Human PAH is characterized by a pattern of lipid-related insulin resistance

Hemnes, Anna R.; Luther, James M.; Rhodes, Christopher J.; Burgess, Jason P.; Carlson, James E.; Fan, Ruitai; Fessel, Joshua P.; Fortune, N.; Gerszten, Robert E.; Halliday, Stephen; Hekmat, Rezzan; Howard, Luke; Newman, John H.; Niswender, Kevin D.; Pugh, Meredith E.; Robbins, Ivan M.; Sheng, Quanhu; Shibao, Cyndya A.; Shyr, Yu; Sumner, Susan; Talati, Megha; Wharton, John; Wilkins, Martin R.; Ye, Fei; Yu, Chang; West, James; Brittain, Evan L.

doi:10.1172/jci.insight.123611

Cited by 83 publications

(96 citation statements)

References 50 publications

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“…In a recent PAH plasma proteomics study, IGFBP2 was significantly increased compared to healthy controls [20]. In the current study, we measured IGFBP2 and total IGF1/2 levels in two independent PAH cohorts, as well as a healthy control cohort to evaluate the value of these proteins as diagnostic biomarkers for PAH; we then evaluated the relationships of these protein biomarkers with PAH progression and severity; finally, we evaluated IGFBP2 in the human PAH lung and pulmonary vascular cells.…”

Section: Introductionmentioning

confidence: 94%

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival

Yang

Griffiths

Nies

et al. 2020

BMC Med

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Background Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival. Methods Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis. Results In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient − 50.235 and − 57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37–11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC. Conclusions IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.

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Section: Introductionmentioning

confidence: 94%

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival

Yang

Griffiths

Nies

et al. 2020

BMC Med

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“…Given that PAH is associated with insulin resistance in other contexts [5][6][7][8], it is surprising that PAH patients exhibited increased insulin sensitivity and hepatic insulin extraction. Upon closer examination, however, other studies in PAH [7,18] have also found decreased insulin concentrations during oral glucose tolerance testing which indirectly suggests greater insulin sensitivity (calculated by HOMA-IR). Hepatic insulin extraction is typically reduced in individuals with impaired glucose tolerance, diabetes [19], and obesity [20], and contributes to the hyperinsulinaemia associated with these pathological states.…”

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confidence: 91%

Altered metabolism in pulmonary hypertension: fuelling the fire or just smoke?

Duan

Jun

2020

Eur Respir J

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]. Pulmonary arterial hypertension (PAH) is characterised by progressive obliteration of the pulmonary vasculature, culminating in right-sided heart failure (HF). In recent years, studies have observed an association between systemic metabolic dysfunction, PAH and right ventricular failure [1]. Patients with PAH have an increased prevalence of obesity [2] and type 2 diabetes [3, 4]. Interestingly, abnormal glucose metabolism is evident even in non-diabetic individuals with PAH [5-7], and serves as an independent predictor of prognosis [8]. Right ventricular function is also associated with metabolic syndrome [9, 10], and myocardial tissue in mouse models of PAH exhibit defects in fatty acid oxidation associated with increased lipid deposition [11]. In addition, peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis and glucose homeostasis, has been implicated in the pathogenesis of vascular remodelling and subsequent development of PAH [12, 13]. PPARγ is also a downstream target of bone morphogenic protein receptor 2 (BMPR2) [14]. BMPR2 mutations are seen in up to 80% of hereditary PAH, and BMPR2 sporadic mutations occur in idiopathic PAH [15]. A rodent model of inducible BMPR2 overexpression develops insulin resistance preceding features of PAH [16]. Collectively, these observations suggest that impaired glucose metabolism may be a causative factor in PAH. However, most of the clinical data above is derived from cross-sectional studies with very limited metabolic outcomes. In this issue of European Respiratory Journal, MEY et al. [17] utilised hyperglycaemic clamp methodology and plasma metabolomics to further characterise metabolism in patients with idiopathic PAH (n=6) compared to age-, sex-and BMI-matched controls (n=6). To perform the hyperglycaemic clamp, glucose was infused at a variable rate to maintain continuous hyperglycaemia (180 mg•dL −1). Levels of insulin and C-peptide were measured to quantify pancreatic β-cell function, while the rate of glucose infused was used as a surrogate for insulin sensitivity. During the clamp, the authors found that peripheral insulin concentrations were lower in subjects with PAH, which translated to a 92% increase in insulin sensitivity in the PAH group. Hepatic insulin extraction (calculated as insulin/C-peptide molar ratio) was greater in PAH than in controls. However, pancreatic β-cell insulin secretion, as assessed by C-peptide concentrations, was similar between the two groups. In addition, PAH was associated with increased fatty acid oxidation and ketogenesis, as evidenced by elevated acetylcarnitine and β-hydroxybutyrate (βOHB) levels. The authors confirmed this metabolic shift using plasma metabolomics in a larger cohort of PAH patients.

