PMID- 37762353
OWN - NLM
STAT- MEDLINE
DCOM- 20231004
LR  - 20231004
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 18
DP  - 2023 Sep 13
TI  - Regulation of Transporters for Organic Cations by High Glucose.
LID - 10.3390/ijms241814051 [doi]
LID - 14051
AB  - Endogenous positively charged organic substances, including neurotransmitters and 
      cationic uremic toxins, as well as exogenous organic cations such as the 
      anti-diabetic medication metformin, serve as substrates for organic cation 
      transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). These 
      proteins facilitate their transport across cell membranes. Vectorial transport 
      through the OCT/MATE axis mediates the hepatic and renal excretion of organic 
      cations, regulating their systemic and local concentrations. Organic cation 
      transporters are part of the remote sensing and signaling system, whose activity 
      can be regulated to cope with changes in the composition of extra- and 
      intracellular fluids. Glucose, as a source of energy, can also function as a 
      crucial signaling molecule, regulating gene expression in various organs and 
      tissues. Its concentration in the blood may fluctuate in specific physiological 
      and pathophysiological conditions. In this work, the regulation of the activity 
      of organic cation transporters was measured by incubating human embryonic kidney 
      cells stably expressing human OCT1 (hOCT1), hOCT2, or hMATE1 with high glucose 
      concentrations (16.7 mM). Incubation with this high glucose concentration for 48 
      h significantly stimulated the activity of hOCT1, hOCT2, and hMATE1 by increasing 
      their maximal velocity (V(max)), but without significantly changing their 
      affinity for the substrates. These effects were independent of changes in 
      osmolarity, as the addition of equimolar concentrations of mannitol did not alter 
      transporter activity. The stimulation of transporter activity was associated with 
      a significant increase in transporter mRNA expression. Inhibition of the 
      mechanistic target of rapamycin (mTOR) kinase with Torin-1 suppressed the 
      transporter stimulation induced by incubation with 16.7 mM glucose. Focusing on 
      hOCT2, it was shown that incubation with 16.7 mM glucose increased hOCT2 protein 
      expression in the plasma membrane. Interestingly, an apparent trend towards 
      higher hOCT2 mRNA expression was observed in kidneys from diabetic patients, a 
      pathology characterized by high serum glucose levels. Due to the small number of 
      samples from diabetic patients (three), this observation must be interpreted with 
      caution. In conclusion, incubation for 48 h with a high glucose concentration of 
      16.7 mM stimulated the activity and expression of organic cation transporters 
      compared to those measured in the presence of 5.6 mM glucose. This stimulation by 
      a diabetic environment could increase cellular uptake of the anti-diabetic drug 
      metformin and increase renal tubular secretion of organic cations in an early 
      stage of diabetes.
FAU - Steinbuchel, Martin
AU  - Steinbuchel M
AD  - Experimental Nephrology, Department of Internal Medicine D, University Hospital 
      Munster, 48149 Munster, Germany.
FAU - Menne, Johannes
AU  - Menne J
AD  - Experimental Nephrology, Department of Internal Medicine D, University Hospital 
      Munster, 48149 Munster, Germany.
FAU - Schroter, Rita
AU  - Schroter R
AD  - Experimental Nephrology, Department of Internal Medicine D, University Hospital 
      Munster, 48149 Munster, Germany.
FAU - Neugebauer, Ute
AU  - Neugebauer U
AD  - Experimental Nephrology, Department of Internal Medicine D, University Hospital 
      Munster, 48149 Munster, Germany.
FAU - Schlatter, Eberhard
AU  - Schlatter E
AD  - Experimental Nephrology, Department of Internal Medicine D, University Hospital 
      Munster, 48149 Munster, Germany.
FAU - Ciarimboli, Giuliano
AU  - Ciarimboli G
AUID- ORCID: 0000-0002-4365-3656
AD  - Experimental Nephrology, Department of Internal Medicine D, University Hospital 
      Munster, 48149 Munster, Germany.
LA  - eng
GR  - CI107/11-1-2 and CI107/14-1/Deutsche Forschungsgemeinschaft/
PT  - Journal Article
DEP - 20230913
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Organic Cation Transport Proteins)
RN  - 0 (Organic Cation Transporter 2)
RN  - 9100L32L2N (Metformin)
RN  - 0 (Cations)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Humans
MH  - *Organic Cation Transport Proteins/metabolism
MH  - Organic Cation Transporter 2/genetics
MH  - *Metformin/pharmacology/metabolism
MH  - Cations/metabolism
MH  - RNA, Messenger
PMC - PMC10531077
OTO - NOTNLM
OT  - diabetes
OT  - glucose
OT  - organic cation transporters
OT  - regulation
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2023/09/28 06:43
MHDA- 2023/10/04 06:43
PMCR- 2023/09/13
CRDT- 2023/09/28 01:18
PHST- 2023/08/01 00:00 [received]
PHST- 2023/09/08 00:00 [revised]
PHST- 2023/09/11 00:00 [accepted]
PHST- 2023/10/04 06:43 [medline]
PHST- 2023/09/28 06:43 [pubmed]
PHST- 2023/09/28 01:18 [entrez]
PHST- 2023/09/13 00:00 [pmc-release]
AID - ijms241814051 [pii]
AID - ijms-24-14051 [pii]
AID - 10.3390/ijms241814051 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Sep 13;24(18):14051. doi: 10.3390/ijms241814051.