Hepatic expression of sodium–glucose cotransporter 2 (SGLT2) in patients with chronic liver disease

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Abstract

Sodium–glucose cotransporter 2 (SGLT2) occurs in the proximal renal tubule cells. We investigate the hepatic expression of SGLT2 and its related factors in patients with chronic liver disease. This is a retrospective human study. The liver tissues were biopsied from patients with chronic liver disease ( n = 30). The expression levels of SGLT2 were evaluated by immunostaining. Furthermore, the undirected graphical model was used to identify factors associated with hepatic expression levels of SGLT2. The SGLT2 expression was observed in not only the kidney, but also the liver in immunostaining (SGLT2 intensity: kidney 165.8 ± 15.6, liver 114.4 ± 49.0 arbitrary units, P < 0.01) and immunoblotting. There was no significant difference in hepatic expression of SGLT2 in the stratified analysis according to age, sex, BMI, and the severity of the liver disease. In the undirected graphical model, SGLT2 directly interacted with various factors such as sex, fatty change, neutrophil-to-lymphocyte ratio, triglyceride, hemoglobin A1c, creatinine, and albumin (partial correlation coefficient 0.4–0.6 for sex and 0.2–0.4 for others). The expression of SGLT2 was observed in the hepatocytes of patients with chronic liver disease. The undirected graphical model demonstrated the complex interaction of hepatic expression levels of SGLT2 with gender, inflammation, renal function, and lipid/glucose/protein metabolisms.

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The online version contains supplementary material available at 10.1007/s00795-022-00334-9.

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SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review

Subodh Verma, John J V McMurray (2018)

Sodium-glucose cotransporter (SGLT)2 inhibitors have been demonstrated to reduce cardiovascular events, particularly heart failure, in cardiovascular outcome trials. Here, we review the proposed mechanistic underpinnings of this benefit. Specifically, we focus on the role of SGLT2 inhibitors in optimising ventricular loading conditions through their effect on diuresis and natriuresis, in addition to reducing afterload and improving vascular structure and function. Further insights into the role of SGLT2 inhibition in myocardial metabolism and substrate utilisation are outlined. Finally, we discuss two emerging themes: how SGLT2 inhibitors may regulate Na+/H+ exchange at the level of the heart and kidney and how they may modulate adipokine production. The mechanistic discussion is placed in the context of completed and ongoing trials of SGLT2 inhibitors in the prevention and treatment of heart failure in individuals with and without diabetes.

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The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels.

Simon A. Hawley, Rebecca Ford, Brennan K. Smith … (2016)

Canagliflozin, dapagliflozin, and empagliflozin, all recently approved for treatment of type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting glucose reuptake by sodium/glucose cotransporter (SGLT) 2 in the kidney, without affecting intestinal glucose uptake by SGLT1. We now report that canagliflozin also activates AMPK, an effect also seen with phloretin (the aglycone breakdown product of phlorizin), but not to any significant extent with dapagliflozin, empagliflozin, or phlorizin. AMPK activation occurred at canagliflozin concentrations measured in human plasma in clinical trials and was caused by inhibition of Complex I of the respiratory chain, leading to increases in cellular AMP or ADP. Although canagliflozin also inhibited cellular glucose uptake independently of SGLT2, this did not account for AMPK activation. Canagliflozin also inhibited lipid synthesis, an effect that was absent in AMPK knockout cells and that required phosphorylation of acetyl-CoA carboxylase (ACC) 1 and/or ACC2 at the AMPK sites. Oral administration of canagliflozin activated AMPK in mouse liver, although not in muscle, adipose tissue, or spleen. Because phosphorylation of ACC by AMPK is known to lower liver lipid content, these data suggest a potential additional benefit of canagliflozin therapy compared with other SGLT2 inhibitors.

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Functional expression of sodium-glucose transporters in cancer.

Claudio Scafoglio, Bruce Hirayama, Vladimir Kepe … (2015)

Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[(18)F]fluoro-D-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.

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Author and article information

Contributors

Dan Nakano:

ORCID: http://orcid.org/0000-0001-6098-1224

nakano_dan@med.kurume-u.ac.jp

Journal

Journal ID (nlm-ta): Med Mol Morphol

Journal ID (iso-abbrev): Med Mol Morphol

Title: Medical Molecular Morphology

Publisher: Springer Nature Singapore (Singapore )

ISSN (Print): 1860-1480

ISSN (Electronic): 1860-1499

Publication date (Electronic): 21 September 2022

Publication date PMC-release: 21 September 2022

Publication date (Print): 2022

Volume: 55

Issue: 4

Pages: 304-315

Affiliations

[1 ]GRID grid.410781.b, ISNI 0000 0001 0706 0776, Division of Gastroenterology, Department of Medicine, , Kurume University School of Medicine, ; 67 Asahi-machi Kurume, Kurume, 830-0011 Japan

[2 ]GRID grid.470127.7, ISNI 0000 0004 1760 3449, Department of Pathology, , Kurume University Hospital, ; Kurume, Japan

[3 ]GRID grid.410781.b, ISNI 0000 0001 0706 0776, Liver Cancer Division, Research Center for Innovative Cancer Therapy, , Kurume University, ; Kurume, Japan

Author information

Dan Nakano http://orcid.org/0000-0001-6098-1224

Article

Publisher ID: 334

DOI: 10.1007/s00795-022-00334-9

PMC ID: 9606064

PubMed ID: 36131166

SO-VID: 608b6b58-2ef0-42c3-99c0-eb112fd1448b

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Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 18 April 2022

Date accepted : 24 August 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100015386, Japan Society for Aeronautical and Space Sciences;

Award ID: JP19K17446

Award Recipient : Dan Nakano

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Hepatic expression of sodium–glucose cotransporter 2 (SGLT2) in patients with chronic liver disease

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Karger: Oncology

Most cited references 31

SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review

The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels.

Functional expression of sodium-glucose transporters in cancer.

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