PT  - JOURNAL ARTICLE
AU  - In Gyu Kwon
AU  - Chan Woo Kang
AU  - Jong-Pil Park
AU  - Ju Hun Oh
AU  - Eun Kyung Wang
AU  - Tae Young Kim
AU  - Jin Sol Sung
AU  - Namhee Park
AU  - Yang Jong Lee
AU  - Hak-Joon Sung
AU  - Eun Jig Lee
AU  - Woo Jin Hyung
AU  - Su-Jin Shin
AU  - Sung Hoon Noh
AU  - Mijin Yun
AU  - Won Jun Kang
AU  - Arthur Cho
AU  - Cheol Ryong Ku
TI  - Serum glucose excretion after Roux-en-Y gastric bypass: a potential target for diabetes treatment
AID  - 10.1136/gutjnl-2020-321402
DP  - 2021 Oct 01
TA  - Gut
PG  - 1847--1856
VI  - 70
IP  - 10
4099  - http://gut.bmj.com/content/70/10/1847.short
4100  - http://gut.bmj.com/content/70/10/1847.full
SO  - Gut2021 Oct 01; 70
AB  - Objective The 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.Design 2-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.Results The 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.Conclusion Bariatric 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.Data are available upon reasonable request.