Evidence-Based Nutrition For Chronic Disease Prevention

Insulin Resistance: Top Causes & Contributing Factors

Published: October 12, 2023

Insulin resistance is a key risk factor for devastating chronic diseases, including type 2 diabetes, heart disease, stroke, and cancer.

That is bad news because the majority of the adult population in many countries is now thought to be insulin-resistant. 

We can get a sense of the problem if we consider that, for example in the United States, about 50% of the adult population, about 133 Million people, have either diabetes or prediabetes. And the main factor underlying this epidemic is clearly insulin resistance. And even if we only consider those adult Americans who do not have manifest diabetes and who are relatively young at 18 to 44 years, we still have a prevalence of insulin resistance (defined by a HOMA-IR of 2.5 or higher) of 40%. I have not seen prevalence estimates for insulin resistance for the entire world, but one can appreciate the scale of the problem when considering that 537 Million adults have manifest diabetes and another 541 Million have prediabetes worldwide.

And what is it that causes insulin resistance? There are a lot of different triggers for insulin resistance, but I have tried to group them into a list of the sixteen most common ones. In this blog post, I will touch briefly on each cause, but we will go into much more detail in future blog posts in which we’ll discuss how to address these specific causes to reverse insulin resistance.

The way I suggest the information in this blog post could be used is that if you are not insulin resistant yet, then this blog post will teach you what to watch out for and ideally avoid in the future to make sure you will remain insulin sensitive.

But if you know or suspect that you are insulin resistant, then you can go through this blog post to try to figure out which of these triggers could be the cause, or causes, of your insulin resistance. If this blog post gives you some ideas, I suggest you discuss these further with your doctor.

By the way, if you are uncertain about what insulin does in the body and what insulin resistance is, I strongly suggest that you read this blog post about the basics of the regulation of blood sugar first.

And now: the causes of insulin resistance. 

1. Visceral and Ectopic Fat

There is a lot of evidence linking insulin resistance to the accumulation of visceral fat and ectopic fat. Visceral fat is also called intra-abdominal fat, and consists of several fat depots inside the abdominal cavity, surrounding the inner organs. Ectopic fat is fat that is deposited inside muscles and inner organs that are not designed to store fat, such as the liver. In the image below, we can see clearly that even though these two men, Mark and Jim, have an identical total body fat percentage, Jim has a lot of visceral fat while Mark has very little. Ectopic fat cannot be seen here, but usually, if someone has more visceral fat, they also tend to have more ectopic fat as well. There are numerous factors that can contribute to fat accumulation in visceral and ectopic depots, but probably the most important one is that the main storage site for fat in the body, the subcutaneous fat tissue just under the skin, is at full capacity and can no longer store more fat. So Jim, here in this example, would be expected to be much more insulin-resistant than Mark.

Visceral vs. abdominal subcutaneous fat and their relationship to insulin resistance
Visceral vs. abdominal subcutaneous fat and their relationship to insulin resistance

For more detail on the relationship between healthy fat storage in subcutaneous fat depots and the deposition of visceral and ectopic fat leading to insulin resistance, please take a look at the dedicated blog post I made about this topic.

The conclusion here is that you want to minimize the amount of fat in visceral and ectopic depots if you want to be insulin-sensitive.

2. Chronic Hyperinsulinemia

We also do have evidence that chronic hyperinsulinemia can cause insulin resistance. As I discussed in more detail in the last blog post, chronically elevated insulin concentrations, as we see in a clinical procedure called a hyperinsulinemic clamp or in patients with a benign tumor of the pancreas called an insulinoma, do seem to cause insulin resistance.

I also discussed that this does not seem to be the case for the typical up and down in blood insulin levels that results from consuming a diet rich in carbohydrates, because there is no consistent evidence that high-carb diets lead to insulin resistance compared to low-carb diets.

However, several of you wondered whether constant snacking on refined carbs, or drinking sugary drinks all day, may keep insulin levels chronically elevated, and whether this could lead to insulin resistance in these individuals. So an example could be someone who starts the day with a breakfast of toast and jam, which is refined grains and mostly sugar. Then they are hungry again two hours later and have a muffin as a snack, again refined grains and sugar. For lunch, they have a sandwich with cheese and a regular can of soda, followed by a couple of chocolate chip cookies as an afternoon snack and rice with vegetables for dinner.

