Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study

Abstract

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.

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

“…More importantly, their work suggested compartmental changes in insulin sensitivity, with increased insulin sensitivity in the skeletal muscle despite a decreased insulin response to hyperglycemia. While their study cannot directly comment on myocardial insulin sensitivity, their study corroborates previous studies confirming an important and direct role for insulin signaling in the pathogenesis of PAH (129,131,144).…”

“…Finally, the presence of metabolic syndrome, and not obesity alone, is associated with a load-dependent decrease in RV function, suggesting a loss of contractile reserve in the setting of insulin resistance (143). Most recently, Mey et al have utilized a hyperglycemic clamp in patients with PAH and controls to demonstrate global alterations in glucose homeostasis with a reduced response of insulin response to hyperglycemia (144). More importantly, their work suggested compartmental changes in insulin sensitivity, with increased insulin sensitivity in the skeletal muscle despite a decreased insulin response to hyperglycemia.…”

Liver abnormalities in pulmonary arterial hypertension

“…Surprisingly, the reduction in the insulin response was not due to reduced pancreatic insulin secretion or poor peripheral tissue insulin response, as expected in patients with insulin resistance and metabolic syndrome. The authors rather found an increased hepatic insulin extraction in PAH patients contributing to abnormal oral glucose homeostasis 82 . These findings underscore that abnormal glucose homeostasis in PAH patients is unlikely due to peripheral tissue level (skeletally muscle) insulin resistance and perhaps mediated by decreased systemic insulin circulation due to increased hepatic extraction of insulin.…”

What’s new in pulmonary hypertension clinical research: lessons from the best abstracts at the 2020 American Thoracic Society International Conference

“…Abnormal fatty acid metabolism is also a recognized feature of PAH, as fatty acid accumulation has been observed in the myocardium of patients 119 . Recent work demonstrates a shift towards lipid and ketone metabolism at the expense of glucose control, perhaps as an adaptive response to supply the failing cardiac tissue with an additional source of energy 120 121 (a composite score of disease burden risk). The relationship of BMI with survival was non-linear across the BMI spectrum, with a sharp increase in risk as BMI transitioned from the normal to underweight range (Fig.…”

“… 119 Recent work demonstrates a shift towards lipid and ketone metabolism at the expense of glucose control, perhaps as an adaptive response to supply the failing cardiac tissue with an additional source of energy. 120 Building on this body of work implicating dysregulated metabolism in PAH, Drs. Aaron Trammell and Anna Hemnes each presented studies which investigated metabolic features of PH across the spectrum of WSPH subgroups.…”