Insulin resistance is a well-established driving factor behind the progression of modern disease. Insulin, a primary signal in charge of blood sugar balance, is an important signal for the body to listen to closely to ensure that blood sugar stays within a healthy range. The inability for cells to properly respond to blood sugar levels is an incredibly dangerous state to be in, as even slightly elevated blood sugar becomes acutely toxic to exposed tissues, and low blood sugar is an energy crisis for those tissues that can only be supported by glucose (e.g. red blood cells or the brain).
Why then, when it comes to addressing modern disease, is insulin resistance so often overlooked?
There are any number of reasons why this topic is overlooked (not least of which being that there are no effective drug solutions). While I will touch upon a few of these reasons as we move along, I wish to focus our attention on one primary reason:
A primary problem with addressing insulin resistance seems to be the problem surrounding the question of what exactly it is. The thing is, it is difficult to address a problem when the problem itself is difficult to pinpoint. Although it is simple to give insulin resistance a basic definition (i.e. the lowered ability for a cell to respond to the insulin signal), the problem is that the insulin resistance mechanism varies greatly depending on context, that context being the tissue/organ it arises in, along with those factors under which the condition arises.
As a pathophysiologic state that arises due to a number of factors in a variety of tissues – each tissue presenting its own unique circumstances – well, it creates quite the conundrum for the traditional scientist coming in with a reductionist perspective. How is one to create a precise treatment when no such precision exists?
The good news is that this need not be a problem for us, as we removed our reductionist hats back here. Instead, with our systems approach perspective, we can actually quite easily come to some decisions on what exactly insulin resistance is.
As stated above, the problem with insulin resistance is that it seems to appear in different tissues in response to different circumstances. To make matters more difficult, sometimes these circumstances are clearly pathophysiologic (e.g. when fat cells expand beyond a healthy amount they fill up with pro-inflammatory, pro-oxidative compounds, which results in insulin resistance). Yet, sometimes insulin resistance arises as a seemingly normal physiologic process (e.g. in response to a high-fat meal or during fasting). This makes it rather puzzling for someone to pinpoint exactly what seems to be going on here.
Yet, I am confident that with a conceptual understanding of what insulin resistance is, we will be able to better understand its role in poor health and modern disease, allowing us to effectively address the extraordinary health problems this world is facing.
To get us started, let me give you a brief background on how insulin plays a role in the regulation of energy.
Design principle: glucose and fat oxidation
The body uses two primary substrates as fuel to synthesize ATP: glucose and fat. Both of these are important fuel sources that are both regularly used throughout the body; however, there is one key concept in regards to how they are used that tends to distort my initial statement:
Both glucose and fatty acids are regularly used as fuel in a cell; yet, a key feature of metabolism is that only one fuel type can be used at a time.* This means that, when both are present, the cell is going to choose one to utilize while making the other wait its turn.
So how does the cell make its “choice?”
The answer, quite simply, is that glucose is the priority. The reasoning behind this choice is also rather simple – glucose, when elevated in the bloodstream, is acutely toxic, while fatty acids are not as toxic.
Therefore, when it comes to using up (and thus lowering levels of) one of the fuel sources, natural selection has offered a simple solution: choose the acutely toxic substance first, then come back to the other fuel source later.
The body uses both glucose and fatty acids as fuel substrates. However, glucose gets priority because it is acutely toxic. Therefore, in the presence of fat and glucose, the cell will deal with glucose first, leaving fatty acids to be dealth with later on
An important concept for us to understand is how the cell actually accomplishes this. How does a cell “choose” to burn glucose first and come back to fat later on? Obviously, a cell doesn’t really choose a fuel source to let in. It has no real choice in the matter, as the choice was made for it as natural selection selected for the choice that resulted in favorable outcomes for survival.
A cell doesn’t choose anything – it operates under biochemical principles which result in changes to the cell in response to specific signals. In this case, the signal is insulin, and the response to insulin is:
- The admittance of glucose into the cell to be used as fuel
- The inability for fats to enter the mitochondria, and thus, the inability to be used as fuel
The signal: glucose —> insulin secretion
The response: Insulin secretion —> glucose oxidation and halted fatty acid oxidation
In the presence of glucose, insulin is released from the pancreas. In response to insulin, cells allow glucose inside and signal for the utilization of this fuel type. Meanwhile, the ability to oxidize fatty acids gets inhibited, putting a halt on fatty acid oxidation.*
Then, later when glucose levels have declined, that inhibition is lifted, once again allowing fatty acids to be oxidized.
glucose —> insulin —> glucose utilization and halted fatty acid oxidation
Remember, this design decision makes logical sense: because glucose can cause direct damage when it becomes elevated, it makes sense that nature has designed organisms that preferentially use it up first.** While this may result in some temporary fat build-up, this really isn’t a problem as that fat isn’t going to do any damage in the short term. At least, not if that fat is in any moderate amount.