This type of highly glycemic diet, with regular snacks in between the main meals, would certainly be expected to keep blood insulin levels elevated above baseline all day. Whether this could cause insulin resistance, I don’t know. I think it could, but we just don’t have a good human intervention study that has tested this. What I will say, though, is even if we had clinical trial data that this way of eating does not cause an increase in insulin resistance, I’d still say it’s certainly not a good habit to consume refined grains and sugars regularly, particularly sugars in liquid form. And it’s also not a good idea to never give your body a break and consume calories constantly. 

While chronic hyperinsulinemia triggers insulin resistance, a modest up and down in blood insulin levels that results from eating high-carbohydrate meals does not appear to do so. However, the available evidence is limited, in that it is indirect (trials compared diets differing in their carb and fat content, not their diurnal insulin concentrations) and in that no diets were tested that would keep blood insulin levels chronically elevated.
While chronic hyperinsulinemia triggers insulin resistance, a modest up and down in blood insulin levels that results from eating high-carbohydrate meals does not appear to do so. However, the available evidence is limited, in that it is indirect (trials compared diets differing in their carb and fat content, not their diurnal insulin concentrations) and in that no diets were tested that would keep blood insulin levels chronically elevated.

In his context, let me explain one mechanism through which chronic hyperinsulinemia may induce insulin resistance. In a previous blog post, I explained that insulin binds to the insulin receptor, for example, in muscle cells. That stimulates a cascade inside the cell that has several effects, and these effects differ slightly depending on which cell the insulin is bound to. In a muscle cell, the insulin signal causes glucose transporters called GLUT-4 to move to the cell membrane, and then glucose from the blood can enter the cell through these glucose transporters.

Now, there are several mechanisms through which this cell could become insulin resistant. One is related to the fact that after insulin binds to the insulin receptor, they are bound firmly and cannot just let go. So the cell takes the entire complex up inside the cell, and either degrades it, which means it digests the proteins into their amino acid components, or recycles it, which means that the receptor is separated from the insulin in a specific part of the cell. This is important because it means that insulin binding to the insulin receptor temporarily reduces the number of free available insulin receptors on the cell surface. It takes a while until the number of insulin receptors on the cell surface is increased to a normal level again, and this would suggest that it’s a good idea to give the cells time to recover after a highly glycemic and insulinemic meal. This is supported by data showing that hyperinsulinemia reduces the number of insulin receptors on the surface of insulin target cells, both in vitro and in vivo in mice.

The conclusion here is that you want to avoid chronically elevated insulin concentrations. To be safe, it would make sense to minimize the consumption of foods with a high glycemic index, and to give the body a few hours between meals to get back into a fasting state.

3. Inflammation

So inflammation in the body is known to directly induce insulin resistance in all cells exposed to the inflammation. Why may that be?

Let’s imagine you cut yourself while preparing dinner. And some nasty bacteria from your knife are entering your skin through that cut. So now, you have bacteria attacking your skin cells, and threatening to get into your bloodstream, from which they could travel anywhere in your body. We need to prevent that from happening.

Fortunately, our body has defensive forces: our white blood cells, part of our immune system. These white blood cells move from the blood into the skin, and within moments the bacteria and our immune cells are involved in a gruesome battle. We can see this from the outside: within a few hours, the skin is getting warm and red, and this activation of immune cells is what we call inflammation.

The problem is that more and more bacteria are entering the wound, and our immune cells are getting tired and hungry. They need more energy. Their preferred source of energy is glucose. So the fighting immune cells start taking up glucose from the blood. The problem is that there is sometimes fairly little glucose available in the blood, and a lot of hungry mouths to feed, so evolution has done something very smart: the white blood cells make certain signaling molecules called cytokines to tell the other skin cells that there is inflammation going on. One effect of these cytokines is that they make non-immune cells insulin-resistant, which prevents them from taking up glucose. That makes a lot of sense: we are trying to defend the body, and the fighting immune cells get their food first, right?

Locally, here in the tissue after you have cut yourself, it does make a lot of sense that inflammation causes insulin resistance in the tissue. The cells residing in that tissue can do with a little less glucose for a few hours, and making them insulin-resistant ensures that the fighting immune cells have all the energy they need. And because this inflammation affects only this local tissue, this means that only this small part of your body is insulin resistant, and the rest of the body is not affected.

