Previously, I established that energy dysregulation is the primary driver of the progression of metabolic dysfunction, and in turn, the progression of modern disease. With this article, I will continue this thought process by walking you through some mechanisms by which this energy dysregulation can result in metabolic dysfunction. Once we understand this central mechanism driving the common pathophysiology experienced by the population, we then have a possible mechanism we can target to effectively address modern disease.
As energy is a key requirement for the functioning of every single cell and system in the human body, finding a starting place to begin understanding energy regulation is a bit tricky. However, we have to start somewhere, and so to begin our journey into understanding energy (dys)regulation, let’s examine a central site of energy transportation – the circulatory system, or more specifically, a blood vessel.
Blood Vessels – energy and nutrient highways
Energy and nutrients are shipped around the body via the circulatory system, primarily in the blood. Blood vessels carry energy primarily in the form of fat (lipids) or sugar (carbohydrates) to cells throughout the body.
The body works hard to regulate levels of each of these macronutrients, as fluctuations in either will result in the inability for cells to properly function. It does this via an incredible number of sensors that work to continuously monitor changing levels of both sugar and lipids, while ensuring that any deviations result in a shift back towards normal levels. While both bllod sugar and blood lipids are regulated, it is very important to note that the body maintains much tighter control over blood sugar levels. This tight regulation over blood sugar levels occurs because either high or low blood sugar levels become acutely dangerous (e.g. hypoglycemia results in energy deprivation for the brain and red blood cells, which can mean a fast approaching death; hyperglycemia can make the blood toxic, as elevated concentrations of sugar cause direct damage to cells and tissues), while the same variations in lipid levels aren’t immediately damaging.
One important implication of this is that, when it comes to whether a cell should burn fat or glucose first (as the cell can only use one fuel type at a time), it will (almost always) choose glucose. This means that glucose gets the preferential treatment – if it is present, it will be used as fuel first, followed by fat.
The result of all this is a blood vessel in contact with every system throughout the body, wherein there is tight control over blood lipid levels and even tighter control over blood sugar levels.
The question from here, then, is what is actually doing the regulating.
To introduce a few of these components involved in energy regulation:
- Liver: The liver is in charge of converting one form of energy into other forms. It stores glucose (as glycogen) and uses these levels to help determine what type of energy needs to be produced.
- Adipose Tissue: Main storage depot for lipids; major site for synthesis and release of biochemical messengers
- Muscle: Main source of energy utilization; Main storage depot for glucose (as glycogen); can also store some lipids.
- Pancreas: Main controller of blood sugar levels via the release of insulin and glucagon
- Digestive System: The input for energy sources; also involved in regulation via the release of biochemical messengers
- Hypothalamus: Master regulator of energy levels throughout the body via secretion of hormones
- Thyroid: Systemic changes in energy levels via the release of specific hormones
Keep in mind that all of these components are at play working to regulate energy levels. To keep things simple, we will focus on the first few components along with their control over energy levels in the bloodstream.
How this works:
To help you understand how the body loses its ability to regulate energy levels, I have developed a series of diagrams modeling how energy flows throughout the body. By examining this flow of energy, we can work towards an understanding of how energy is regulated under normal physiologic conditions, along with how abnormal physiologic conditions drive the inability to manage energy levels.
As we will see, it is in this chronic state of abnormal energy that the body loses its ability to properly regulate energy, driving any number of pathophysiologic conditions and modern disease.
As we continue, keep a few things in mind:
- This walkthrough is going to include incredibly simplified models, allowing us to focus on the key components involved.
- This is a dynamic process, which is difficult to show with these limited dimensions. The form you are about to see refers to simplified snapshots of this system in action.
To begin this walk through energy regulation, we will begin at the site of energy distribution – the blood vessel. Remember, energy travels throughout the body primarily through the blood, in the form of either carbohydrate or lipids. Although these can take different forms in the bloodstream, for our purposes, I will simply model lipids as a fatty acid, and carbohydrate as a single glucose molecule.
