Diabetologia

, Volume 61, Issue 2, pp 445–454 | Cite as

Acute renal metabolic effect of metformin assessed with hyperpolarised MRI in rats

  • Haiyun Qi
  • Per M. Nielsen
  • Marie Schroeder
  • Lotte B. Bertelsen
  • Fredrik Palm
  • Christoffer Laustsen
Article

Abstract

Aims/hypothesis

Metformin inhibits hepatic mitochondrial glycerol phosphate dehydrogenase, thereby increasing cytosolic lactate and suppressing gluconeogenesis flux in the liver. This inhibition alters cytosolic and mitochondrial reduction–oxidation (redox) potential, which has been reported to protect organ function in several disease states including diabetes. In this study, we investigated the acute metabolic and functional changes induced by metformin in the kidneys of both healthy and insulinopenic Wistar rats used as a model of diabetes.

Methods

Diabetes was induced by intravenous injection of streptozotocin, and kidney metabolism in healthy and diabetic animals was investigated 4 weeks thereafter using hyperpolarised 13C-MRI, Clark-type electrodes and biochemical analysis.

Results

Metformin increased renal blood flow, but did not change total kidney oxygen consumption. In healthy rat kidneys, metformin increased [1-13C]lactate production and reduced mitochondrial [1-13C]pyruvate oxidation (decreased the 13C-bicarbonate/[1-13C]pyruvate ratio) within 30 min of administration. Corresponding alterations to indices of mitochondrial, cytosolic and whole-cell redox potential were observed. Pyruvate oxidation was maintained in the diabetic rats, suggesting that the diabetic state abrogates metabolic reprogramming caused by metformin.

Conclusions/interpretation

This study demonstrates that metformin-induced acute metabolic alterations in healthy kidneys favoured anaerobic metabolism at the expense of aerobic metabolism. The results suggest that metformin directly alters the renal redox state, with elevated renal cytosolic redox states as well as decreased mitochondrial redox state. These findings suggest redox biology as a novel target to eliminate the renal complications associated with metformin treatment in individuals with impaired renal function.

Keywords

Diabetes Hyperpolarised MRI Metformin Renal function Renal metabolism Renal redox 

Abbreviations

AMPK

AMP-activated protein kinase

LDH

Lactate dehydrogenase

MAP

Mean arterial pressure

mGPD

Mitochondrial glycerophosphate dehydrogenase

PDH

Pyruvate dehydrogenase

pO2

Oxygen tension

QO2

Oxygen consumption

RBF

Renal blood flow

RVR

Renal vascular resistance

STZ

Streptozotocin

TNa

Tubular Na+ reabsorption

Notes

Acknowledgements

The technical support of H. Vestergaard Nielsen (MR Research Centre, Department of Clinical Medicine, Aarhus University) and A. Fasching (Department of Medical Cell Biology, Uppsala University) are gratefully acknowledged.

Data availability

Data is available on request. Correspondence and requests for materials should be addressed to C Lautsen (cl@clin.au.dk).

Funding

The study was supported by the Sundhed og Sygdom, Det Frie Forskningsråd, Aarhus University research fund.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

HQ wrote the manuscript and contributed to acquisition and analysis of data. PMN and LBB contributed to acquisition of data and revised the manuscript. MS contributed to the acquisition of data, revised the manuscript and contributed to discussion. FP and CL conceived and designed the study, contributed to the analysis and interpretation of data, contributed to discussion, and wrote and reviewed the manuscript. All authors approved the final version to be published. CL is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Supplementary material

125_2017_4445_MOESM1_ESM.pdf (550 kb)
ESM (PDF 549 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.MR Research Centre, Department of Clinical MedicineAarhus UniversityAarhus NDenmark
  2. 2.Department of Medical Cell BiologyUppsala UniversityUppsalaSweden

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