Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycaemia in PAH. 12 participants (six PAH, six controls) were administered a hyperglycaemic clamp, while 52 (21 PAH, 31 controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples. The clamp verified a reduced insulin response to hyperglycaemia in PAH (−53% versus control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% versus control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p<0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer six-min walk distance. Poor glucose control in PAH could not be explained by pancreatic β-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favours lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH. Highly technical metabolic approaches show that fasting nutrient metabolism in pulmonary arterial hypertension favours lipid and ketone metabolism and that, in response to hyperglycaemia, pancreatic β-cell function is similar to control participants http://bit.ly/2uihG2Q

中文翻译：

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脂质和酮在肺动脉高血压中以葡萄糖控制为代价主导代谢：高血糖钳和代谢组学研究

患有特发性肺动脉高压 (PAH) 的个体表现出口服葡萄糖耐量降低。这可能涉及胰腺功能或胰岛素敏感性的缺陷，但该假设尚未得到验证；此外，在 PAH 中对空腹营养代谢的描述仍然很差。因此，我们旨在表征空腹营养代谢，并研究 PAH 对高血糖的代谢反应。12 名参与者（6 名 PAH，6 名对照组）接受了高血糖钳夹，而 52 名（21 名 PAH，31 名对照组）接受了血浆代谢组学分析。从钳夹评估葡萄糖、胰岛素、C-肽、游离脂肪酸和酰基肉碱。对空腹血浆样品进行血浆代谢组学。钳夹证实了对 PAH 中高血糖的胰岛素反应降低（-53% 与对照相比），但与胰腺胰岛素分泌相似。PAH 中骨骼肌胰岛素敏感性出乎意料地更高。PAH 中的肝胰岛素提取升高（+11% 与对照相比）。血浆代谢组学鉴定了 862 种代谢物：PAH 中 213 种升高，145 种降低（p<0.05）。在钳夹组和代谢组组中，PAH 中的脂质氧化和酮均升高。胰岛素敏感性、脂肪酸、酰基肉碱和酮与 PAH 的严重程度相关，而肝脏提取和脂肪酸：酮比与更长的六分钟步行距离相关。PAH 血糖控制不佳不能用胰腺 β 细胞功能或骨骼肌胰岛素敏感性来解释。相反，肝脏胰岛素提取升高成为潜在因素。一致认为，PAH 中的营养代谢有利于脂质和酮代谢，而牺牲了葡萄糖控制。未来的研究应该调查加强脂质和酮代谢对 PAH 临床结果的治疗潜力。高度技术化的代谢方法表明，肺动脉高压中的空腹营养代谢有利于脂质和酮代谢，并且在应对高血糖时，胰腺 β 细胞功能与对照参与者相似 http://bit.ly/2uihG2Q