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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-[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.

Affiliations

In Gyu Kwon #  1 , Chan Woo Kang #  2 , Jong-Pil Park  3 , Ju Hun Oh  2   4 , Eun Kyung Wang  4 , Tae Young Kim  5 , Jin Sol Sung  2 , Namhee Park  6 , Yang Jong Lee  4 , Hak-Joon Sung  5 , Eun Jig Lee  4 , Woo Jin Hyung  7 , Su-Jin Shin  8 , Sung Hoon Noh  1 , Mijin Yun  6 , Won Jun Kang  6 , Arthur Cho  9 , Cheol Ryong Ku  10
1 Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
2 Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
3 Department of Forensic Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
4 Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
5 Department of Medical Engineering, Yonsei University College of Medicine, Seoul, Republic of Korea.
6 Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
7 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
8 Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
9 Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea cr079@yuhs.ac artycho@yuhs.ac.
10 Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea cr079@yuhs.ac artycho@yuhs.ac.
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