The purpose of the current study was to investigate if hyperpolarized [1-¹³C]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 [1-¹³C]pyruvate to [1-¹³C]lactate in the kidney 2 and 4 h after treatment with TEPP-46. All rats were scanned with hyperpolarized [1-¹³C]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 [1-¹³C]pyruvate-to-[1-¹³C]lactate conversion can predict treatment outcome.

中文翻译：

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超极化丙酮酸测量 PKM2 激活对健康肾脏葡萄糖代谢的影响

当前研究的目的是调查超极化的 [1- ¹³ C]丙酮酸是否可以告知我们在用丙酮酸激酶 M2 (PKM2) 激活剂 TEPP-46 治疗后对肾脏葡萄糖代谢的代谢后果，TEPP-46 已显示出前景糖尿病肾病的新治疗靶点。使用健康雄性 Wistar 大鼠模型研究用 TEPP-46 治疗后 2 和 4 小时肾脏中 [1- ¹³ C]丙酮酸向[1- ^{13 C]乳酸的转化。}用超极化扫描所有大鼠 [ ^1-13C]丙酮酸肾MR和重要参数扫描后采集血样。PKM2 激活剂 TEPP-46 增加了肾脏的糖酵解活性，导致乳酸产生增加，如超极化的丙酮酸到乳酸的转化所示。结果得到血乳酸增加、血糖水平降低和丙酮酸激酶 (PK) 活性增加的支持。用 TEPP-46 治疗后在两个肾脏中观察到的代谢变化在很大程度上与肾功能无关，因此可能代表未来靶向 PKM2 药物的新的和极其敏感的代谢读数。这些结果需要在疾病模型中进行进一步研究，以评估 [1- ¹³ C]丙酮酸到-[1- ¹³ C]乳酸的转化是否可以预测治疗结果。