Role of human organic cation transporter-1 (OCT-1/SLC22A1) in modulating the response to metformin in patients with type 2 diabetes

Background Organic cation transporter 1 primarily governs the action of metformin in the liver. There are considerable inter-individual variations in metformin response. In light of this, it is crucial to obtain a greater understanding of the influence of OCT1 expression or polymorphism in the conte...

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Published in:BMC endocrine disorders Vol. 22; no. 1; pp. 140 - 11
Main Authors: Kawoosa, Fizalah, Shah, Zafar A., Masoodi, Shariq R., Amin, Asif, Rasool, Roohi, Fazili, Khalid M., Dar, Abid Hamid, Lone, Asif, ul Bashir, Samir
Format: Journal Article
Language:English
Published: London BioMed Central 26.05.2022
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
AMPK
Antidiabetics
Care and treatment
Cluster analysis
Diabetes
Diabetes mellitus (non-insulin dependent)
Endocrinology
Ethylenediaminetetraacetic acid
Gene expression
Genetic aspects
Genetic diversity
Genotyping
Hypoglycemic agents
Ligands
Liver
Medicine
Medicine & Public Health
Metabolic Diseases
Metformin
Monoclonal antibodies
Mutagenesis
Oct-1 protein
Organic cation transporter
Organic cation transporter 1(OCT-1/SLC22A1)
Patients
Proteins
RNA
rology
Simulation
Single-nucleotide polymorphism
Type 2 diabetes
India
United States > US
AMPK
Organic cation transporter 1(OCT-1/SLC22A1)
Metformin
ISSN:1472-6823, 1472-6823
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Summary:Background Organic cation transporter 1 primarily governs the action of metformin in the liver. There are considerable inter-individual variations in metformin response. In light of this, it is crucial to obtain a greater understanding of the influence of OCT1 expression or polymorphism in the context of variable responses elicited by metformin treatment. Results We observed that the variable response to metformin in the responders and non-responders is independent of isoform variation and mRNA expression of OCT-1. We also observed an insignificant difference in the serum metformin levels of the patient groups. Further, molecular docking provided us with an insight into the hotspot regions of OCT-1 for metformin binding. Genotyping of these regions revealed SNPs 156T>C and 1222A>G in both the groups, while as 181C>T and 1201G>A were found only in non-responders. The 181T>C and 1222A>G changes were further found to alter OCT-1 structure in silico and affect metformin transport in vitro which was illustrated by their effect on the activation of AMPK, the marker for metformin activity. Conclusion Taken together, our results corroborate the role of OCT-1 in the transport of metformin and also point at OCT1 genetic variations possibly affecting the transport of metformin into the cells and hence its subsequent action in responders and non-responders.
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ISSN:1472-6823
1472-6823
DOI:10.1186/s12902-022-01033-3