Novel mechanism whereby metformin improves glucose homeostasis: TXNIP-GLUT1 axis modulation enhances intestinal glucotonic effects

Chan Woo Kang; Jung Ho Nam; Ju Hun Oh; Eun Kyung Wang; Soo Hyun Lee; Hye Ju Shin; Ye Bin Kim; Eun Jig Lee; Byung Kook Lim; Sungsoon Fang; Arthur Cho; Cheol Ryong Ku

doi:Metformin is widely used as a first-line therapy for type 2 diabetes mellitus. However, the molecular mechanisms by which it modulates intestinal glucose metabolism remain incompletely defined. Here metformin was orally administered to male C57BL/6 mice, followed by intraperitoneal glucose tolerance testing and fluorine-18 fluorodeoxyglucose tracing to evaluate glucose homeostasis. To investigate changes in intestinal glucose metabolism, IEC6 and Caco-2 cell lines were used for in vitro analysis, with organoid experiments conducted for further validation. qRT-PCR, western blotting, flow cytometry and immunohistochemistry were performed to elucidate the effects of metformin on glucose metabolism pathways. Metformin enhanced glucose uptake and excretion in the distal intestine, particularly in the ileum and colon. Mechanistically, metformin upregulated the expression and membrane localization of glucose transporter 1 (GLUT1) by downregulating thioredoxin-interacting protein (TXNIP) expression. Consistently, intestinal-specific overexpression of TXNIP abolished metformin-induced improvements in glucose tolerance, while pharmacological inhibition of GLUT1 similarly negated metformin's glucose-lowering effects. Our findings identified intestinal glucose excretion, mediated through the intestinal TXNIP-GLUT1 regulatory axis, as a previously unrecognized contributor to metformin's glucoregulatory action. These results highlight a novel intestinal mechanism underlying metformin's efficacy and provide insights for potential therapeutic strategies beyond traditional glucose regulation.

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Novel mechanism whereby metformin improves glucose homeostasis: TXNIP-GLUT1 axis modulation enhances intestinal glucotonic effects

Authors: Chan Woo Kang ; Jung Ho Nam ; Ju Hun Oh ; Eun Kyung Wang ; Soo Hyun Lee ; Hye Ju Shin ; Ye Bin Kim ; Eun Jig Lee ; Byung Kook Lim ; Sungsoon Fang ; Arthur Cho ; Cheol Ryong Ku

Citation: EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.57(8) : 1775-1788, 2025-08

Journal Title: EXPERIMENTAL AND MOLECULAR MEDICINE

ISSN: 1226-3613

Issue Date: 2025-08

MeSH: 0

Keywords: Animals ; Caco-2 Cells ; Carrier Proteins* / genetics ; Carrier Proteins* / metabolism ; Glucose Transporter Type 1* / genetics ; Glucose Transporter Type 1* / metabolism ; Glucose* / metabolism ; Homeostasis* / drug effects ; Humans ; Hypoglycemic Agents* / pharmacology ; Intestinal Mucosa* / drug effects ; Intestinal Mucosa* / metabolism ; Male ; Metformin* / pharmacology ; Mice ; Mice, Inbred C57BL ; Thioredoxins* / metabolism

Article Number: 10.1038/s12276-025-01518-w

DOI: Metformin is widely used as a first-line therapy for type 2 diabetes mellitus. However, the molecular mechanisms by which it modulates intestinal glucose metabolism remain incompletely defined. Here metformin was orally administered to male C57BL/6 mice, followed by intraperitoneal glucose tolerance testing and fluorine-18 fluorodeoxyglucose tracing to evaluate glucose homeostasis. To investigate changes in intestinal glucose metabolism, IEC6 and Caco-2 cell lines were used for in vitro analysis, with organoid experiments conducted for further validation. qRT-PCR, western blotting, flow cytometry and immunohistochemistry were performed to elucidate the effects of metformin on glucose metabolism pathways. Metformin enhanced glucose uptake and excretion in the distal intestine, particularly in the ileum and colon. Mechanistically, metformin upregulated the expression and membrane localization of glucose transporter 1 (GLUT1) by downregulating thioredoxin-interacting protein (TXNIP) expression. Consistently, intestinal-specific overexpression of TXNIP abolished metformin-induced improvements in glucose tolerance, while pharmacological inhibition of GLUT1 similarly negated metformin's glucose-lowering effects. Our findings identified intestinal glucose excretion, mediated through the intestinal TXNIP-GLUT1 regulatory axis, as a previously unrecognized contributor to metformin's glucoregulatory action. These results highlight a novel intestinal mechanism underlying metformin's efficacy and provide insights for potential therapeutic strategies beyond traditional glucose regulation.

Appears in Collections:: 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers

Yonsei Authors: Kang, Chan Woo(강찬우)
Ku, Cheol Ryong(구철룡) https://orcid.org/0000-0001-8693-9630
Lee, Eun Jig(이은직) https://orcid.org/0000-0002-9876-8370
Cho, Arthur Eung Hyuck(조응혁) https://orcid.org/0000-0001-8670-2473
Fang, Sungsoon(황성순) https://orcid.org/0000-0003-0201-5567

URI: https://ir.ymlib.yonsei.ac.kr/handle/22282913/207466

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