NOS3 and diabetes mellitus: Additionally, reduced expression of GTP-cyclohydrolase 1, the rate-limiting enzyme in BH4 synthesis, and dihydrofolate reductase, the enzyme that recycles BH2 to BH4, further contributes to eNOS uncoupling in diabetes and hypercholesterolemia (Alp and Channon, 2004; Xu et al., 2009; Xu J. et al., 2007; Whitsett et al., 2007; Munzel and Daiber, 2017; Chuaiphichai et al., 2017).