However, the same thing can also happen in the entire body. Imagine you have a major acute infection, such as the flu or pneumonia, then many more immune cells in your body are in fighting mode, and as a result, your entire body will become somewhat insulin-resistant. Or if you have an autoimmune disease such as Systemic Lupus Erythematosus, where your own immune system is attacking your own body. That could also lead to insulin resistance. Or if you’ve just had major surgery, your inflammation markers are going up quite a lot usually, and you will be very insulin-resistant for a few days. Or what we discussed in a recent blog post: low-grade chronic inflammation in fat cells all over your body, which is a result of these fat cells being too large and overwhelmed. 

What all of these have in common is that the immune system is activated, and that the resulting inflammation causes insulin resistance in all of the cells that are in contact with the inflammation.

The good news is that once the inflammation subsides, insulin sensitivity will normalize again.

4. Low Muscle Mass

Now, this is an interesting one that many people don’t know about. Even if you don’t have excess body fat or excess visceral and ectopic fat mass, you could be insulin resistant if you have low muscle mass. In one cross-sectional study, as one example, participants were insulin sensitive if they had low body fat mass and high muscle mass, and insulin resistant either if they had elevated body fat mass or if they had low muscle mass. In other words, having a low muscle mass and low body fat mass was associated with insulin resistance just as much as having high body fat mass and high muscle mass.

Low muscle mass can be a cause of insulin resistance, even in people with low body fat mass
Low muscle mass can be a cause of insulin resistance, even in people with low body fat mass

This is consistent with another study in 132 adults, mostly young and overweight, in whom investigators measured insulin resistance and muscle mass, but also body fat mass and even visceral and ectopic fat mass. They found that those with the lowest muscle mass were the most insulin resistant, even after statistically adjusting for body fat, visceral fat, and ectopic fat.

Similarly, Srikanthan and Karlamangla found that among 13,644 participants of the United States National Health and Nutrition Examination Study (NHANES), higher muscle mass relative to body size was associated with better insulin sensitivity.

The conclusion here is that optimal insulin sensitivity requires both high muscle mass and low body fat mass, or – to be more precise – low visceral and ectopic fat.

5. Physical Inactivity

Maybe it’s not a surprise to anyone that people who are very sedentary are more insulin-resistant. Because wouldn’t they be expected to have less muscle mass and more fat mass, two factors we already discussed that cause insulin resistance? Yes, this is probably true, but interestingly, we can detect a major negative impact of physical inactivity on insulin sensitivity even independent of lower muscle or higher fat mass. 

For example, if you take someone and put them on bed rest for even just 3 days, they develop pretty massive insulin resistance even though their body weight and fat mass barely change during this time. There may be a small reduction in muscle mass after a few days of bed rest, but generally not enough to fully explain the huge increase in insulin resistance in this setting.

This same observation has been observed in numerous other studies. For example, Hamburg et al. found that in 20 healthy participants, insulin sensitivity was massively reduced after five days of bed rest.

Even without changes in muscle mass or fat mass, physical inactivity such as bed rest can induce insulin resistance
Even without changes in muscle mass or fat mass, physical inactivity such as bed rest can induce insulin resistance

Bowden Davies and colleagues conducted an intervention in 45 highly active participants who were asked to reduce their daily step count by about 80%, which led to an average increase in daily sedentary time by 223 min. Even just 14 days of reduced activity led to a substantial reduction in insulin sensitivity, which in this case was associated with a measurable decline in muscle mass and an increase in fat mass.

What these data mean is that independent of your body composition, spending long periods of time in sedentary behaviors will make you insulin resistant. And even if you exercise, say, twice a week, if otherwise you just sit at a desk or on the couch, you may become quite insulin resistant just because of these periods of inactivity in between the formal exercise sessions. It is also worth emphasizing that excessive inactivity is a bit of a double-whammy: inactivity itself triggers insulin resistance and the low muscle mass and higher body fat mass that result from long-term inactivity cause additional insulin resistance on top of that.

6. Stress

Throughout evolution, stress has been a complex, coordinated response of our body to danger. So let’s assume you are a Stone Age human, and you just ate some meat and some berries. Your insulin levels are moderately elevated, and insulin is shuttling the sugar from the berries and the fat from the meat into your fat cells for long-term storage. 

After a meal rich in carbs and fat, insulin orchestrates the uptake of glucose and fatty acids into fat cells for long-term storage
After a meal rich in carbs and fat, insulin orchestrates the uptake of glucose and fatty acids into fat cells for long-term storage

Suddenly you see a huge cave bear approaching your camp, and that triggers what we commonly call the fight or flight or acute stress response. Your body secretes a number of hormones, most notably cortisol and adrenaline, which is also called epinephrine. One of the things these two hormones do is make your tissues immediately insulin-resistant. Why does that make sense?