As this energy travels through the bloodstream, it has a number of options for where to go. For today we will focus on:
- Energy can be stored – fats stored primarily in adipose tissue; glucose stored as glycogen, primarily in muscle and the liver.
- Energy can be oxidized (burned as fuel by the mitochondria to produce ATP, the body’s usable form of energy). Keep in mind that mitochondria are found everywhere, in (almost) every cell type, all throughout the body.
An important question for us, to begin with, is how does the body know what to do with this energy flow, including whether or not to store or burn this energy.
The answer to this question is that the body directs energy flow via a large number of signaling molecules. As it would take a textbook to adequately explain all of these, to get started, we will begin with the most powerful signal, that signal being none other than insulin. Insulin drives the bulk of energy storage based on signals from the environment (primarily, from food). Simply put, when insulin is elevated, energy is stored. When insulin levels are low, fat is free to be released from storage and oxidized in the mitochondria to make ATP.
Now remember, cells can, for the most part, only burn glucose or fat one energy type at a time, and if glucose is present, it gets the priority. This means that, if glucose (and therefore insulin) is present, then fat will not get oxidized. If insulin is present for an extended period of time, fat does not get a chance to get oxidized and it accumulates.
Moving forward with our model, let’s look at this same information in a simplified form, in which we are only taking into consideration our long-term energy storage:
Now we can ask our important question on how the body knows whether to burn or store this fat. The simple answer: insulin.
Not to worry though – this fat storage is only temporary. Once that insulin signal goes back down, fat is then free to be released from the adipose tissue and flow towards the mitochondria for oxidation.
This balance between insulin on/off and fat storage/oxidation results in a beautifully regulated energy balance. With the help of insulin, we are able to store energy in times of plenty, and then use that energy when food is not available. This mechanism allows us to make it through each and every day (energy is stored when we eat and released at night while we fast) and also has allowed our success throughout our evolutionary history (energy is stored during times of feast and released during times of famine).
Unfortunately, this beautifully designed system has a fatal flaw, one that has been forcefully brought to our attention in the last few decades.
To unravel this design flaw, let’s pose a second question: What would happen if this insulin signal were to be excessively turned on?
When insulin is turned on too frequently for too long, fat accumulation begins to reach capacity. Fat cells (adipocytes) can only hold so much fat, so after a point, excess fat cannot be crammed in any longer (more on this here). Furthermore, these over-stuffed adipocytes can become leaky at this point, leaking out fatty acids, along with signaling molecules like pro-inflammatory cytokines.
Image 7: Adipocytes expand as they accumulate with fat. As their size increases beyond a threshold, the cell signals that it is in trouble – this “help” signal is an inflammatory response, which, if severe enough, results in an impaired ability to receive fat, along with leakage of its stored fat into the bloodstream.
Once the body reaches a point where adipocytes are overstuffed and overflowing, there are no longer any good, safe options for all this fat storage. Unfortunately, that fat has to go somewhere, so the body forces it into storage in other tissues, those tissues being any tissue that is not adipose tissue, and therefore not designed to store large amounts of fat (i.e. ectopic fat storage).
At last, we have reached the turning point towards a pathophysiologic condition. The body may be designed to be good at storing fat, but that fat is supposed to be safely tucked away under the skin in adipose tissue. It is not, however, designed to be forced into storage in organs and other tissues. Once the body reaches this point, we have a problem.
The overflow of fat into the bloodstream and into ectopic fat storage is a strong signal to the body that something is wrong. Now remember, the body is not passive – it has survived throughout the past millions of years because it is designed as to be very responsive to any alterations in normal functioning. Thus, the body is prepared with one final attempt to manage this disruption in proper energy regulation. If fat levels have exceeded the normal level, then the body understands it needs to change its priorities to burning fat instead of glucose. How does it do this?
Via insulin resistance – the decreased ability of a cell to respond to normal levels of insulin, thus allowing the cell more time to burn fat instead of glucose. Remember, cells can only burn glucose or fat one fuel type at a time, and if glucose is present, it gets the priority. Therefore, to allow the cell to burn some of that fat, the cell has no choice but to stop listening to insulin.
