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

In Gyu Kwon, Chan Woo Kang, Jong Pil Park, Ju Hun Oh, Eun Kyung Wang, Tae Young Kim, Jin Sol Sung, Namhee Park, Yang Jong Lee, Hak Joon Sung, Eun Jig Lee, Woo Jin Hyung, Su Jin Shin, Sung Hoon Noh, Mijin Yun, Won Jun Kang, Arthur Cho, Cheol Ryong Ku

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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-[ 18 F]-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 14 C-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.

Original languageEnglish
Pages (from-to)1847-1856
Number of pages10
JournalGut
Volume70
Issue number10
DOIs
Publication statusPublished - 2021 Oct 1

Bibliographical note

Funding Information:
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).

Publisher Copyright:
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All Science Journal Classification (ASJC) codes

  • Gastroenterology

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