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

Abstract

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.

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus

“… SLC family Gene name Protein name Genetic polymophism Drug (category) Ref. SLC21/SLCO SLCO1B1 OATP1B1 rs4149056, rs2306283, rs4149015 Repaglinide, nateglinide (Meglitinide derivatives); Rosiglitazone (Tiazolidinediones) 104 , 105 , 106 , 107 , 108 SLC22 SLC22A1 OCT1 rs12208357, rs34130495, rs72552763, rs34059508, rs34104736, rs36103319, rs34447885, rs628031, rs200684404, rs1867351, rs622342, rs3413095, rs461473, rs4646272 Metformin (Biguanide) 111 , 112 , 113 , 114 , 115 , 116 , 117 SLC22A2 OCT2 rs145450955, rs316019, rs201919874 Metformin (Biguanide) 119 , 120 , 121 , 122 SLC22A3 OCT3 rs2076828, rs68187715, rs8187725, V423F Metformin (Biguanide) 123 , 124 SLC47 SLC47A1 MATE1 rs2252281, rs2289669, rs8065082, rs77630697, rs77474263, rs35790011, rs76645859, rs35395280, rs149774861, A310V rs35646404 Metformin (Biguanide) 126 , 127 , 128 , 129 , 130 SLC47A2 MATE2 K64N, G211V, G393R, rs34399035, rs146901447, rs12943590 Metformin (Biguanide) 115 , 130 , 131 …”

“…Among these members, SLC22A1 (OCT1), SLC22A2 (OCT2), and SLC22A3 (OCT3) have been found to play essential roles in the pharmacokinetics of metformin 110 . Genetic polymorphisms in SLC22A1 , including R61C (rs12208357), G401S (rs34130495), M420del (rs72552763), G465R (rs34059508), S189L (rs34104736), G220V (rs36103319), S14F (rs34447885), M408V (rs628031), and P117L (rs200684404), have been associated with decreased cellular uptake and reduced therapeutic effectiveness of metformin 111 , 112 , 113 , 114 , 115 , 116 . Variants, such as R61C, G401S, M420del, G465R, and a promoter-linked synonymous variant (rs1867351) of the SLC22A1 gene, are thought to increase the renal clearance of metformin 114 .…”

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

“…Recommended daily dosage of metformin is 1 to almost 2.5 g/day depending upon individual tolerance of gastrointestinal side effects. Absorption of dietary Zn 2+ from the gut is 16-50% (Maares & Haase 2020); and absorption of a dose of metformin is approximately 60% (Zake et al 2021(Zake et al , 2022. Much dietary Zn 2+ is wasted due to the low bioavailability associated with binding to intestinal contents.…”

Association of Single Nucleotide Polymorphism in OCT1 and OCT3 Genes with the Efficacy of Metformin Response in North Indian Type 2 Diabetes Mellitus Patients.

“…According to the in vitro and in silico analysis, Met408Val missense polymorphism reduce OCT1 mRNA expression [6], alters the structure of OCT-1 protein and thus affects disposition of metformin [7]. On the other hand, the OCT3 rs2292334 (1233G > A) is a variant in which G > A displacement converts one alanine codon into another codon for alanine (A411A) resulting in altered mRNA expression levels of OCT3 gene [8].…”