Autonomic regulation of automatic processesNeurons are classified by the neurotransmitter that they use. On one hand you have adrenergic nerve fibers that use epinepherine and/or norepinepherine and on the other you have cholinergic nerve fibers that use acetylcholine. Adrenergic neurons tend to be stimulatory while cholinergic nerve fibers tend to be inhibitory. When you think of the autonomic nervous system, the sympathetic nervous system tends to be composed of adrenergic nerve fibers while the parasympathetic branch is composed of cholinergic nerve fibers. It's actually a bit more nuanced and other neurotransmitters are also involved, but we'll keep it simple.
The autonomic nervous system helps partition resources in a way that promotes survival of the organism and has two branches, the sympathetic and parasympathetic. The sympathetic branch prepares you for fight or flight, initiating the stress response to mobilize resources to do battle while the parasympathetic branch helps you recover from stress. For the purposes of this blog, think of sympathetic nerve fibers as the accelerator while the parasympathetic nerve fibers function as the brake. Organs responsible for regulating automatic processes such as heart rate, blood pressure, and respiration are both innervated by the sympathetic and parasympathetic branches of the ANS where the sympathetic branch tends to increase these things while the parasympathetic tends to decrease them. The two branches work in the opposite manner when it comes to digestion, but we'll cover that in the next blog. In essence, they work together to regulate these processes so that you deal with stress and then recover from it properly. While many consider the two branches as competitive with one another, they are actually complimentary of one another. If one branch were to not keep the other in check, it would be like a game of tug of war where one team just lets go of the rope; one branch would take full control and successful adaptation would be compromised.
The vagus nerve and acetylcholineThe vagus nerve is not only the conduit through which the gut and brain communicate, it is also the nerve responsible for control of the parasympathetic branch of the autonomic nervous system. The vagus nerve fibers tend to be cholinergic, so the vagus nerve utilizes acetylcholine as its chief neurotransmitter. Simply put, the vagus nerve functions as the brake line and the principal neurotransmitter of the brake, aka the brake fluid, is acetylcholine.
The importance of acetylcholine to vagus nerve function has been known since the early 1920s when Otto Noewi stimulated the vagus nerve of a frog heart and discovered that a substance he called Vagusstoff was responsible for decreasing heart rate. Vagusstoff was later discovered to be acetylcholine(1). Since then, acetylcholine has been discovered to function as the primary neurotransmitter in muscle contraction and parasympathetic nervous system and is heavily involved in a neural circuit referred to as the inflammatory reflex.
The inflammatory reflex
The inflammatory reflex, shown above, is a process which links the immune and nervous systems together where the nervous system helps regulate the inflammatory process. The vagus nerve senses the presence of inflammatory cytokines and, upon stimulation, sends a signal to the brain that relays the message to the celiac ganglion where parasympathetic nerve fibers meet sympathetic fibers. The sympathetic fibers trigger the spleen to release T cells that release acetylcholine to dampen inflammation by signaling macrophages to reduce pro-inflammatory cytokine output and increase anti-inflammatory cytokine output(1, 2). Patients with non-resolving inflammation, such as those with autoimmune diseases, obesity, and Type 2 diabetes have impaired vagus nerve function that prevents resolution of their inflammation. In addition, animals with experimentally induced defects in acetylcholine signaling tend to succumb to sepsis, constant non-resolving inflammation. This indicates that this feedback loop is critical to the resolution of inflammation.
Acetylcholine synthesisSince inflammatory reflex is dependent on cholinergic neurons to sense inflammation and relay that information to the brain and through the celiac ganglion, acetylcholine is necessary. The tricky thing about acetylcholine is that optimal synthesis of acetylcholine in neurons is dependent on adequate glycolysis. Acetylcholine is synthesized from Acetyl CoA and choline. Since nerves are not able to metabolize triglycerides, Acetyl CoA must come from glycolysis. While some Acetyl CoA can be synthesized from acetate, acetate cannot be stored in neurons since the storage form of acetate is a triglyceride, which neurons don't store. Any Acetyl CoA synthesized from acetate must be obtained on the fly, and research has shown that the Acetyl CoA that is incorporated in to acetylcholine comes from pyruvate, the breakdown product of glycolysis(3)
This means that people at lower carbohydrate intake probably have suboptimal cholinergic neuron function, which could help explain why some people on a ketogenic diet often sleep less as REM sleep is heavily dependent on acetylcholine availability. Bringing this back to thiamine, the focus of this blog series, neurons require adequate thiamine to convert pyruvate in to Acetyl CoA. Thus thiamine is very important for any process that requires acetylcholine, including the inflammatory reflex. It is also interesting to note that upon stimulation of the vagus nerve, thiamine is released. In the late 1930s, researchers referred to thiamine as Vagusstoff II(4). Why this is important and why it happens is not completely understood, but evidence indicates that it may be due to the ability of thiamine to bind to nicotinic choline receptors and/or the ability of thiamine to prevent degradation of acetylcholine in synapses(5).
ConclusionSo, how does this relate to adrenal fatigue? First, a state of constant inflammation, in theory, should increase requirements of acetylcholine due to triggering the inflammatory reflex. Whether this requirement is met is dependent on the availability of its precursors Acetyl CoA and choline. In neurons, Acetyl CoA is dependent on thiamine status. Here, a state of constant inflammation could induce a state of thiamine deficiency in two ways. First, GI inflammation can interfere with thiamine uptake in to the bloodstream. Second, an increased need for acetylcholine would concomitantly increase thiamine requirements above normal intake levels.
In people with Type 2 diabetes, a state of chronic inflammation is the norm. In addition, as mentioned in my previous blog, thiamine metabolism and status is dysregultaed in people with Type 2 diabetes. Could this be a consequence of chronic inflammation? It is also interestingt to note that people with Type 2 diabetes have suboptimal vagus nerve function and a chronically elevated sympathetic tone. In other words, they are in a constant state of stress. Could this be due to an insufficient level of brake fluid in the brake line causing a stuck accelerator?
It's hard to draw a parallel between Type 2 diabetics and people who consume low levels of carbohydrates while performing high levels of glycolytically demanding exercise as their lifestyle habits are polar opposite to one another. However, when a person relies on their body to generate glucose because they are not consuming enough carbohydrates, there is likely a limit to this capacity. Rather than state that thiamine needs are dependent on the amount of carbohydrate that is consumed, it's more prudent to state that thiamine needs are dependent on the level of glycolysis that is required of the body.
In a person with Type 2 diabetes, glycolysis is forced due to excessive carbohydrate consumption, creating an allostatic load by chronically attempting to process that level of carbohydrate in most every cell in the body other than the cells most capable of utilizing high levels of glucose: muscle cells. In people who slash carbohydrate levels down to nothing and go ape shit doing crossfit 5 times a week, the allostatic load shifts from processing high levels of exogenous glucose consumption in organs and tissues to providing enough glucose endogenously to meet the physical requirements of exercise in addition to the level of glucose required to keep the nervous system running smoothly. There is likely a limit to this capacity, and that capacity is likely dependent on enough cellular thiamine to fully utilize carbohydrates both as energy in muscles and to synthesize acetylcholine in neurons.
Throughout the last several blogs, I have laid out a rationale for how adrenal dysfunction is related to thiamine status. While I have focused on how thiamine deficiency negatively impacts adrenal function directly, there are other ways thiamine deficiency can impact adrenal function indirectly by causing dysfunction in other systems. In my next blog I will go over how thiamine deficiency affects other systems including thyroid function, the immune system, as well as the digestive system.
Previous: NADPH, the folate cycle, and adrenal function