Nitric oxide is a gaseous molecule that is emerging as a central regulator of energy metabolism and body composition inside the human body. It carries out integral physiological functions like regulating the blood pressure and maintaining a healthy blood flow inside the vessels by dilating them. It is because of this major function that this chemical compound was initially referred to as Endothelial Derived Relaxing Factor (EDRF) and at later date, it was realized the EDRF is a gaseous molecule, Nitric Oxide. Three American scientists were awarded the Nobel Prize in 1998 for their discoveries concerning “the nitric oxide as a signaling molecule in the cardiovascular system”.
Insulin resistance is the diminished ability of the cells inside the body to respond to insulin in order to maintain a normal level of glucose. This impaired response results in elevated levels of glucose. This also leads to a compensatory increase in insulin (hyperinsulinemia) in an attempt to maintain normal blood glucose. Resistance to insulin is a state that is experienced in Type 2 diabetes mellitus. This type of diabetes is known to be associated with elevated levels of systolic and diastolic blood pressure, increased plasma triglycerides, reduced HDL or obesity.
A wide range of research has been carried out that links these two important components with each other. The insulin resistance has been found to have a direct effect on the nitric oxide produced in the cells of the vessels, the endothelial cells. With the current epidemic of obesity and diabetes mellitus, its relationship with NO has received its fair share of attention in an attempt to better understand the mechanisms involved in causing the adverse effects of diabetes mellitus.
Nitric oxide is an important molecule produced inside the human body whose synthesis is a vital biochemical process involving nitric oxide synthase (NOS) enzyme family. An important substrate in the process that produces NO is L-arginine. The availability, transport and utilization of L-arginine determines how fast or slow the NO production will be. Studies have also demonstrated that the extracellular availability of NO precursor, L-arginine, is the most important determinant in the production of nitric oxide.
It has been established for ages that the control of the vasomotor tone of the endothelial membrane is critically regulated by the bioavailability of NO. As important as the role L-arginine molecule plays in the synthesis of this important chemical compound, it is the transport of the very same molecule, L-arginine, that has been known to be impaired in hypertension and heart disease. Both of these diseases have one key feature in common; endothelial dysfunction. This is an important mechanism and association to remember to draw out many conclusions about the long-term complications that arise in diabetes mellitus.
Many biochemical studies have brought forward the evidence that insulin causes vasodilation of the blood vessels at skeletal muscle vascular beds. This vasodilatory effect is associated with the activation of the L-arginine-NO pathway of nitric oxide production. Given that insulin is a well-known vasodilator whose actions are mediated by NO pathway, an important connection is built that helps to clearly understand the role insulin plays in nitric oxide synthesis and bioavailability. This has also aided in pinpointing the impact insulin resistance has not only on the synthesis of nitric oxide but also the functions carried out by it.
The relationship between insulin resistance, NOS enzyme activity and NO synthesis, and action has been studied in depth. As mentioned earlier, insulin is a vasodilator and its vasodilatory effect is induced by the nitric oxide pathway.
A considerable amount of evidence has been provided in order to prove that in insulin-resistant states, like type 2 diabetes mellitus, obesity, dyslipidemia or hypertension, the production of nitric oxide in the arteries is markedly reduced. Studies have also proved that a high level of glucose inhibits the synthesis of nitric oxide in the endothelial cells by inhibiting the NO synthase enzyme whereas insulin stimulates the production of this significant vascular relaxation factor.
The mechanism by which insulin impacts NO synthesis is by stimulating the enzyme NO synthase (NOS) involved in the production of nitric oxide. Therefore, diminished levels of NO in diabetics may be due to decreased expression of NOS or impairments of NOS activity.
Another important implication found in this mechanism of impairment explains the development of cardiovascular diseases via dysfunction of the endothelial surface. It has already been established that on a biochemical level many cardiovascular diseases are related to impaired transport of L-arginine molecules. Since this molecule is primarily involved in the biosynthesis of nitric oxide as discussed above, NO levels drastically fall. The understanding of this mechanism has led to building of a direct relevance between endothelial dysfunction and insulin resistance. In light of the above, insulin resistance contributes substantially to the onset of coronary artery disease. It does this by causing significant endothelial dysfunction through abnormal insulin-mediated L-arginine transport.
Metabolic disorders like diabetes mellitus type 2, obesity, and hypertension are associated with impaired levels of NOS activity as well as elevated levels of disease markers that are associated with atherosclerotic cardiovascular disease. Results of a wide range of research have been consistent with the concept that a reduced basal NOS activity and impaired insulin-stimulated NOS activity contributes to development of certain complications. Accelerated process of atherosclerosis, impaired endothelium-dependent vasodilation and hypertension in type 2 diabetes mellitus have all been attributed to this mechanism. This has led to a clear understanding of these complications that develop in a patient suffering from type 2 diabetes mellitus.
A lot of in-depth research has been done to get mechanistic insight into the vascular actions of insulin. This has been done to understand the mechanisms involved in the impact it has on nitric oxide and ultimately its functions. Moreover, a threefold association between insulin-resistant states, endothelial dysfunction, and nitric oxide production has been developed. In conclusion, decreased endogenous availability of NO underlies insulin resistance. This further explains endothelial dysfunction caused by this metabolic state. This is a further elaboration of all the complications that develop for example the coronary artery diseases and hypertension. The process of development of these metabolic diseases and complications have been narrowed down to reduced synthesis and bioavailability of nitric oxide.
NEOGEN Scientific Advisory Board