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Sodium-glucose transporter-2 (SGLT2; SLC5A2) enhances cellular uptake of aminoglycosides.

ABSTRACT: Aminoglycoside antibiotics, like gentamicin, continue to be clinically essential worldwide to treat life-threatening bacterial infections. Yet, the ototoxic and nephrotoxic side-effects of these drugs remain serious complications. A major site of gentamicin uptake and toxicity resides within kidney proximal tubules that also heavily express electrogenic sodium-glucose transporter-2 (SGLT2; SLC5A2) in vivo. We hypothesized that SGLT2 traffics gentamicin, and promotes cellular toxicity. We confirmed in vitro expression of SGLT2 in proximal tubule-derived KPT2 cells, and absence in distal tubule-derived KDT3 cells. D-glucose competitively decreased the uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescent analog of glucose, and fluorescently-tagged gentamicin (GTTR) by KPT2 cells. Phlorizin, an SGLT2 antagonist, strongly inhibited uptake of 2-NBDG and GTTR by KPT2 cells in a dose- and time-dependent manner. GTTR uptake was elevated in KDT3 cells transfected with SGLT2 (compared to controls); and this enhanced uptake was attenuated by phlorizin. Knock-down of SGLT2 expression by siRNA reduced gentamicin-induced cytotoxicity. In vivo, SGLT2 was robustly expressed in kidney proximal tubule cells of heterozygous, but not null, mice. Phlorizin decreased GTTR uptake by kidney proximal tubule cells in Sglt2+/- mice, but not in Sglt2-/- mice. However, serum GTTR levels were elevated in Sglt2-/- mice compared to Sglt2+/- mice, and in phlorizin-treated Sglt2+/- mice compared to vehicle-treated Sglt2+/- mice. Loss of SGLT2 function by antagonism or by gene deletion did not affect gentamicin cochlear loading or auditory function. Phlorizin did not protect wild-type mice from kanamycin-induced ototoxicity. We conclude that SGLT2 can traffic gentamicin and contribute to gentamicin-induced cytotoxicity.

SUBMITTER: Jiang M

PROVIDER: S-EPMC4182564 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Sodium-glucose transporter-2 (SGLT2; SLC5A2) enhances cellular uptake of aminoglycosides.

Jiang Meiyan M Wang Qi Q Karasawa Takatoshi T Koo Ja-Won JW Li Hongzhe H Steyger Peter S PS

PloS one 20140930 9

Aminoglycoside antibiotics, like gentamicin, continue to be clinically essential worldwide to treat life-threatening bacterial infections. Yet, the ototoxic and nephrotoxic side-effects of these drugs remain serious complications. A major site of gentamicin uptake and toxicity resides within kidney proximal tubules that also heavily express electrogenic sodium-glucose transporter-2 (SGLT2; SLC5A2) in vivo. We hypothesized that SGLT2 traffics gentamicin, and promotes cellular toxicity. We confirm ...[more]

PMID: 25268124

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Project description:IntroductionThe first cardiovascular safety trial in the sodium-glucose co-transporter-2 (SGLT2) inhibitor drug class, the Empagliflozin Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, demonstrated significant cardiovascular risk reduction with empagliflozin. It is currently not clear what proportions of people with type 2 diabetes (T2DM) have the same high cardiovascular risk as those included in the trial, and will therefore be likely to experience the same cardiovascular benefit. We aimed to identify and describe the proportion of people with T2DM from a representative English national population who have the comparable high cardiovascular risk to those included in the EMPA-REG trial.MethodA cross-sectional analysis of cardiovascular risk in people with T2DM and a subgroup prescribed SGLT2 inhibitors. Patients were identified from the Royal College of General Practitioners Research and Surveillance Centre database. Cardiovascular risk factors were identified from electronic patient records.ResultsFrom 1,238,909 patients at 128 GP practices, we identified 60,327 adults with T2DM (mean age 66.1 years, SD 13.9) of whom 55.6% were male. From these 1642 (2.7%) people had been initiated on an SGLT2 inhibitor (mean age 58.1 years, SD 10.4; 58.8% male). In the complete T2DM group only 15.7% (95% CI 15.5-16.0%) had the same high cardiovascular risk as those included in the EMPA-REG trial. In those already initiated on SGLT2 inhibitors this proportion was 11.1% (95% CI 9.8-12.4%). Whilst the proportion was higher in the oldest age groups, in those 70+ years old less than a quarter met the EMPA-REG trial high cardiovascular risk criteria.ConclusionsThe EMPA-REG trial results are applicable only to a small proportion of people with T2DM and a smaller proportion of those currently treated with SGLT2 inhibitors. Additional data are required to identify any cardiovascular benefit in people with lower cardiovascular risk.FundingAstraZeneca.

Project description:Sodium-glucose co-transporter-2 (SGLT2) inhibitors (gliflozins) are the newest class of medication available to treat type 2 diabetes (T2DM). Recent findings from the first complete cardiovascular safety trial in SGLT2 inhibitors, the Empagliflozin, Cardiovascular Outcomes, and Mortality in type 2 diabetes (EMPA-REG OUTCOMES) trial, demonstrated reduced cardiovascular outcomes in people with high cardiovascular risk. How to apply these findings to clinical practice remains unclear, with questions remaining on who will reap this cardiovascular benefit.To describe the proportion of people in the real world currently treated with SGLT2 inhibitors who meet the inclusion criteria of the EMPA-REG trial and therefore could expect the cardiovascular benefit identified by the trial. Similarly, to describe the proportion of people from the whole T2DM population who could also expect this same benefit.Routinely collected data from UK primary care in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database will be used. The study population will include all people with T2DM within this database (approximately 60,000). We will perform a cross-sectional investigation to describe the characteristics of people currently using SGTL2 inhibitors compared with the population of the EMPA-REG trail. We will similarly compare the characteristics of the RCGP RSC T2DM cohort with the inclusion criteria of the EMPA-REG trial.People with T2DM using a pre-existing verified clinical ontological process will be identified, as will people with prescriptions for SGLT2 inhibitors and other medications using Read coded and other proprietary coding systems. Descriptive statistics will be used to characterise the key clinical characteristics of people with T2DM using SGLT2 inhibitors and to compare these characteristics to people included in EMPA-REG trial; the proportion of people who match the trial criteria will be reported.Peer review publication reporting the real world lessons for clinical practice.AstraZeneca.

Project description:OBJECTIVE:To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies. DESIGN:We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs). INTERVENTION:SGLT2 inhibitors, compared with placebo or active comparators. PRIMARY OUTCOMES:Acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations. RESULTS:We screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95%?CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95%?CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95%?CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95%?CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95%?CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture. CONCLUSIONS:Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear. PROSPERO REGISTRATION NUMBER:CRD42016038715.

Dataset Information

Sodium-glucose transporter-2 (SGLT2; SLC5A2) enhances cellular uptake of aminoglycosides.

Publications

Sodium-glucose transporter-2 (SGLT2; SLC5A2) enhances cellular uptake of aminoglycosides.

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