BACK TO PANDAEMONIUM
But I am bound upon a wheel of fire, That my own tears do scald like molten lead.
– Lear, in King Lear, in pre-Roman Britain, as penned by William Shakespeare
I begin to see it in my mind all the time, like a great wheel of fire.
– Frodo Baggins, in The Lord of the Rings, in the year 3019 of the Third Age of Arda (1418 Shire Reckoning), as penned by J.R.R. Tolkien
In us all exists a wheel of fire.
In Blood Sugar, Sex Hormone Magik (from here on out, BSSHM), I discussed how the metabolic syndrome and its associated pathologies form a positive feedback loop.
In this sequel to BSSHM, I will look at this circle and its axis in some more depth. I have described some the complicated relationship between insulin resistance and the sex hormones, but there is much more to it. So much more to it, in fact, that it requires several more metaphors to do it justice. The chief metaphor that I will now introduce and keep coming back to will be the “wheel of fire”. For the positive feedback loop introduced in BSSHM can be better thought of as a spinning circle. And it spins upon the axis of chronic inflammation, making these interrelated phenomena something of a self-propagating, or spinning, wheel of inflammation.
After establishing a few more basic tenets of the wheel of fire, I will also explore two key ideas necessary to better understand these concepts and to help better direct further research and treatment. I will then discuss how traumatic brain injury, post traumatic stress disorder, depression, anxiety, chronic pain, and chronic opioid use are all intimately related to each other and can both cause and be caused by the wheel of fire. I will conclude by trying to bring this all together in a more inclusive model and briefly discuss some current treatment philosophies and directions for further research.
In BSSHM, I explored some parts of the complicated web of interactions involving the sex hormones, insulin resistance, what happens when the stress hormone cortisol behaves badly, and a few other things. There was also some discussion about how these all create the dreaded “positive feedback loops”, or processes whereby one thing amplifies another thing, which goes back and amplifies the first thing. This of course creates a vicious cycle, causing all hell to break loose.
In other words, pandaemonium.
By looking at physiology and pathology this way, in which normally self regulating negative feedback loops misbehave and become positive, we can develop a heuristic, or set of general rules, by which to understand some very complicated but widespread pathologies. In the meantime, by visiting Pandaemonium (the city of all demons, per John Milton), King Lear (Shakespeare), and Mordor (Tolkien), we can see that there is precedent for this phenomenon in worlds both real (Middle Earth) and imagined (Shakespeare’s pre-Roman England). As such, we should be able to develop a complete theory of all existence. Perhaps even explore quantum entanglement, Hugh Everett’s Many World’s interpretation of the wave function, and what this has to do with Plato’s Forms and the Mathematical Universe Hypothesis. Most of these last part won’t happen in this article, though.
Rather, we’ll just stick with the positive feedback loops for now.
The thirty thousand foot view of this positive feedback loop, in regard to insulin resistance and the sex hormones, can be stated, simply, that “the metabolic syndrome can lead to sex hormone dysfunction and sex hormone dysfunction can lead to the metabolic syndrome.”
A diagram of this could look something like this:
There are numerous ways that this can happen, but as of now, some of the most salient appear to be:
- Low sex hormones are related to loss of skeletal muscle. Skeletal muscle is insulin sensitizing. Loss of skeletal muscle thus leads to insulin resistance and the metabolic syndrome.
- Normal sex hormone status normalizes glucose-dependent insulinotropic polypeptide (GIP). GIP acts on the pancreas and the intestines to normalize glucose absorption and insulin secretion. When the sex hormones are not great, GIP becomes not great. This leads to insulin/glucose dysregulation and the metabolic syndrome.
- The sex hormones normalize the oxidative phosphorylation (OXPHOS) pathway in mitochondria. When OXPHOS is running smoothly, there should be proper glucose utilization, wound healing, muscle mass, and numerous other things. The absence of good OXPHOS functioning may lead to the metabolic syndrome.
- Increased visceral adipose tissue causes a body-wide pro-inflammatory milieu. When this inflammation affects the hypothalamus, it can mess up the pulsatile secretion of gonadotropin releasing hormone (GnRH). This, in turn, will decrease the amount of luteinizing hormone (LH), which will, in turn, lower the amount of testosterone or estrogen secreted.
