Purpose

The purpose of this study was to characterize tissue-specific alterations in metabolism of hyperpolarized (HP) gluconeogenic precursors ¹³ C-lactate and ¹³ C-pyruvate by rat liver and kidneys under conditions of fasting or insulin-deprived diabetes.

Methods

Seven normal rats were studied by MR spectroscopic imaging of both HP ¹³ C-lactate and ¹³ C-pyruvate in both normal fed and 24 h fasting states, and seven additional rats were scanned after induction of diabetes by streptozotocin (STZ) with insulin withdrawal. Phosphoenolpyruvate carboxykinase (PEPCK) expression levels were also measured in liver and kidney tissues of the STZ-treated rats.

Results

Multiple sets of significant signal modulations were detected, with graded intensity in general between fasting and diabetic states. An approximate two-fold reduction in the ratio of ¹³ C-bicarbonate to total ¹³ C signal was observed in both organs in fasting. The ratio of HP lactate-to-alanine was markedly altered, ranging from a liver-specific 54% increase in fasting, to increases of 69% and 92% in liver and kidney, respectively, in diabetes. Diabetes resulted in a 40% increase in renal lactate signal. STZ resulted in 5.86-fold and 2.73-fold increases in PEPCK expression in liver and kidney, respectively.

Conclusion

MRI of HP ¹³ C gluconeogenic precursors may advance diabetes research by clarifying organ-specific roles in abnormal diabetic metabolism. Magn Reson Med 77:1429-1437, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Hyperpolarized (HP) ¹³C Magnetic Resonance Imaging (MRI) was applied for the first time to image and quantify the uptake and metabolism of [2-¹³C]pyruvate in the human brain to provide new metabolic information on cerebral energy metabolism. HP [2-¹³C]pyruvate was injected intravenously and imaged in 5 healthy human volunteer exams with whole brain coverage in a 1-minute acquisition using a specialized spectral-spatial multi-slice echoplanar imaging (EPI) pulse sequence to acquire ¹³C-labeled volumetric and dynamic images of [2-¹³C]pyruvate and downstream metabolites [5-¹³C]glutamate and [2-¹³C]lactate. Metabolic ratios and apparent conversion rates of pyruvate-to-lactate (k_PL) and pyruvate-to-glutamate (k_PG) were quantified to investigate simultaneously glycolytic and oxidative metabolism in a single injection.

We developed methods for the preparation of hyperpolarized (HP) sterile [2-¹³C]pyruvate to test its feasibility in first-ever human NMR studies following FDA-IND & IRB approval. Spectral results using this MR stable-isotope imaging approach demonstrated the feasibility of investigating human cerebral energy metabolism by measuring the dynamic conversion of HP [2-¹³C]pyruvate to [2-¹³C]lactate and [5-¹³C]glutamate in the brain of four healthy volunteers. Metabolite kinetics, signal-to-noise (SNR) and area-under-curve (AUC) ratios, and calculated [2-¹³C]pyruvate to [2-¹³C]lactate conversion rates (k_PL) were measured and showed similar but not identical inter-subject values. The k_PL measurements were equivalent with prior human HP [1-¹³C]pyruvate measurements.