What causes insulin resistance?

Insulin resistance is a shockingly common condition spurred on by diet and lifestyle. Here are the processes in your body that lead to this dangerous state.


Article highlights

  • Insulin resistance is surprisingly common, even among people without a diabetes diagnosis, with as much as 88% of Americans potentially suffering it to some degree.
  • Diet and lifestyle are critical drivers of insulin resistance, but the underlying root causes are broader and include stress, inflammation, and chronically elevated insulin.
  • The fact that so much of our dietary fat comes from processed oils also plays a role, promoting cellular processes that exacerbate insulin resistance.


Insulin resistance is the epidemic we don’t talk about enough. It’s perhaps the most common health disorder in the U.S. and is, to varying degrees, associated with nearly all chronic conditions, such as heart disease, diabetes, infertility, and Alzheimer’s disease. Half of all U.S. adults, and roughly one in three Americans, are known to have it.

“Insulin resistance is perhaps the most common health disorder in the U.S.: Half of all U.S. adults, and roughly one in three Americans, are known to have it.”

If you’re unfamiliar with insulin resistance, you can read more about it in Part I of this series, What is Insulin Resistance?, but here’s a quick primer: Insulin is a crucial hormone that affects every cell in the body. It has several effects, but the most well known is stimulating cells to take up sugar from the bloodstream to be used for energy or stored. I’ll get into all the factors that can cause cells (or the whole body) to become insulin resistant, but the effect is that cells essentially become “numb” to the effects of insulin. That means your body needs more insulin to do the same work, which only exacerbates insulin resistance.

The cause of insulin resistance is often oversimplified to “too much sugar,” and while that is a key driver, insulin resistance is a complicated condition with a complicated backstory.

In this article, let’s go a little deeper and look at the processes happening in your body that lead to insulin resistance. I think of the stimuli that drive insulin resistance in two classifications:

  1. Primary refers to factors that can cause insulin resistance directly in isolated cells and the whole body.
  2. Secondary are causes that contribute to cellular changes that, in turn, lead to insulin resistance and likely contribute to whole-body insulin resistance.

Primary Causes


Hyperinsulinemia simply means an abundance of insulin. And too much insulin causes insulin resistance. To be precise about it, for every 1 µU change in blood insulin level (a pretty small change), a person can experience an approximately 20% increase in insulin resistance.

Many factors can cause this insulin abundance, including insulin resistance itself (yes, there’s a bit of a snake-eating-its-tail quality to this—more on that later). But because one of insulin’s primary jobs is to regulate glucose in our blood, having too much circulating glucose can lead to too much insulin. Glucose levels are primarily driven by what you eat and exacerbated by lifestyle factors, like poor sleep, too much stress, or too little exercise.

That too much of something might cause resistance to the thing itself might seem like a strange cause and effect. But it represents a fundamental feature of how the body works: When a process is excessively activated—repeated glucose spikes from eating sugary foods leads to repeated insulin surges to clear the glucose—the body will often dampen its response to reduce the activation. Think of how bacteria become resistant to antibiotics or how a caffeine addict needs more caffeine than he used to.

If a cell in your muscle or liver is inundated with insulin, it can’t stop insulin from being produced—that’s happening in the pancreas—but it can alter itself so the insulin has a smaller effect; it becomes resistant to insulin. As this occurs in countless cells in several tissues throughout the body, the body as a whole eventually becomes insulin resistant.

The effect of insulin on insulin resistance is clear in animal and human studies. In one study, when researchers infused healthy insulin-sensitive men with insulin—even at a physiological level—the men became insulin resistant in just a few hours.


Inflammation often calls to mind something red or swollen, but it’s actually the body’s natural defense system against what it sees as threats. To mount that defense, it sends proteins to the affected area. In the context of insulin resistance, we’re talking about a kind of inflammation where immune cells trigger responses throughout the body that can be so subtle they’re almost undetectable. However, the proteins these cells secrete, like Tnf, can interfere with insulin signaling, contributing to insulin resistance. As with hyperinsulinemia, we see this in research across cells, and rodents, and humans.