- Increased body fat has an enzyme called aromatase that turns testosterone into estradiol (a type of estrogen). Increased body fat is frequently part of the metabolic syndrome. Because of increased aromatase, too much body fat lowers testosterone and increases estradiol.
- When there is too much estradiol, it can go back to the hypothalamus and pituitary gland and tell them to change GnRH and LH secretion, further messing up normal testosterone and estrogen levels.
- Increased inflammation, from increased visceral adipose tissue, or because of other reasons, causes the body to go into “fight or flight” or “sympathetic” mode, releasing the stress hormone cortisol. Too much cortisol increases glucose by its actions on the liver and altering normal hypothalamus and pituitary function. Changes in hypothalamus and pituitary function worsen sex hormone secretion. Too much cortisol also works on fat cells to make them resistant to testosterone.
So, that’s it for review. Let’s take this further.
THE WHEEL OF FIRE
While the above model is good enough to represent the bulk of what was covered in BSSHM, it’s not quite inclusive enough for our current purposes.
In order to make a new, more inclusive model, let’s change the metaphor slightly. Instead of calling this a “loop”, let’s call it a wheel.
It is necessary to refine our metaphor because, as mentioned earlier, there is more than just a circle of dysfunction going on. There is also an axis about which this circle spins. The common denominator, or axis, of this circle is chronic inflammation.
And what is inflammation? Well, I’ve touched on this in other essays, but its name should be a hint. Something that is inflamed is something that is in flame. It is something that is on fire.
As you likely well know, inflammation is a crucial part of staying alive. Without well placed inflammation, nothing would heal, no one’s muscles would ever grow after exercise, no one would ever get calluses or a tan, and no one would ever make it past a few hours of birth as he or she would quickly succumb to some pathogen such as a virus, bacterium, fungus, or paper cut.
But, sometimes this healing fire of inflammation can go awry. Sometimes, instead of being well placed, it is haphazardly placed and widespread. When we talk about a pro-inflammatory milieu with the metabolic syndrome, this haphazardly placed inflammation is exactly what we mean. The body’s signals that cause inflammation, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are kind of like the kindling and matches of our bodies’ inflammatory system. That is why when we say that it is bad when visceral adipose tissue secretes too much IL-6 and TNF-alpha. When this happens, the body has a smoldering fire going on everywhere. And instead of facilitating healing, this fire is promoting damage.
So, the metabolic syndrome and its associated phenomena exist in something of a circle. One causes more of the other, that then causes more of the one. And the axis by which this circle spins is inflammation. There is a circle of pathology rotating about an axis of inflammation. A circle spinning on its axis. What we have is a wheel. A wheel of fire.
In BSSHM, I discussed how the metabolic syndrome is related to various health problems that are frequently thought to be totally unrelated. We have already explored this idea some when talking about the sex hormones. In this second part, I will describe how this involves many other previously unlinked pathologies. And this is important because these health problems make up the bulk of the medical issues afflicting most “developed” countries.
I have already discussed how obesity, hypertension, gout, cardiovascular disease, neurodegenerative disorders, diabetes, osteoarthritis, and back pain are all related. Yet, also in this wheel are less obvious members. There are many that I am not going to address in this article for brevity’s sake (such as cancer), but a few that I will address are anxiety disorder, traumatic brain injury, post-traumatic stress disorder, chronic generalized pain syndromes and chronic opioid pain medication usage.
In order to understand how these are related, however, there are two concepts that are critical to understanding the wheel of fire.
The first concept is that the wheel of fire exists on a spectrum. It is not all or nothing. It is not either present or absent. The second concept is that there are many ways to get on the wheel of fire. It can be through a head injury, stress from a bad relationship, poor sleep, Twinkies, or any number of things. And the more someone does to set the wheel spinning, or the more avenues one takes to enter the wheel, the more he or she will experience the full repertoire of the wheel’s unpleasantness.
Let us explore these concepts in some more depth.
This concludes part 1 of The Wheel of Fire: Back to Pandaemonium.