Image 9: The overflow of fat into the bloodstream results in hyperlipidemia. Because high quantities of fat cannot stay in the bloodstream, the body forces this fat into storage anywhere it can. This results in ectopic fat storage, and these organs/tissues fight back with their own signal: insulin resistance.
Why does insulin resistance arise?
It is common to think of insulin resistance simply as a pathological state – something that just happens to the body and the body breaks down because of it. A common model is that fat just happens to clog the insulin receptor – proponents of this model tend to argue that fat is bad because it goes around blocking the insulin receptors, like gum in a lock. Therefore, glucose is unable to get into the cell because the excess fat is blocking its path.
This view is naïve because it ignores the remarkable ability of the human body to take care of itself. The human body has made it this far in evolutionary history because it is well-adapted to changing environmental conditions. These adaptations include mechanisms to handle fluctuations in energy levels.
Instead of a passive, pathological condition that just happens to the body in response to high amounts of fat, this condition is likely an evolved mechanism to handle a situation in which stored energy levels fluctuate too high. When too much fat has been stored, the body signals to itself that it needs to shift towards preferentially burning fat, instead of the usual priority to burn glucose.
This mechanism likely arose because it benefitted humanity. Those ancestors of ours who happened to consume a bit too much probably benefitted by having their cells shift towards preferentially burning fat. By temporarily responding less to glucose, the body could shift to temporarily burning more fat, thus putting the body back in a state of equilibrium.
Unfortunately, this is not the way it works today, as insulin resistance seems to be the very mechanism at the heart of today’s severe issues involving poor health and modern disease. We’ll discuss exactly why next.
The Pathophysiology of Insulin Resistance – Why is this insulin-resistant state so damaging?
By understanding the insulin-resistant state we can move on to how this state causes damage throughout the body, thus driving the progression of modern disease. Back to our model, now an insulin-resistant individual:
What exactly follows this insulin resistant state? Insulin resistance is comprised of the following:
- The decreased ability to respond to an insulin signal, which leads to
- Hyperglycemia (elevated blood sugar), which leads to
- Elevated insulin to overcome the now elevated blood sugar, which leads to
- Even more fat storage, which leads to
- More insulin resistance
This is what I like to refer to as the vicious insulin resistance cycle. Once the body is in an insulin resistant state, involving high levels of circulating fat along with high levels of glucose/insulin, the body loses its ability to regulate
energy, and this dysregulation spirals out of control as blood insulin keeps getting released and the body keeps closing off more cells to that insulin signal.
Unfortunately, evolution didn’t design the human body with a good failure mode when it comes to this situation. The typical option is a downward spiral to TIID, wherein this cycles progresses as the pancreas continuously pumps out more and more insulin – that is, until the pancreas can no longer handle that load, it fails, and insulin stops coming.
But even before this cycle progresses all the way to TIID, this insulin resistant state is doing a number on the body. I’ll talk about this in greater depth soon, but for now, here are some basic reasons why insulin resistance is dangerous:
- Insulin resistance means blood sugar fluctuates greatly, resulting in energy swings and energy crashes.
- Insulin resistance means blood sugar elevates frequently. Elevated blood sugar isacutely toxic – it results in direct tissue damage
- Insulin resistance goes hand in hand with excessive fat accumulation – the result of this is obvious – more fat storage, more insulin resistance, and eventually, obesity.
At this point, I have established one pathway to metabolic syndrome, by which fat accumulates excessively, eventually leaking into the bloodstream and leading to insulin resistance. Unfortunately, it gets a little more complex from here, as this is not the only means by which to cause excess fat circulation and inflammation, along with the downstream effects caused by insulin resistance.
Hang with me here, because we are almost at the final model. Before we move forward from here to tieing in the practical components (i.e. the inputs into our system), we need to first address the broader scope of the pathways driving this energy dysregulation and disease progression. We won’t go into great detail on these, but I do need you to understand that they exist, as this knowledge will be useful moving forward.
