Serum glucose excretion after Roux-en-Y gastric bypass: a potential target for diabetes treatment

Abstract

ObjectiveThe mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We suspected that glucose excretion may occur in the small bowel based on observations in humans. The aim of this study was to evaluate the mechanisms underlying serum glucose excretion in the small intestine and its contribution to glucose homeostasis after bariatric surgery.Design2-Deoxy-2-[18F]-fluoro-D-glucose (FDG) was measured in RYGB-operated or sham-operated obese diabetic rats. Altered glucose metabolism was targeted and RNA sequencing was performed in areas of high or low FDG uptake in the ileum or common limb. Intestinal glucose metabolism and excretion were confirmed using 14C-glucose and FDG. Increased glucose metabolism was evaluated in IEC-18 cells and mouse intestinal organoids. Obese or ob/ob mice were treated with amphiregulin (AREG) to correlate intestinal glycolysis changes with changes in serum glucose homeostasis.ResultsThe AREG/EGFR/mTOR/AKT/GLUT1 signal transduction pathway was activated in areas of increased glycolysis and intestinal glucose excretion in RYGB-operated rats. Intraluminal GLUT1 inhibitor administration offset improved glucose homeostasis in RYGB-operated rats. AREG-induced signal transduction pathway was confirmed using IEC-18 cells and mouse organoids, resulting in a greater capacity for glucose uptake via GLUT1 overexpression and sequestration in apical and basolateral membranes. Systemic and local AREG administration increased GLUT1 expression and small intestinal membrane translocation and prevented hyperglycaemic exacerbation.ConclusionBariatric surgery or AREG administration induces apical and basolateral membrane GLUT1 expression in the small intestinal enterocytes, resulting in increased serum glucose excretion in the gut lumen. Our findings suggest a novel, potentially targetable glucose homeostatic mechanism in the small intestine.

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut–Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice

“…In the i.p. protocol, we found that a minor portion of 18 FDG was counter-transported from blood to GI lumen, which confirms previous observations in rodents and humans [14,17]. It remains to be demonstrated whether the leakage of glucose from the circulation, and its putative increase in diseased states (e.g., hyperglycemia) might influence the intestinal milieu and GI function, or whether glucose excretion may become a potential target in disease states, as suggested by observations in bariatric surgery studies [14].…”

“…In addition, the administration of a single glucose or standard meal, passing through the GI tract, has been associated with systemic and liver inflammation [ 11 , 12 ], though it remains to be established whether these effects require specifically the GI entry route. Accumulating evidence from, e.g., bariatric surgery [ 13 , 14 , 15 ] or drugs affecting GI function (GLP1 agonists [ 15 , 16 ], metformin [ 17 , 18 , 19 , 20 ]), point to the GI tract as an important regulator of tissue glucose uptake (GU).…”

Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations

“…RYGB surgery improves metabolic health and diabetes remission more effectively than other treatment strategies, including pharmacotherapy and lifestyle interventions [25,26]. Several murine RYGB studies show a positive impact of the surgery on various metabolic parameters reducing the risk of type 2 diabetes mellitus [27][28][29] and hyperlipidemia [30]. RYGB surgery leads to reduced glycemia, as shown by functional studies of the liver and brain.…”

Leptin Receptors Are Not Required for Roux-en-Y Gastric Bypass Surgery to Normalize Energy and Glucose Homeostasis in Rats

“…Because RYGB reduces stomach size and excludes the duodenum from contact with ingested food, physical restriction and malabsorption of nutrients, respectively, were originally thought to mainly account for its beneficial effects on energy and glucose homeostasis [ 6 ]. With the aid of rodent models of RYGB, however, it is becoming increasingly evident that complex changes in various molecular, cellular, and systems processes take place postoperatively [ 7 , 8 , 9 , 10 ], better understanding of which may guide the development of more effective, noninvasive treatments against metabolic disease.…”