Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress

Abstract

Background: Cardiovascular disease accounts for at least 85 percent of deaths for those patients with type 2 diabetes mellitus (T2DM). Additionally, 75 percent of these deaths are due to ischemic heart disease.

Hypothesis: Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress.

Testing of the hypothesis: The vulnerable three arms of the eNOS reaction responsible for the generation of eNO is discussed in relation to the hypothesis: (1) The L-arginine substrate. (2) The eNOS enzyme. (3) The BH4 cofactor.

Implications of the hypothesis: If we view T2DM as a vascular disease initially with a later manifestation of hyperglycemia, we may be able to better understand and modify the multiple toxicities associated with insulin resistance, metabolic syndrome, prediabetes, overt T2DM, and accelerated atherosclerosis (atheroscleropathy). The importance of endothelial nitric oxide synthase, endothelial nitric oxide, tetrahydrobiopterin (BH4), L-arginine, and redox stress are discussed in relation to endothelial cell dysfunction and the development and progression of atheroscleropathy and T2DM. In addition to the standard therapies to restore endothelial cell dysfunction and stabilization of vulnerable atherosclerotic plaques, this article will discuss the importance of folic acid (5MTHF) supplementation in this complex devastating disease process. Atheroscleropathy and hyperglycemia could be early and late manifestations, respectively, in the natural progressive history of T2DM.

Figure 1

Oxygen reacts with the eNOS enzyme in which the BH4 cofactor has coupled NAD(P)H with L-arginine to be converted to NO and L-citrulline. When uncoupling occurs the NAD(P)H reacts with O2 and the endothelial cell becomes a net producer of superoxide (O2').

Figure 2

The multiple stressors causing uncoupling of the eNOS enzyme by decreased DDAH and the increased endogenous inhibitor of eNOS: ADMA.

Figure 3

Hcy (demethylated Methionine) can enter the remethylation cycle with the aid of Folic Acid (5-Methyl-tetrahydrofolate) and the Folate cycle, the enzyme Methionine Synthase, and the necessary Cofactor B12. Folic Acid in addition to being a methyl-donor can serve as an electron or hydrogen donor to restore the required BH4 Cofactor to recouple the eNOS enzyme necessary for the production of eNO from L-arginine. Hcy may also enter the Transsulfuration Pathway with the assistance of Cystathionine Beta Synthase (CBS) enzyme and the necessary Cofactor B6 to form Cystathionine and Cysteine which can then be excreted in the urine or converted to the very important antioxidant Glutathione. The substrate Folic Acid and the Cofactors B6 and B12 are very important not only for improving hyperhomocysteinemia but also important for the recoupling of the BH4 cofactor to the eNOS enzyme for the production of eNO.