In addition, although glucose metabolism appears to be disrupted, excess glucose accumulation as a result of reduced glycolysis leads to the production of sorbitol, and, consequently, the potential formation of glycation products that can generate free radicals and trigger tissue damage. Lactate levels did not significantly change, suggesting that excess glucose is used instead by the sorbitol pathway or pentose phosphate pathway. Based on our metabolomics and microarray data, we tentatively suggest that the human lung with advanced PAH does not produce high levels of lactate that are typically a signature trait of the Warburg effect in the earlier developing stages of PAH. Further experimentation based on the radioactive targeted approach on the human PAH lung will clarify this issue. Our study suggests that the process of vascular remodeling in PAH involves alterations in glycolysis in multiple cells, limited not only to SMCs but also includes endothelial cells and other tissues such as collagen fibers around the peri-vascular tissue. Lung samples from PAH patients exhibited higher levels of glucose, sorbitol, and fructose. By gene array and immunostaining, we showed that genes in vascular smooth muscle cells encoding the key enzymes for glycolysis, such as LDH-B, were significantly increased, whereas genetic expression of other key enzymes in the glycolytic pathway, specifically glucose-6-phosphatase subunit C3 was significantly downregulated. Glucose-6-phosphate, a key rate-limiting metabolite in normal glycolysis and a substrate for G6PC3, can enter many pathways, including gluconeogenesis to produce glucose, glycogenesis for storing glucose, anaerobic glycolysis to convert to pyruvate, or entrance to the pentose phosphate pathway for generating ribose5-phsophate for the synthesis of nucleotides and erythrose-4- phosphate for the biosynthesis of aromatic amino acids. In particular, the enzyme glucose-6-phosphatase plays a major role in the gluconeogenesis process of dephosphorylating glucose-6- phsophate to generate glucose. Our studies showed that G6PC3 was down-regulated in PAH at both the transcriptional and translational level, suggesting that decreased expression of G6PC3 may be due to a decrease of G6P as a result of glucose being shuttled towards the sorbitol fructose pathway. Despite a decrease in glycolytic key intermediates and enzymes, PFKFB2, an enzyme responsible for irreversibly converting fructose-6-phosphate to fructose-1,6-bisphosphate in the committed step of glycolysis was increased, perhaps in response to Tubacin increased F6P levels, yet there was a decrease in the product fructose 1,6-bisphosphate in PAH lungs. An increase in PFKFB2 may be a feedback mechanism of decreased fructose 1,6- bisphosphate in an attempt to restore normal glycolysis, although protein levels of PFKB2 did not display significant changes.