Dataset Information

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 &2 and AMP-activated Protein Kinase in the Kidney.

ABSTRACT: The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3-day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic cation transporters (OCTs). To test whether the effects of metformin in the kidney are dependent on these transporters, we tested metformin treatment in OCT1/2^-/- mice. Even though exposure of metformin in the kidney was severely decreased in OCT1/2^-/- mice when evaluated with [¹¹C]-Metformin and PET/MRI, we found that the protective effects of metformin were OCT1/2 independent when tested in this model. AMP-activated protein kinase (AMPK) has been suggested as a key mediator of the effects of metformin. When using an AMPK-?1 KO mouse model, the protective effects of metformin still occurred in the 3dUUO model. In conclusion, these results show that metformin has a beneficial effect in early stages of renal disease induced by 3dUUO. Furthermore, these effects appear to be independent of the expression of OCT1/2 and AMPK-?1, the most abundant AMPK-? isoform in the kidney.

SUBMITTER: Christensen M

PROVIDER: S-EPMC5080611 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 &2 and AMP-activated Protein Kinase in the Kidney.

Christensen Michael M Jensen Jonas B JB Jakobsen Steen S Jessen Niels N Frøkiær Jørgen J Kemp Bruce E BE Marciszyn Allison L AL Li Hui H Pastor-Soler Núria M NM Hallows Kenneth R KR Nørregaard Rikke R Nørregaard Rikke R

Scientific reports 20161026

The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3-day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic catio ...[more]

PMID: 27782167

Similar Datasets

Project description:Background and Aims: Metformin is the most widely-used anti-diabetic drug in the United States. However, medication management fails to achieve therapeutic goals in ~20% of patients. This study attempted to identify genetic polymorphisms associated with metformin treatment failure. We studied the associations between polymorphisms in two liver and kidney organic cation transporter genes (OCT1 & OCT2) and two kidney multidrug and toxin extrusion transporter genes, (MATE1 & MATE2K) and response to metformin monotherapy. Methods: At Kaiser Permanente Southeast and Marshfield Clinic Research Foundation we identified 304 type 2 diabetes (T2DM) patients on metformin monotherapy who: were enrolled for >=6 months prior to initiation; remained on metformin >= 90 days following initiation; and had a HgbA1c measured prior to first metformin prescription and then after initiation. From this group we selected 171 patients who had not received metformin or other anti-diabetics previously, and had baseline HbA1c levels >7.0% prior to metformin initiation. We genotyped 10 SNPs, and assessed response by measuring absolute and relative change in HbA1c after after metformin initiation. Results: Three SNPs were identified that were significantly associated with reduced response to metformin, after adjustment for baseline HbA1c, dose, and ethnicity. In a dominant model, heterozygosity or homozygosity for minor A allele in the MATE1 intronic SNP, rs2289669, resulted in a smaller absolute change in HbA1c (mean of 0.45% less reduction in absolute change in HbA1c; 95% CI 0.17 to 0.74%) compared to individuals homozygous for major G allele. In a recessive model, homozygosity for minor A allele in MATE2K 5′-UTR SNP, rs12943590, resulted in smaller absolute change in HbA1c (mean of 0.43% less reduction in absolute change in HbA1c, 95% CI 0.053 to 0.86%). The reduced function SNPs in OCT1 & OCT2 were not associated with metformin response, except for rs34059508 (G465R). This SNP showed a positive (but not statistically significant) association with smaller absolute change in HbA1c (mean of 0.49%; 95% CI −0.06354 to 1.045%). Conclusions: These three variants of metformin transporter genes may be important for personalizing treatment for patients with T2DM. A replication study in a larger population is currently being planned.

Dataset Information

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 &2 and AMP-activated Protein Kinase in the Kidney.

Publications

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 &2 and AMP-activated Protein Kinase in the Kidney.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets