Insulin resistance is a key pathophysiologic condition driving modern disease. When the body is unable to properly respond to the signal that blood sugar is elevated, it is put in immediate danger due to the acute toxicity of a high concentration of blood sugar. Therefore, if the body wants to survive, it must take action to handle the situation by ensuring that blood sugar concentration comes back down. This is done by the pancreas releasing even more insulin, creating a stronger insulin signal and forcing insulin-resistant cells to respond to the elevated blood sugar.
This situation is problematic for the entire body for two primary reasons:
1. Elevated blood sugar damages proteins and tissues, disrupting the health of everything touched by the circulatory system – that being, every part of the body. Any time spent with elevated blood sugar means time spent accruing damage.
2. The hyperinsulinemic state that results from the pancreas pumping out excess insulin to overcome insulin resistance puts the entire system in a stronger pro-energy storage state. Moreover, as this system progresses down a path of increased insulin resistance and increased need for higher levels of insulin, the pancreas is put under an incredible load, ultimately leading to pancreas burn out and Type II Diabetes.
This article aims to help shed light on the pathways involved in the progression of insulin resistance so that we can arrive at potential solutions to addressing insulin resistance. By understanding how insulin resistance progresses, along with the key inputs driving this progression, we can make decisions that lead to the avoidance of these pathways, thus preventing, or potentially even reversing, these dangerous pathways.
Quick Refresher
Remember from the last article why insulin resistance arises in the first place. Insulin resistance seems to be the body’s method of creating a metabolic switch – a switch from the primary focus on managing sugar to a primary focus on managing fat. Under normal conditions, sugar is the body’s primary focus because it poses an immediate danger when it fluctuates out of a tight window. However, during certain conditions, fat can become a danger to the body, and in these conditions, nature has selected for cells that respond by switching their metabolic preference to fat. Remember, it is this switch that we refer to with the term “insulin resistance.”
Insulin resistance as a pathophysiologic mechanism: when a cell finds itself exposed to both elevated glucose and elevated fat, nature has decided that the cell will lower its response to glucose in the name of taking care of some of that fat. This metabolic switch is accomplished by making the cell insulin resistant. If a cell is less capable of responding to insulin, it will be better able to deal with fat.
This is a problem in the modern, industrialized world – a world filled with most foods containing incredible amounts of easily available sugar. In the modern world, the human body does not have the time to temporarily halt its managing of glucose. The modern, industrialized world presents the body with large amounts of glucose, forcing the need to continuously deal with glucose.
This means that cells have no business becoming resistant to the insulin signal – at least, not without serious repercussions (in this case, these “serious repercussions” would be metabolic dysfunction and modern disease).
Yet, given the design of the human body, cells do become insulin resistant when faced with elevated blood sugar and elevated lipids.
So what is the body to do?
We know that answer already – the body’s solution is to secrete more insulin, bringing us full circle.
Now that we have an understanding of what exactly insulin resistance is and why it is so dangerous, we can move forward towards our ultimate goal of understanding what we can do to avoid or counteract this condition. Unfortunately, before we jump into the discussion of how to avoid insulin resistance, we need to first understand more information surrounding the pathways involved in insulin resistance.
Understanding these pathways is essential to making decisions as to how we can approach this condition. As you will soon see, this understanding is necessary due to the fact that the obvious answers may not be the best approaches to the problem. If we want to find an effective solution, we need to have a full picture of the pathways involved so that we address the important factors driving the dysfunction.
Previously, I introduced you to three primary components involved with insulin resistance: adipose tissue, the liver, and skeletal muscle. We approached this previous discussion from the perspective of why tissue may become insulin resistant, concluding that insulin resistance is a choice these tissues make to switch from primarily managing glucose to managing fat. Now that you understand why nature may have selected for this trait, let us move forward to see how it plays out in pathways.
To begin, let me introduce you to the well-established mechanism of insulin resistance. The concept will seem familiar – I am just adding in a bit more detail and introducing our pathway form:
Here, all I am showing is how elevated lipids result in insulin resistance – the mechanism being through a signal that is ROS and Inflammation.
A few quick clarifications on the terms:
Elevated Lipids refers generally to the above normal amount of lipid (fat) exposed to a particular tissue. Remember, this specific form of lipid will vary depending on the specific tissue. As we walk through these pathways, the specific definition will vary depending on the context, but for now, you can think of this term simply as above normal exposure of a tissue to lipid.
Reactive Oxygen Species (ROS) and Pro-inflammatory molecules (inflammation) are two primary forms of a body’s “help” signal. As a system shifts out of balance, or other dangerous situations are detected, the body uses these two signaling mechanisms as a call for help.
Insulin Resistance: The exposure to high levels of fat is a primary example of a system that needs help – more specifically, a change needs to occur so that the tissue can shift its regular operations to deal with the problem at hand. As we know, the tissue does this by lowering its response to insulin, thus allowing it to take care of the elevated fat levels.
For more information on this specific mechanism, stay tuned. For now, let us continue on to understanding the pathways involved, as this basic understanding of this central mechanism is sufficient for understanding these pathways.
As we walk through these pathways, keep our end goal in mind: we wish to have the information we need to be capable of preventing (or even counteracting) these pathways so that we have the ability to avoid insulin resistance and its path to metabolic dysfunction and modern disease. A word of precaution with this mindset – while it is easy to jump to conclusions as to what factors may be driving these pathways, we must be cautious not to make any premature judgments before we understand the network. As we walk through these pathways, I encourage you to think about how these pathways could possibly tie into this network, being careful not to draw any strong conclusions without the entire picture.
Pathways of Insulin Resistance
General Pathway:
In the presence of elevated lipids, tissue cannot properly manage glucose, resulting in insulin resistance and associated dysfunction.
