Evidence mapPaperPMID 40260754Full record

ArticleJournal of diabetes investigation2025

Induction of proximal tubular proliferation and lengthening in response to sodium glucose linked cotransporter-2 inhibition in experimental rats.

Ellen Wu, Sarah Macklin, Yanling Zhang, Kerri Thai, Linda Nghiem, Caterina Di Ciano-Oliveira, Nuno Coelho, Hai Wang, Suzanne L Advani, Jean-François Desjardins and 5 more

Abstract read
In one paragraph

Article in Journal of diabetes investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Ellen WuKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Sarah MacklinKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Yanling ZhangKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Kerri ThaiKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Linda NghiemKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Caterina Di Ciano-OliveiraKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Nuno CoelhoKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Hai WangKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Suzanne L AdvaniKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Jean-François DesjardinsKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Darren A YuenKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Paraish MisraDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada.
Kim A ConnellyKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Jens R NyengaardSection for Stereology and Microscopy, Department of Clinical Medicine, Core Centre for Molecular Morphology, Aarhus University, Aarhus, Denmark.
Richard E GilbertKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.ORCID https://orcid.org/0000-0002-6858-823X

Funding

Astra ZenecaMorris A. Hunter Charitable Trust
6 · The paper itself

Abstract

AIMS/

introductionWhile SGLT2 accounts for >90% of kidney glucose reabsorption, its pharmacological inhibition or genetic knockdown reduces glucose reabsorption by only 50%. MATERIALS AND

methodsWe postulated that the less than expected glucosuric response to SGLT2 inhibition might result from a compensatory increase in the length of the proximal tubule as seen in experimental diabetes where early tubular proliferation is followed by tubular lengthening. Taking advantage of their differing anatomical locations, stereological techniques were used to differentiate the SGLT1 expressing straight proximal tubule that lies within the outer stripe of the outer medulla (S3 segment) and that of the predominantly SGLT2 expressing early proximal convoluted tubule located within the kidney cortex (S1, S2 segments).

resultsThe SGLT2 inhibitor, dapagliflozin, induced an early, transient hyperplastic response (3-fold increase of Ki67 labelling, P < 0.0001) in S3 proximal tubular cells followed by a 32% increase in its length (P < 0.0001). In contrast, the length of the SGLT2 expressing S1, S2 segments of the proximal tubule was unaffected.

conclusionsThe finding that SGLT2 inhibition leads to expansion of the S3 segment of the proximal tubule, the site of SGLT1, is suggestive of a physiological response to diminish urinary glucose loss akin to that occurring in experimental diabetes. These findings provide a cogent explanation for the less-thanthan-expected effect of this drug class on glucose reabsorption.

Indexed as

Benzhydryl CompoundsCell ProliferationDiabetes Mellitus, ExperimentalGlucosidesKidney Tubules, ProximalSodium-Glucose Transporter 2 InhibitorsAnimalsMaleRatsSodium-Glucose Transporter 2Benzhydryl CompoundsdapagliflozinGlucosidesSlc5a2 protein, ratSodium-Glucose Transporter 2Sodium-Glucose Transporter 2 InhibitorsKidney growthproximal kidney tubulesodium‐glucose linked cotransporter 1, 2

Identifiers

PMID40260754
PMCPMC12209515

What Socratic holds

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.