Hyperpolarized Pyruvate To Measure The Influence Of Pkm2 Activation On Glucose Metabolism In The Healthy Kidney

The purpose of the current study was to investigate if hyperpolarized [1-C-13]pyruvate can inform us on the metabolic consequences for the kidney glucose metabolism upon treatment with the pyruvate kinase M2 (PKM2) activator TEPP-46, which has shown promise as a novel therapeutic target for diabetic nephropathy. A healthy male Wistar rat model was employed to study the conversion of [1-C-13]pyruvate to [1-C-13]lactate in the kidney 2 and 4 h after treatment with TEPP-46. All rats were scanned with hyperpolarized [1-C-13]pyruvate kidney MR and vital parameters and blood samples were taken after scanning. The PKM2 activator TEPP-46 increases the glycolytic activity in the kidneys, leading to an increased lactate production, as seen by hyperpolarized pyruvate-to-lactate conversion. The results are supported by an increase in blood lactate, a decreased blood glucose level and an increased pyruvate kinase (PK) activity. The metabolic changes observed in both kidneys following treatment with TEPP-46 are largely independent of renal function and could as such represent a new and extremely sensitive metabolic readout for future drugs targeting PKM2. These results warrant further studies in disease models to evaluate if [1-C-13]pyruvate-to-[1-C-13]lactate conversion can predict treatment outcome.