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Abstract: PO0714

Hyperpolarized MRI Detection of Dapagliflozin Effect on Gluconeogenesis in Live Animals: Proof of Principle

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Shabbir, Waheed, University of California San Francisco, San Francisco, California, United States
  • Takagi, Enzo, University of California San Francisco, San Francisco, California, United States
  • Ohliger, Michael, University of California San Francisco, San Francisco, California, United States
  • Pearce, David, University of California San Francisco, San Francisco, California, United States

Group or Team Name

  • David Pearce group
Background

SGLT2 inhibitors including dapagliflozin (dapa) ameliorate hyperglycemia by inducing glucosuria but also induce gluconeogenesis (GNG), thus blunting efficacy. The lack of insight into the relative contributions of kidney and liver to GNG in different states is due at least in part to limitations in the technology to separately assess liver and kidney GNG in live animals. Our study exploits a powerful technology, Hyperpolarized Magnetic Resonance Imaging (HP-MRI), which can detect metabolic conversions non-invasively in specific organs in animals and humans, in real-time, in vivo. Notably, the chemicals based on stable isotopes of carbon (13-C) used here are approved for multiple diagnostic uses in humans, for example in monitoring metabolism in cancers.

Methods

Metabolic features of healthy WT (male, age ~12 weeks) rats were studied in vivo using hyperpolarized (HP) 13C magnetic resonance imaging (MRI) is based on ~50,000-fold nuclear magnetic resonance (NMR) signal enhancements of 13C-labeled substrates via dissolution dynamic nuclear polarization (DNP). To account for potential metabolic effects of infusion of pyruvate, we also performed [1- 13C] pyruvate tolerance tests (PTT).

Results

We successfully detected the conversion of [1-13C]pyruvate to [1-13C]lactate and [1-13C]alanine in the liver and kidneys of rats. We found that Intravenously injected HP [1- 13C]pyruvate was rapidly metabolized to [1- 13C]lactate and [1- 13C]alanine in the liver and kidneys of rats. The PTT data show that there is a clear trend toward an increase in blood glucose following [1- 13C]pyruvate injection. Dapa increased glycosuria, as expected. Furthermore, an effect of dapa was on the conversion of [1-13C]pyruvate to [1-13C]lactate and [1-13C]alanine in the kidney but not the liver. This effect, however, was variable and appeared to be influenced by baseline GNG in the rats.

Conclusion

We establish here for the first time that HP-MRI technology can detect SGLT2i effects on metabolism in live rats, and can distinguish metabolic markers of GNG in kidney vs. liver in this context. Although the methodology requires further development to be useful as a consistent marker of SGLT2i effects on GNG, it could be useful in humans both for characterizing sub-categories of T2DM and detecting risk factors for SGLT2i resistance and/or side effects.

Funding

  • NIDDK Support