Of course, this begs the question – what happens if that fat is not in a moderate amount? What happens if a particular individual has chosen to consume a large amount of fat? Or, alternatively, what if that individual has consumed too much overall for a few days, such that fat is beginning to build up in excess? What then – would this same “glucose first” mentality still be relevant?
The answer, as nature has shown us**, is no. When a cell encounters large amounts of fat, it no longer has the same basic choice. At this point, both the elevated glucose and the elevated fat pose a danger.
- elevated glucose causes direct damage through glycation of proteins, rendering them dysfunctional, useless, and even dangerous
- elevated fatty acids pose a different sort of problem, and this problem is going to depend on the specific tissue
Next question: What is the cell to do when facing elevated glucose and substantially elevated fat?
This brings us back to our main topic – insulin resistance.
Remember, insulin is the signal that allows cells to preferentially burn lots of glucose (which, consequently, results in the halted oxidation of fat). However, when a cell encounters a large amount of fat, this fat becomes a problem, which means it, too, needs to be oxidized.
Therefore, nature has designed a sort of metabolic substrate switch – that is, the cell is able to lower its ability to respond to insulin, thus allowing it to burn more fat.
The term for this is insulin resistance, which reflects the lowered ability for a cell to respond to insulin.
The result is that less glucose will be taken care of, while allowing the cell to take care of the other fuel type – fat.
Now, before we get too far into what insulin resistance is, note that, as this trait did arise in our species, this trait is most likely a beneficial adaptation. This means that, at some point on the evolutionary timeline, the ability to switch preference for fuel type would have offered an enhanced ability to survive, thus allowing the trait to be passed on.
And this makes sense when we think about the context under which our ancestors operated. It is easy to think about situations when our ancestors would have encountered situations where they had to consume large amounts of food at once – for example, when a large animal was taken down. This would have resulted in the consumption of large meals with lots of fat, and in these situations the body would have needed to handle that fat, even if it meant a slight rise in blood sugar.
Before going too far down that rabbit hole, let’s get back to the topic at hand – we got into this because I so firmly stated that insulin resistance is a key pathophysiologic principle driving modern disease (a statement I will support as we dive into great detail up next). Quite clearly, this condition is not beneficial to us today – it is a key factor driving the progression of the modern disease epidemic.
So then, what happened to promote this change?
Let’s think about it for a minute. Insulin resistant cells only provide a benefit when the trade-off isn’t so bad. A slight, temporary rise in blood sugar isn’t going to kill an individual. It may cause some damage, but that damage could just be repaired later on if it is minimal.
You probably caught the key idea here – a slight, temporary rise in blood sugar isn’t a real problem. But today, with our highly refined, ever-present industrial not-so-foods, is there anything remotely “slight” or “temporary” about blood sugar elevation?
Absolutely not, which is why we need insulin signaling to be on its A-game. When glucose enters the bloodstream in surges, which it does throughout the day in most individuals, there is no time to put off dealing with it until later. When glucose surges into the bloodstream, it must be taken care of immediately. Otherwise, that individual is headed directly down a dark and gloomy road.
Which brings us to the beginning of how insulin resistance has become a pathophysiologic state.
The Modern, Industrialized World and Insulin Resistance:
Given the information above, a safe way to get us started with our conceptualizing of insulin resistance is this: Insulin resistance arises when a cell is exposed to large amounts of fat.
An important note here: while the details are nuanced, this is a safe interpretation of the data if you keep your mind open to the concept of “exposed to fat,” something we will need to keep in mind as we continue forward.
To understand this, let me introduce you to the key pathways in which insulin resistance is involved. Then, in the next article, we will dive into the details to get a more in-depth understanding of how this concept pertains to each tissue type, along with the big picture that is an insulin resistant individual on a path to modern disease:
Pathway 1: Insulin-resistant adipose tissue arises in response to excess fat build-up
The primary job of the adipose tissue is to store energy as fat (note: a second job is to communicate the state of its fat storage, allowing the rest of the body to understand whether its energy stores or high or low). Adipose tissue will take in energy in either form (glucose or fat) and store this energy as triglycerides (three fatty acids attached to a glycerol backbone).
When glucose is elevated in the bloodstream, insulin levels rise, allowing glucose to enter the adipocyte and allowing it to get stored as fat.