As we discussed in previous blog posts, after a meal, insulin coordinates the long-term storage of energy. However, in a fight or flight response, we need all the energy we can mobilize to be readily available, and as a result, we want blood levels of glucose and also fatty acids to be elevated to enable us to fight or flee. So by making fat cells insulin resistant, the fat cells immediately stop taking up glucose from the blood, and instead, they now secrete fatty acids into the blood, as if you were in the fasting state. In the liver, insulin resistance initiates the release of glucose into the blood, again as if you were in the fasting state. In insulin-resistant muscle tissue, insulin is also less able to help glucose into the cells. 

During a stress response, insulin resistance develops in fat tissue, muscle, and liver, which causes blood levels of the two major fuels, glucose and fatty acids, to rise.
During a stress response, insulin resistance develops in fat tissue, muscle, and liver, which causes blood levels of the two major fuels, glucose and fatty acids, to rise.

As a result of all of these actions, blood levels of the two main body fuels, glucose and fatty acids, increase. That makes sense, right? The body wants to make sure we have all of the fuel we need. But how does it make sense that muscle cells become insulin-resistant? Wouldn’t it be better to allow the muscles to continue to take up glucose so that we have the energy to fight or flee? Remember that if our muscles contract, as in exercise, but also as we are fighting a cave bear or running away from it, our muscles can take up glucose from the blood in a manner that is independent of insulin. So, all is good. The cortisol and epinephrin response triggers insulin resistance everywhere, raising our blood glucose and fatty acid levels. But our contracting muscles are able to take up sugar from the blood as needed, and we have all the energy we need to fight the bear and – hopefully – defeat it. Great.

Except it isn’t great these days. You are developing the same fight or flight response all day as you are sitting in your office, again and again. Just from getting that upsetting email from your boss, because you are nervous about that presentation you need to give, or because you have a deadline and know you won’t make it. And now you are having so many moments of acute stress response that the stress, and with it the elevated cortisol and adrenaline levels, becomes chronic. And chronically being exposed to these hormones will keep you insulin resistant.

There are two other noteworthy consequences of chronic stress. For one, there is evidence to suggest that chronic stress may trigger low-grade chronic inflammation. That may sound counterintuitive, because usually corticosteroids are anti-inflammatory, but there are data to support the idea that both acute and chronic stress are commonly associated with low-grade chronic inflammation. And as we discussed earlier, low-grade inflammation induces insulin resistance in its own right.

The second aspect is that under the influence of chronic stress, we start to accumulate more fat in our visceral fat depots. Remember that acutely, stress causes fat cells to become insulin resistant and to release fatty acids. These fatty acids need to go somewhere, and they tend to partially accumulate in visceral fat. So note that this is one instance where someone could accumulate quite a lot of visceral fat even though they haven’t crossed their personal fat threshold and where they could theoretically still store excess fat in their subcutaneous fat depots. The insulin resistance in fat cells induced by chronic stress is simply preventing the storage of fat in subcutaneous depots.

Taken together, stress acutely makes the entire body insulin resistant, and also triggers a low-grade inflammatory response as well as, in the long run, an accumulation of fat in visceral depots, all of which are major contributors to insulin resistance.

7. Sleep Deprivation

We do have quite compelling data that as little as a single night of insufficient sleep measurably reduces insulin sensitivity. For example, in one study, participants were allowed to sleep for only 4 hours one night and as much as they wanted, up to 8.5 hours, another night. So this was to assess the effect of a single night of sleep deprivation on insulin sensitivity, which was measured by the gold-standard clamp the following morning each time. And even just sleeping 4 hours less for one night, insulin resistance was reduced by a whopping 25% after sleep deprivation.

As little as one night of sleep deprivation can trigger insulin resistance.
As little as one night of sleep deprivation can trigger insulin resistance.

In another study, sleep was limited to 5 hours each night for one week, and again insulin sensitivity was reduced by 20% compared to normal sleep duration, where participants were allowed to sleep for as long as they wanted.

Sleep deprivation leads to an increase in cortisol levels in blood, and one study could demonstrate that artificially keeping cortisol levels low partially blocked the insulin resistance-stimulating effect of sleep deprivation. This suggests that sleep deprivation at least partly causes insulin resistance through an increase in cortisol levels. Another study showed that sleep restriction increases free fatty acid flux from adipose tissue, suggesting that this could be another mechanism through which sleep restriction reduces insulin sensitivity. There is also evidence that biomarkers of low-grade chronic inflammation are elevated in individuals who are chronically sleep-deprived, which has been suggested to also potentially mediate the relationship between lack of sleep and insulin resistance.