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“…This approach has the disadvantage of not allowing the discrete analysis of specific fatty acid substrates, which could be handled differently. However, the relevance of the substrates we analyzed is supported by the reported increase in circulating plasma concentrations of palmitic acid, oleic acid and lineolic acid by 12.0, 5.0 and 4.9-fold, respectively, in PAH versus control subjects 41 .…”

Section: Discussionmentioning

confidence: 86%

“…The pathologic phenotype of PH cells can be reversed, at least in part, by targeting the altered metabolism. Excessive proliferation and apoptosis resistance in PASMCs can be reversed by increasing glucose oxidation by treating the cells with DCA or blocking fatty acid oxidation such as with ranolazine, which increases glucose intake into the cells via the Randle cycle 5,41,42 . Our studies broaden these data, with the observation that even in the context of increased glycolysis induced by TGF-β in PASMCs, glucose remains a major source of carbons for the TCA cycle.…”

Section: Discussionmentioning

confidence: 99%

Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment

Hernández-Saavedra

Sanders

Freeman

et al. 2020

Sci Rep

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Altered metabolism in pulmonary artery smooth muscle cells (pASMcs) and endothelial cells (pAecs) contributes to the pathology of pulmonary hypertension (pH), but changes in substrate uptake and how substrates are utilized have not been fully characterized. We hypothesized stable isotope metabolomics would identify increased glucose, glutamine and fatty acid uptake and utilization in human pASMcs and pAecs from pH versus control specimens, and that tGf-β treatment would phenocopy these metabolic changes. We used 13 c-labeled glucose, glutamine or a long-chain fatty acid mixture added to cell culture media, and mass spectrometry-based metabolomics to detect and quantify 13 c-labeled metabolites. We found pH pASMcs had increased glucose uptake and utilization by glycolysis and the pentose shunt, but no changes in glutamine or fatty acid uptake or utilization. Diseased pAecs had increased proximate glycolysis pathway intermediates, less pentose shunt flux, increased anaplerosis from glutamine, and decreased fatty acid β-oxidation. tGf-β treatment increased glycolysis in pASMcs, but did not recapitulate the pAec disease phenotype. in tGf-β-treated pASMcs, glucose, glutamine and fatty acids all contributed carbons to the tcA cycle. in conclusion, pASMcs and pAecs collected from pH subjects have significant changes in metabolite uptake and utilization, partially recapitulated by TGF-β treatment. Changes in cellular metabolism are increasingly recognized as a hallmark of pulmonary hypertension (PH) pathobiology 1-4. Shifts in the uptake of metabolic substrates and how they are utilized downstream enables the disease phenotype of vascular cells in PH, including increased proliferation, apoptosis resistance, hypertrophy and vasoconstriction 3. One critical metabolic shift observed in PH is an increase in glycolysis, which is thought to occur in resident vascular wall cells including pulmonary artery smooth muscle cells (PASMCs), endothelial cells (PAECs) and fibroblasts 5-7. Increased glucose uptake can be demonstrated in vivo by increased uptake of the glucose analog 18 F-fluorodeoxyglucose in the lung parenchyma of PH subjects 6,8. The concept that glycolysis in PH is detrimental has led to investigation of the potential utility of dichloroacetate (DCA), which by blocking pyruvate dehydrogenase kinase causes increased glucose flux into the TCA cycle, and less glycolysis 9. Glutamine uptake and metabolism by PAECs has also been shown to contribute to their disease phenotype 10. However, comprehensive assessment of substrate uptake and how the substrates are utilized by pulmonary vascular cells in PH is lacking. A potential driver of altered cellular metabolism is transforming growth factor β (TGF-β) signaling, which underlies many forms of heritable (through mutations in BMPR2 and other members of the TGF-β signaling superfamily) and idiopathic PAH, and PAH etiologies associated with other conditions such as autoimmune

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Human PAH is characterized by a pattern of lipid-related insulin resistance

Cited by 83 publications

References 50 publications

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival

Altered metabolism in pulmonary hypertension: fuelling the fire or just smoke?

Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment

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