Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus N, Denmark.
The MR Research Center, Aarhus University Hospital, Aarhus N, Denmark.
Exp Physiol. 2021 Dec;106(12):2412-2422. doi: 10.1113/EP089782. Epub 2021 Nov 15.
What is the central question of this study? Is it possible to combine the hyperpolarized magnetic resonance technique and the hyperinsulinaemic clamp method in order to evaluate skeletal muscle metabolism in a large animal model? What is the main finding and its importance? The logistical set-up is possible, and we found substantial increments in glucose infusion rates representing skeletal muscle glucose uptake but no differences in ratios of [1- C]lactate to [1- C]pyruvate, [1- C]alanine to [1- C]pyruvate, and C-bicarbonate to [1- C]pyruvate, implying that the hyperpolarization technique might not be optimal for detecting effects of insulin in skeletal muscle of anaesthetized animals, which is of significance for future studies.
In skeletal muscle, glucose metabolism is tightly regulated by the reciprocal relationship between insulin and adrenaline, with pyruvate being at the intersection of both pathways. Hyperpolarized magnetic resonance (hMR) is a new approach to gain insights into these pathways, and human trials involving hMR and skeletal muscle metabolism are imminent. We aimed to combine the hyperinsulinaemic clamp technique and hMR in a large animal model resembling human physiology. Fifteen anaesthetized pigs were randomized to saline (control group), hyperinsulinaemic euglycaemic clamp technique (HE group) or hyperinsulinaemic hypoglycaemic clamp technique (HH group). Skeletal muscle metabolism was evaluated by hyperpolarized [1- C]pyruvate injection and hMR at baseline and after intervention. The glucose infusion rate per kilogram increased by a statistically significant amount in the HE and HH groups (P < 0.001). Hyperpolarized magnetic resonance showed no statistically significant changes in metabolite ratios: [1- C]lactate to [1- C]pyruvate in the HH group versus control group (P = 0.19); and C-bicarbonate to [1- C]pyruvate ratio in the HE group versus the control group (P = 0.12). We found evidence of profound increments in glucose infusion rates representing skeletal muscle glucose uptake, but interestingly, no signs of significant changes in aerobic and anaerobic metabolism using hMR. These results imply that hyperpolarized [1- C]pyruvate might not be optimally suited to detect effects of insulin in anaesthetized resting skeletal muscle, which is of significance for future studies.
本研究的核心问题是什么？是否可以将超极化磁共振技术和高胰岛素正葡萄糖钳夹技术结合起来，以评估大型动物模型中的骨骼肌代谢？主要发现及其重要性是什么？从逻辑上讲，这种设置是可行的，我们发现葡萄糖输注率有实质性增加，这代表骨骼肌对葡萄糖的摄取，但 [1-13C] 乳酸与 [1-13C] 丙酮酸、[1-13C] 丙氨酸与 [1-13C] 丙酮酸和 13C 碳酸氢盐与 [1-13C] 丙酮酸的比值没有差异，这意味着超极化技术可能不适用于检测麻醉动物骨骼肌中胰岛素的作用，这对未来的研究具有重要意义。
在骨骼肌中，胰岛素和肾上腺素之间的相互关系对葡萄糖代谢进行严格调节，而丙酮酸则处于这两条途径的交汇点。超极化磁共振（hMR）是一种深入了解这些途径的新方法，涉及 hMR 和骨骼肌代谢的人体试验即将进行。我们的目的是在类似于人体生理学的大型动物模型中结合高胰岛素正葡萄糖钳夹技术和 hMR。15 头麻醉猪被随机分为生理盐水（对照组）、高胰岛素正葡萄糖钳夹技术（HE 组）或高胰岛素低血糖钳夹技术（HH 组）。在基线和干预后，通过超极化 [1-13C] 丙酮酸注射和 hMR 评估骨骼肌代谢。HE 组和 HH 组的葡萄糖输注率/kg 显著增加（P<0.001）。超极化磁共振显示，代谢物比值无统计学意义变化：HH 组 [1-13C] 乳酸与 [1-13C] 丙酮酸的比值与对照组相比（P=0.19）；HE 组 13C 碳酸氢盐与 [1-13C] 丙酮酸的比值与对照组相比（P=0.12）。我们发现葡萄糖输注率显著增加，这代表骨骼肌对葡萄糖的摄取，但有趣的是，使用 hMR 没有发现静息麻醉骨骼肌中胰岛素作用的明显变化。这些结果表明，超极化 [1-13C] 丙酮酸可能不适用于检测麻醉静止骨骼肌中胰岛素的作用，这对未来的研究具有重要意义。
