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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 
 GUT, Vol.70(10) : 1847-1856, 2021-10 
Journal Title
Issue Date
diabetes mellitus ; epidermal growth factor ; gastrectomy ; glucose metabolism
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.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Forensic Medicine (법의학과) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Medical Engineering (의학공학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Won Jun(강원준) ORCID logo https://orcid.org/0000-0002-2107-8160
Kang, Chan Woo(강찬우)
Ku, Cheol Ryong(구철룡) ORCID logo https://orcid.org/0000-0001-8693-9630
Kwon, In Gyu(권인규) ORCID logo https://orcid.org/0000-0002-1489-467X
Noh, Sung Hoon(노성훈) ORCID logo https://orcid.org/0000-0003-4386-6886
Park, Jong Pil(박종필) ORCID logo https://orcid.org/0000-0002-6525-3012
Sung, Hak-Joon(성학준) ORCID logo https://orcid.org/0000-0003-2312-2484
Shin, Su Jin(신수진) ORCID logo https://orcid.org/0000-0001-9114-8438
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
Cho, Arthur Eung Hyuck(조응혁) ORCID logo https://orcid.org/0000-0001-8670-2473
Hyung, Woo Jin(형우진) ORCID logo https://orcid.org/0000-0002-8593-9214
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