-Y gastric bypass (RYGB) may contribute to this improvement (15)(16)(17)(18)(19). After RYGB, the rapid delivery of undigested nutrients to the lower small intestine may affect the regulation of taste receptors and/or glucose transporters on EECs, resulting in an enhanced release of GLP-1 (20)(21)(22) although a recent study demonstrated that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion (23). Therefore, the mechanisms driving the alteration of enterohormone secretion in obesity and after RYGB might not be restricted to GLP-1 incretin effects alone (17).…”