7 Factors That Can Affect Nitric Oxide When Blood Sugar Runs High
Nitric oxide helps your blood vessels relax and adjust when blood flow needs to increase.
But making nitric oxide is only one part of the process.
Your body also has to produce it correctly, protect it from being broken down, and maintain the cellular signals that tell blood vessels when to release it.
When blood sugar remains elevated, several of those processes can be affected at the same time.
Here are 7 factors that can affect nitric oxide when blood sugar runs high.
1. More Oxidative Stress Can Use Up Nitric Oxide
High glucose levels can increase the production of molecules known as reactive oxygen species, or ROS.
One of those molecules is superoxide.
Superoxide matters because it can react directly with nitric oxide. When the two meet, nitric oxide can be converted into another compound called peroxynitrite.
That means nitric oxide may be produced, but some of it can be used up before the blood vessel can fully use it for normal relaxation and signaling.
Research on high blood sugar and vascular function identifies increased oxidative stress as an important factor that can reduce nitric oxide availability. [1]
2. The Enzyme That Makes Nitric Oxide Can Stop Working Normally
Much of the nitric oxide used by blood vessels is produced by an enzyme called endothelial nitric oxide synthase, or eNOS.
Normally, eNOS uses L-arginine and other supporting compounds to produce nitric oxide.
But under excessive oxidative stress, eNOS can become “uncoupled.”
Instead of efficiently producing nitric oxide, the enzyme can begin producing more superoxide.
One factor involved is tetrahydrobiopterin, or BH4, which eNOS needs to function normally.
Oxidative stress can reduce BH4 availability and make it harder for eNOS to perform its normal role. [2]
3. High Glucose Can Alter Cellular Signaling
High glucose can increase the activity of a group of enzymes known as protein kinase C, or PKC.
PKC helps control a wide range of signals inside cells.
When certain forms of PKC become overly active, they can influence both nitric oxide production and the generation of reactive oxygen species.
That can create pressure from two directions:
The vessel may have a harder time maintaining normal nitric oxide production while oxidative stress simultaneously makes existing nitric oxide less available.
Research examining high-glucose environments identifies abnormal PKC activity as one of the processes involved in endothelial dysfunction. [3]
4. Advanced Glycation End Products Can Accumulate
When glucose remains elevated, some of it can attach to proteins and fats through a process called glycation.
Over time, this can contribute to compounds called advanced glycation end products, or AGEs.
AGEs can interact with receptors on cells known as RAGE receptors.
That interaction can increase oxidative stress and inflammatory signaling within the vascular system.
Because both processes can interfere with normal endothelial function, AGE accumulation may provide another way prolonged high blood sugar affects nitric oxide signaling. [4]
5. Insulin Signaling Can Become Less Effective
Insulin does more than help regulate blood sugar.
It also communicates directly with the cells lining your blood vessels.
Under normal conditions, insulin activates signals involving PI3K and Akt. Those signals can then activate eNOS and support nitric oxide production.
When insulin signaling becomes less responsive, that communication may weaken.
Research has shown that insulin resistance can impair the PI3K/Akt signaling system involved in endothelial nitric oxide production. [5]
That means the signal telling blood vessels to produce nitric oxide may not work as efficiently.
6. Mitochondria Can Produce More Reactive Oxygen Species
Mitochondria help your cells convert nutrients into usable energy.
But when cells are exposed to excess glucose, mitochondrial activity can also contribute to increased production of reactive oxygen species.
Those molecules can interfere with the normal environment nitric oxide needs to remain available.
Researchers studying endothelial dysfunction have identified mitochondrial oxidative stress as one factor connecting metabolic changes with abnormal vascular signaling. [6]
So the issue is not only how much nitric oxide your body produces.
It is also whether the surrounding cellular environment allows that nitric oxide to remain available long enough to do its job.
7. Inflammatory Signals Can Interfere With Nitric Oxide Production
Inflammation and nitric oxide signaling are closely connected.
Certain inflammatory compounds can interfere with the cellular signals that normally activate eNOS.
Research has found that inflammatory cytokines can disrupt parts of the PI3K/Akt/eNOS system involved in nitric oxide production.
That gives elevated blood sugar another potential way to influence vascular function.
High glucose can contribute to oxidative and inflammatory signaling, while those same signals may make it harder for the endothelium to maintain normal nitric oxide availability. [7]
The Bottom Line
Nitric oxide availability depends on much more than whether your body can produce the molecule in the first place.
When blood sugar runs high, several changes may occur inside the vascular system at the same time.
More nitric oxide can be broken down.
The enzyme responsible for producing it may work less efficiently.
Normal insulin signaling can weaken.
And oxidative and inflammatory signals can further interfere with endothelial function.
That is why researchers often look at nitric oxide availability, rather than nitric oxide production alone, when studying the relationship between glucose and vascular health.
Supporting healthy blood sugar, regular movement, balanced nutrition, and normal endothelial function can all help support the environment your blood vessels need to produce and use nitric oxide normally.