Tissue-Specific Pathways:
Adipose tissue: The primary job of the adipose tissue is to store energy as fat (fat being one particular type of lipid: a triglyceride). If it cannot do its job properly, then fat will leak out into circulation (hyperlipidemia).
Muscle: A primary job of muscle is to utilize glucose, thus bringing blood glucose levels down. If it cannot do its job properly, then blood sugar levels will elevate (hyperglycemia).
Liver: A primary job of the liver is to manage blood lipid and blood sugar concentrations by releasing stored fuel into circulation and converting fuel sources from one to another. For example, in times of low blood sugar and low insulin, it releases glucose into the bloodstream to keep blood sugar in a healthy range. If it cannot understand the insulin signal that blood sugar is elevated, it will continue operating as if insulin levels were low, thus releasing more glucose into circulation (hyperglycemia).
A note on these pathways: the pathways above have been greatly simplified in the name of building an easily understandable conceptual framework. Understand that I have chosen to only display and discuss what I have deemed the primary output of each insulin resistant tissue based on its primary function (as discussed in the last article). This simplified model will be expanded later on when diving deeper into the intricacies (if you wish to join me in the more detailed series).
Looking at these tissue types independently, we can begin to see why insulin resistance is so problematic. To expand on this and reveal the extent of the problem, let’s combine these tissues to visualize how they interact as a system:
See any problems yet?
Let’s start with the first pathway: the output of insulin-resistant adipose tissue is hyperlipidemia (i.e. elevated lipid in the bloodstream). Sound familiar? This is the primary input into the insulin resistance pathways.
Now looking at the other two pathways, the output of insulin-resistant muscle and liver is hyperglycemia. If blood sugar is elevated then the pancreas will release more insulin, putting the body in a stronger pro-storage state. Thus, hyperglycemia drives the elevation of insulin, thus increasing the amount of fat stored in the adipose tissue.
Thus, we have a positive feedback loop – a pathway that operates in a progressive cycle:

Insulin resistant adipose tissue results in hyperlipidemia, which drives insulin resistance in other tissues (e.g. muscle and liver). Insulin resistant muscle and liver result in hyperglycemia, forcing the pancreas to release more insulin. As more insulin is secreted, the body receives a stronger energy storage signal, thus driving excess fat storage. Thus, a progressive loop is formed in which insulin is increasingly elevated as greater amounts of fat is stored.
Again, note that this is an incredibly simplified model of the inputs and outputs to these pathways. However, this model will suffice for the purposes of this article, so don’t worry about missing these extra variables right now.
This diagram reveals why insulin resistance is an incredibly dangerous state to be in. Insulin resistant liver, adipose tissue, and muscle form loops that feed-forward as insulin levels continue to increase, leading down the path to pancreas burn-out and Type II Diabetes (more on this path soon). All the while, blood sugar levels are frequently elevated (causing body-wide damage) and the body is put under stronger loads of insulin (causing a stronger energy storage signal and more fat storage).
Now that we understand the cycle, we can move forward in our quest to find an effective method for addressing insulin resistance. The next important question for us to answer: What is driving these pathways?
What internal factors are driving these pathways?
The thing is, we already sort of know this answer based on the information provided. Yet, it is worth framing a little differently to clarify our understanding of this network of pathways.
The first thing to note is that there are many answers to this question, and these will sometimes differ between individuals. However, we must keep in mind that we are seeking to answer how the high rates of insulin resistance arise in the modern world, and so, for now we will focus on the primary drivers responsible for the incredible rates of insulin resistance.
We can begin by defining the easy internal input into these pathways. As each pathway begins with elevated lipid, we can address the first internal input as the input causing each tissue to be exposed to excess lipid – that is, excess lipid in each tissue can be caused by excess lipid sent to it via the bloodstream. Keep in mind that this input refers very generally to higher than normal amounts of lipid in the bloodstream, from which it enters into each tissue type.
We know that elevated lipids drive insulin resistance, but there is more than one primary input driving this pathophysiologic insulin resistant system. The answer to what this other variable is is an obvious one – to cause insulin resistance, the system needs insulin! And, if insulin is present, then elevated blood sugar is present as well.
Note, I have simplified insulin + glucose into one arrow “insulin” for simplicity sake, so please keep in mind that one implies the other.

Expanding this to our complete, tissue-specific model:
Finally, we have arrived at a model that may help us make some decisions as to the actions we can take to avoid this dysfunctional system. Before getting into these decisions and actions, I want to make sure we are clear on the model. Therefore, let me show this same information in a different format:
Given these two models, it is easy to see why this dysfunctional system is so dangerous. The system forms progressive loops, with the output of one tissue-specific insulin resistance pathway feeding directly into the insulin resistance pathways of another tissue.
We now know how insulin resistance arises in the body. It is due to the elevation of both lipids and sugar/insulin. When both of these are elevated the body has to choose which one to preferentially take care of, resulting in insulin-resistant cells.
Additionally, in this series we have been introduced to some of the ways in which fat can become elevated in the bloodstream. For example, fat can leak out of over-filled, insulin-resistant adipose tissue and into the bloodstream. Additionally, fat can build up due to a strong insulin signal – a signal that puts the body in energy-storage mode.
At this point we have a model describing the internal inputs and outputs to each of our three insulin-resistant tissues. This model demonstrates what drives the progression of insulin resistance internally (i.e. elevated lipid, elevated blood sugar, and insulin), along with how this insulin resistant system operates as a progressive feed-forward loop.
Now, if we want to be able to intervene, we need to step back one step further to answer what causes these internal drivers: what environmental factors drive insulin resistance. If we know what actions lead to IR, then we can work towards creating a method for avoiding these actions and instead introducing healthy actions into our life.
We’ll do that up next. I’ll see you over there.