Elevated glucose —> elevated insulin —>
- excess glucose converted to fat and stored
- fat stored as fat
These cells are designed such that they can expand to incorporate increased demand for fat storage. In times of plenty (evolutionarily speaking, that would have been summer months), the adipose tissue was able to fill up with stored fat. Then, in times of limited food sources (e.g. cold, dry winter months), the body could then use that fat as fuel, resulting in the shrinkage of those fat cells.
Now, while these cells are designed to expand, their expansion does have a limit. Once their expansion exceeds a certain threshold, the cell begins to enter a dangerous situation.
We could say, here, that the cell is encountering an excess load of fat. In this case of excess fat, the cell needs to make a choice. It can keep responding to insulin signaling to store more energy as fat… or, it can send out a signal that it cannot keep taking on more energy.
As we know, nature made that decision for it. When fat builds up in excess in the adipose tissue, that tissue becomes insulin resistant, allowing it to lower its response to insulin, thus preventing the storage of more fat.
Pathway 2: Insulin Resistant Liver arises due to fat build-up
The liver has many jobs, but to keep things simple I like to think of it as the master metabolic organ. Its job is to continuously sense energy levels and to convert energy from one form to another (e.g. glucose –> fat) based on the signals and macronutrients it receives.
For example, if glucose levels begin to drop, the liver breaks down its stored glycogen to release glucose into the bloodstream. On the other hand, if the liver encounters too much glucose (or fructose for that matter), it converts that sugar to fat for storage. In this way, the liver is a primary organ in charge of keeping blood sugar levels in a normal, healthy range.
However, if fat builds up in the liver (as is the case with fatty liver disease, a result of consumption of too much alcohol or sugar), then the liver needs to reconsider its normal routines, which as we know, manifests in insulin resistance.
Insulin resistance in the liver is a little more complicated than adipose tissue, so to keep things simple, we can think of insulin-resistant liver in its most basic form: fatty liver leads to an inability to properly regulate energy demands of the body. The result is the inability to maintain blood sugar levels within a healthy range (hyperglycemia).
Pathway 3: Insulin Resistant Skeletal Muscle arises due to fat build-up
The primary job of skeletal muscle is to move the body. In doing so, it is responsible for the majority of energy utilization.
Although skeletal muscle doesn’t normally store much fat, it does store glucose (as glycogen). Skeletal muscle can store fat, especially in endurance athletes that need large amounts of fat to fuel long endurance efforts, but in the typical individual who doesn’t spend hours doing endurance training each week, the amount of fat stored in the muscle is very low.
Except, that is, for insulin-resistant individuals who tend to have large amounts of fat stored in their muscle (IMTG – intra-muscular triglyceride). For these individuals, the muscle has been exposed to large amounts of fat – fat that likely arrived from overfilled adipose tissue. In this case, the muscle senses energy as it reaches it via the bloodstream, and is forced to store it internally in lipid droplets (IMTG).
At this point we know the story – this skeletal muscle is exposed to excess fat in the bloodstream, which in turn is stored as IMTG. The response to this excessive load of fat is becoming insulin resistant.
These cells become insulin resistant, which allows this tissue to ignore glucose so that it can take care of the excess amounts of fat. Keep in mind, this insulin resistant muscle only arises when this excess fat is forced into the muscle due to excess fat in the bloodstream. It does not arise, however, for those endurance athletes that have adapted to store that fat in the muscle (and thus have a high demand for energy). Therefore, it is not necessarily the storage of fat being the driver of insulin resistance in the muscle, but rather, the forced storage of fat in muscle when fat is in excess in the bloodstream.
Now that you have a basic understanding of what insulin resistance really is (a metabolic switch allowing tissue to ignore glucose in the name of dealing with rising levels of fat), along with how it arises in three primary metabolic tissues, we can now move forward into understanding how this comes together in common pathways to modern disease.
Up next I will take you further into these pathways, helping you understand these mechanisms at a deeper level. Moreover, we will see how these pathways combine to form metabolic dysfunction at a systemic level, which will help us see the many interacting variables. With this knowledge, my hope is that we can create an effective approach to addressing insulin-resistant tissue so we can avoid insulin resistance and its progression to metabolic dysfunction and modern disease.
Notes:
* I write this as an all-or-none response, but this is not entirely true. The reality is that the inhibited fatty acid oxidation is graded depending on factors, number 1 of which is insulin. A better way to state this may be to say that insulin greatly inhibits, often completely suppressing, the ability for the cell to oxidize fats.
** Nature has selected for organisms that preferentially use glucose first. This makes sense as a beneficial adaptation as organisms that did not burn glucose first would have had acute damage done by rising blood sugar.