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.
- epidermal growth factor
- diabetes mellitus
- glucose metabolism
Data availability statement
Data are available upon reasonable request.
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IGK and CWK contributed equally.
Correction notice This article has been corrected since it published Online First. The email addresses for both corresponding authors have been corrected.
Contributors Conceptualisation: CRK and AC. Data curation and formal analysis: CRK, CWK, IGK and AC. Funding acquisition: CRK. Investigation and methodology: CRK, CWK, EKW, TK, HJS, JPP, EJL, WJH, SHN, IGK and AC. Supervision and validation: CRK, CWK and AC. Visualisation: CRK, CWK, JPP, YJL, JSS, JHO, NP, SS, MJ, WJK, IGK and AC. Writing original draft: CRK, CWK, IGK and AC. Writing review and editing: CRK, CWK, YJL, JSS, JHO, NP, IGK and AC.
Funding This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI18C1603).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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