Again, there are an incredible number of signaling molecules involved in energy regulation pathways. However, for our purposes, we will focus on a select few types of signals. To keep things simple I will break it down for us into two categories (note here – these two categories aren’t anything official or precise; rather, they are just a basic way to sort signals to help us think about the different sorts of signals occurring in this process):
- Macro Signals: these are your hormones, the relatively larger signaling molecules, directing the bulk of the flow of energy. (think macro – bulk flow of macros, where macros = energy)
- Micro Signals: these are the (typically) relatively smaller chemical messengers, comprised of the subtler signals that influence the functionality of components involved in energy regulation. These signals don’t directly influence the flow of energy, but the messages they send influence how components function, thus having an indirect, albeit significant, influence on the longterm flow of energy
The primary macro signal is insulin. It directs the bulk of energy flow to storage, both by signaling for conversion of other energy sources to fat and by sending that fat to storage in adipose tissue. More examples of these types of signals include:
- leptin – released from longterm storage to signal that less energy is needed (i.e. high leptin = eat less)
- glucagon – directs storage and release of glucose
- cortisol – stress hormone, involved in regulating energy flow
Micro signals come in many forms, the primary ones being inflammatory signals and oxidative stress. One example of the inflammatory response discussed earlier is the release of inflammatory markers from adipose tissue in distress. Similar mechanisms occur in other tissues, leading to downstream effects such as insulin resistance. For example, oxidative stress is a strong signal from the mitochondria that it is in distress, allowing it to signal to the cell that it is in need of some aid (more on the mitochondria later on).
These two types of pathways run parallel, both working to signal the state of the body, and in turn, regulate the pathway of energy flow. As we’ve seen, the release of hormones (a macro signal), directly influences the bulk of energy flow. Additional hormones, such as those involved in hunger signaling, also have a large effect directing the bulk of energy flow. At the same time, micro signals, which includes the familiar inflammatory response, along with other signals such as oxidative stress, signals both inside and outside of the cell that the cell is in danger. One such response to these micro signals is insulin resistance.
On second thought, it is really too simplistic to think of these pathways as running parallel. Rather, they work together in a cycle, feeding forward towards the progression of metabolic syndrome. For example, this inflammatory response, combined with fat accumulation, create a positive feedback loop. Within the context of insulin elevation, when the adipose tissue is sending a strong inflammatory signal to burn fat, yet the body is still receiving high quantities of energy, this will only result in more energy storage, more fat accumulation, which means, yes, more inflammation.
More inflammation and more fat accumulation, of course, mean more insulin resistance, which brings us back to the vicious inulin resistance cycle:
The excessive stimulation of insulin, leading to the build-up of fat, is one clear pathway to insulin resistance. Excessive fat build-up puts too much stress on adipose tissue, causing inflammation and overflow of fat in the blood, both of which go on to create an insulin resistant body.
Wrap – Up
At this point I have discussed one primary pathway for which energy dysregulation causes metabolic dysfunction, which in turn drives modern disease.
Remember, this model simply represents a common pathway for which modern disease can arise. It is not an all-encompassing model intended to describe all of modern disease. It is intended as a model to attempt to describe the incredible rates of modern disease as driven by a common underlying mechanism.
We are just about finished uncovering the mechanisms inside our black box – the mechanisms in the human body driving modern disease. However, before we move on to connecting these mechanisms with the environment (e.g. diet, behavior, etc.), we need to include a few more details.
Today we covered the model describing excessive fat accumulation and its relationship to the insulin resistance pathway, which is one of the most significant pathways. Unfortunately, this isn’t the only core pathway by which energy dysregulation drives metabolic dysfunction. In fact, I have identified a few others, which I will introduce up next. Don’t worry, these won’t take another full walkthrough to understand, as they are actually quite simple to tie into our already made model.
For those of you who want more information on this pathway – If you are interested in understanding more about insulin and insulin resistance, I encourage you to take a side trail over to my series on that topic. In the following articles I go into great detail about everything you need to know about insulin.
Understanding Insulin Resistance
Regardless, I encourage you to continue on the main road to understanding modern disease with one last article to put it all together.