The earliest research identifying the role of inflammation in insulin resistance came from studying the problems that accompany infections. People with prolonged infections (which naturally come along with increased inflammation) become insulin resistant. Even people with infection-related illnesses, such as mononucleosis (commonly called mono) or periodontitis (inflammation of the gums), can develop acute insulin resistance.

We also see this relationship clearly in people with autoimmune diseases, in which the body is attacking itself using some of those same proteins. For example, in rheumatoid arthritis, where a person’s body destroys their joints, people who experience the worst inflammation also experience the greatest insulin resistance. We see the same effect with other inflammatory autoimmune diseases, such as lupus and Crohn’s disease. Even the most toxic and lethal forms of inflammation, such as sepsis, lead to insulin resistance.


We all have a general understanding of stress: elevated heart rate, sweaty palms, fast breathing. While these are the most obvious signs of stress, there are numerous other less obvious but more detrimental effects, including metabolic. Regardless of the outward symptoms, what we call stress is just a change in hormones.

The prototypical stress hormones are cortisol and epinephrine; both, to varying degrees, drive those familiar physical signs of stress. But an overlooked, or at least unappreciated, consequence of stress is the rapid and sustained rise in blood glucose. So while insulin is trying to lower blood glucose, the stress hormones are trying to increase it. Indeed, cortisol and epinephrine have another name: insulin antagonists. When these hormones are elevated, we need more insulin to do the same job, and as we’ve seen, more insulin can eventually lead to insulin resistance.

We see the effects of cortisol and epinephrine in cells and animals, as well as in humans. Whether a person is taking a cortisol-like drug, has a condition like Cushing syndrome that causes elevated stress hormones, or even has a restless night of poor sleep, which can raise cortisol levels, insulin resistance will add insult to injury.

Secondary Causes: The Wrong Fat

While excess insulin, inflammation, and stress hormones are all direct causes of insulin resistance, you’ll notice that dietary fat, despite all the bad press, is not listed above. Clinical evidence suggests that dietary fat may help with insulin resistance, as long as carbohydrates are kept low. However, not all fats are benign.

A tremendous shift has occurred over the last century in the way we eat food, including the types of fat we eat. Whereas traditional foods like beef and eggs were a primary source of fat, now most people get their fat from processed seed oils, like soybean oil—the most common fat source in the American diet.

Producers enrich soybean oil, and other processed seed oils, with the omega-6 fatty acid linoleic acid. Among other possible problems with this fat, the more linoleic acid we eat, the more we store it in fat cells. It might be the most prevalent fat in some people’s fat cells.

So what’s the problem with storing more linoleic acid in fat cells? When linoleic acid increases, so too do its metabolic by-products. These by-products force fat cells to grow through a process called hypertrophy, wherein each fat cell gets bigger as it takes on more fat (as opposed to staying a more modest size and recruiting more fat cells to help).

Fat cells getting too big may seem like a trivial development, but it’s the key difference between the cells becoming insulin resistant or staying insulin sensitive. As a fat cell grows, it does two damaging things that can lead to insulin resistance: First, it starts leaking fats. Whereas insulin would normally inhibit fat breakdown, the hypertrophic fat cell stops listening to insulin and begins leaking fats rather than storing them. And intracellular fat impairs insulin signaling. Second, it starts leaking inflammatory proteins, which we’ve already seen contribute to insulin resistance.

Ultimately, this is a one-two punch (leaking fats and pro-inflammatory proteins) from the fat cell, driving both insulin resistance in the cell and other tissues throughout the body. And linoleic acid—processed oil—is the boxing gloves.


These four variables—chronically elevated insulin, stress hormones, inflammation, eating the wrong kind of fat—work together in promoting insulin resistance around the world. Globally, the number of people with insulin resistance has doubled in the past 30 years and may double again in the next 20.

The sneaky danger of insulin resistance is that it will not kill you directly. But it is a driving factor behind so many other, life-threatening conditions. The good news is that we could reduce rates and improve outcomes in so many other diseases by addressing this one root cause.

In the next article in this series, I’ll discuss what we can do about it.