Hyperpolarized [1- C]pyruvate combined with the hyperinsulinaemic euglycaemic and hypoglycaemic clamp technique in skeletal muscle in a large animal model.

NEW FINDINGS

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.

ABSTRACT

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.