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P38 Non-invasive assessment of metformin induced changes in cardiac and hepatic redox state using hyperpolarized [1–13C] pyruvate
  1. Andrew JM Lewis1,
  2. Jack Miller1,2,
  3. Chloe McCallum1,
  4. Oliver Rider3,
  5. Stefan Neubauer3,
  6. Lisa Heather1,
  7. Damian J Tyler1
  1. 1Department of Physiology, Anatomy and Genetics, Sherrington Road, University of Oxford, UK
  2. 2Department of Physics, Clarendon Laboratory, University of Oxford, UK
  3. 3University of Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, UK

Abstract

Background and methods Metformin’s mechanism of action is controversial though may involve suppression of hepatic gluconeogenesis through perturbation of cellular redox state. Hyperpolarized magnetic resonance with [1-13C] pyruvate exploits huge increases in tracer signal to non-invasively assess both the redox coupled lactate dehydrogenase reaction and also pyruvate dehydrogenase activity. We performed hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopic and imaging assessments of heart and liver metabolism in Wistar rats following either a single infusion of metformin or longer term oral treatment.

Results Metformin infusion increased both cardiac and hepatic hyperpolarized [1-13C] lactate:[1-13C] pyruvate ratio (0.22 ± 0.04 versus 0.11 ± 0.01, P = 0.004 and 0.39 ± 0.04 versus 0.30 ± 0.02, P = 0.04 respectively) without changing pyruvate dehydrogenase flux. Metformin also increased both the cardiac and hepatic [lactate]:[pyruvate] ratio, a surrogate of cytosolic redox state (50 ± 8 versus 25 ± 7, P = 0.02 and 72 ± 12 versus 16 ± 8, P = 0.002 respectively). Longer term Metformin treatment for 4 weeks also increased the cardiac and hepatic hyperpolarized [1-13C] lactate:[1-13C] pyruvate ratio (0.27 ± 0.06 versus 0.10 ± 0.01, P = 0.005 and 0.87 ± 0.2 versus 0.36 ± 0.04, P = 0.003 respectively) without significantly changing pyruvate dehydrogenase flux and also increased the cardiac and hepatic [lactate]:[pyruvate] ratio (46 ± 6 versus 30 ± 6, P = 0.04 and 60 ± 9 versus 27 ± 3, P = 0.002 respectively).

Conclusions Both acute and chronic metformin treatment significantly increased both the cardiac and hepatic hyperpolarized [1-13C] lactate:[1-13C] pyruvate ratio, reflecting an increase in cytosolic redox state. These findings 1) identify a novel cardiac effect of metformin, 2) demonstrate the sensitivity of hyperpolarized [1-13C] pyruvate to metformin induced changes in redox biology and 3) have implications for the design of upcoming human studies using hyperpolarized MR to study cardiac metabolism in diabetes.

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