ArticlePhysiological reports2014
SGLT2 inhibitors act from the extracellular surface of the cell membrane.
Article in Physiological reports, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Effects of sodium-glucose co-transporter-2 inhibitors on kidney, cardiovascular, and safety outcomes in patients with advanced chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.Acta diabetologica · 2023Pooled it
- Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review.Journal of diabetes research · 2020Pooled it
- Sotagliflozin Decreases Postprandial Glucose and Insulin Concentrations by Delaying Intestinal Glucose Absorption.The Journal of clinical endocrinology and metabolism · 2020Trial
- Pharmacokinetics and Pharmacodynamics of Luseogliflozin, a Selective SGLT2 Inhibitor, in Japanese Patients With Type 2 Diabetes With Mild to Severe Renal Impairment.Clinical pharmacology in drug development · 2018Trial
- The Chemistry of Gliflozins: Recent Advancements in SGLT-2 Inhibitors.Cardiovascular & hematological agents in medicinal chemistry · 2026Review
- "Efficacy of SGLT2 inhibitors in non-diabetic non-alcoholic fatty liver disease: a systematic review and meta-analysis".Journal of diabetes and metabolic disorders · 2025Article
- Docking-Based Classification of SGLT2 Inhibitors.Molecules (Basel, Switzerland) · 2025Article
- Unraveling the Cardiac Matrix: From Diabetes to Heart Failure, Exploring Pathways and Potential Medications.Biomedicines · 2024Review
- Transport and inhibition mechanism of the human SGLT2-MAP17 glucose transporter.Nature structural & molecular biology · 2024Article
- Sizing SGLT2 Inhibitors Up: From a Molecular to a Morpho-Functional Point of View.International journal of molecular sciences · 2023Review
- Sodium-glucose cotransporter 2 inhibitors and heart failure: the best timing for the right patient.Heart failure reviews · 2023Review
- Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling.The Journal of clinical investigation · 2023Article
- Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future Perspectives.Journal of medicinal chemistry · 2022Review
- Article
- Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function.Annual review of physiology · 2021Review
- SGLT2 and cancer.Pflugers Archiv : European journal of physiology · 2020Review
- Glucose transporters in the kidney in health and disease.Pflugers Archiv : European journal of physiology · 2020Review
- The tubular hypothesis of nephron filtration and diabetic kidney disease.Nature reviews. Nephrology · 2020Review
- Renal effects of SGLT2 inhibitors: an update.Current opinion in nephrology and hypertension · 2020Review
- Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives.Cardiovascular diabetology · 2019Review
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SGLT2 inhibitors are a new class of drugs that have been recently developed to treat type II diabetes. They lower glucose levels by inhibiting the renal Na(+)/glucose cotransporter SGLT2, thereby increasing the amount of glucose excreted in the urine. Pharmacodynamics studies have raised questions about how these inhibitors reach SGLT2 in the brush border membrane of the S1 and S2 segments of the renal proximal tubule: are these drugs filtered by the glomerulus and act extracellularly, or do they enter the cell and act intracellularly? To address this question we expressed hSGLT2 in HEK-293T cells and determined the affinity of a specific hSGLT2 inhibitor, TA-3404 (also known as JNJ-30980924), from the extra- and intracellular side of the plasma membrane. Inhibition of SGLT2 activity (Na(+)/glucose currents) by TA-3404 was determined using the whole-cell patch clamp that allows controlling the composition of both the extracellular and intracellular solutions. We compared the results to those obtained using the nonselective SGLT inhibitor phlorizin, and to the effect of TA-3404 on hSGLT1. Our results showed that TA-3404 is a potent extracellular inhibitor of glucose inward SGLT2 transport (IC50 2 nmol/L) but it was ineffective from the intracellular compartment at both low (5 mmol/L) and high (150 mmol/L) intracellular NaCl concentrations. We conclude that TA-3404 only inhibits SGLT2 from the extracellular side of the plasma membrane, suggesting that it is filtered from the blood through the glomerulus and acts from within the tubule lumen.
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Registered trials
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