8. Dysfunctional Gut Microbiota

As you are probably aware, our body is host to a very large number of microorganisms in our gastrointestinal tract, particularly the colon. There has now been a lot of research showing clearly that the types of bacteria we have in our gut, and their metabolites, are strongly associated with insulin resistance. Now, as we always say, association doesn’t necessarily equate to causation, so one experiment is particularly intriguing. Investigators started with a group of men who were insulin resistant, and actively changed the composition of their gut microbiota by a procedure called a fecal transfer. Yeah, I agree, it does not sound like something I would volunteer for anytime soon. Anyways, this was actually a randomized controlled trial in that men were randomized to either receive a rectal infusion of their own gut bacteria, or gut bacteria from very insulin sensitive people. And the very intriguing finding was that when these insulin-resistant men received gut bacteria from insulin-sensitive people, their insulin sensitivity, as measured by the gold-standard clamp, increased by about 70%. So based on these data, I lean towards the idea that the gut microbiome is not just associated with insulin resistance, but that there is a cause-effect relationship there.

A transfer of gut microbiota from lean, insulin sensitive men improves the insulin sensitivity of insulin resistant men
A transfer of gut microbiota from lean, insulin sensitive men improves the insulin sensitivity of insulin resistant men

Also of interest here is that the gut microbiome is also associated with our overall body fat mass, the amount of fat we store in visceral fat depots, and whether or not we are in a state of low-grade chronic inflammation. As we discussed earlier in the blog post, all of these also determine whether or not we are insulin-resistant. This is a complex literature with hundreds of scientific publications in both animal models and humans, and we’ll leave it for a future blog post to discuss in more detail to which degree cause-and-effect relationships may be underlying these observed associations.

We’ll discuss these relationships between our gut microbiota and our own health in detail in later blog posts. At that time, we will also discuss the evidence of whether and how we can change our own microbiome to improve our insulin sensitivity and other endpoints related to metabolic health.

9. Circadian Rhythm Out of Sync

Well, to understand what is meant with that, let’s start by talking about biological clocks.

This is actually super-fascinating. All of us have what is known as a master clock in our brain. Without going into too much detail here, that master clock consists of a number of molecules, the concentrations of which oscillate up and down roughly in a 24-hour cycle. And that master clock receives inputs from our eyes about whether it’s day or night, and that helps set that internal master clock. 

The brain contains a master clock that received light input from the eyes and is synchronized with individual clocks in each cell. The 'clocks' consist of several molecules, the concentrations of which oscillate up and down in a 24-hour rhythm.
The brain contains a master clock that received light input from the eyes and is synchronized with individual clocks in each cell. The 'clocks' consist of several molecules, the concentrations of which oscillate up and down in a 24-hour rhythm.

The master clock is relevant for basically all biological processes because it is connected to individual clocks in each cell of our body. Through this connection, the brain is able to affect what each tissue is doing at any given time. This is what we call a circadian rhythm, with the word circadian referring to processes that are recurring on a 24-hour cycle.

Normally, we are awake during the day when there is light out, and that is also the time when we eat. So if we expose ourselves to light at night, or eat at night, this would disrupt our normal circadian rhythm, meaning our circadian rhythm is out of sync.

Well, humans historically, before we had electricity, probably ate most or all of their calories during daylight, and it’s therefore maybe not too astonishing that our body’s ability to metabolize food is diminished overnight. So glucose tolerance, our ability to keep our blood sugar within the normal range, is lower already in the evening than in the morning, and then drops further overnight.

So, why is this relevant? For one, people who eat late in the evening or even at night, such as shift workers, would be expected to have higher glucose levels in response to high-carb meals than if they ate the same meals during the day. We also have a lot of evidence from observational studies that people who regularly work the night shift tend to be more insulin-resistant than those who sleep at night. They also tend to weigh more, which makes these data difficult to interpret: do these observations suggest that working the night shift directly affects insulin sensitivity, or does working the night shift regularly simply lead to excess calorie intake, and then the higher body weight and fat mass tend to make people more insulin resistant?

We do have some evidence that suggests that acutely disrupting the normal circadian rhythm leads to insulin resistance in just a few days, even without any changes in body weight or composition. This was tested in laboratory studies. Participants came in twice to spend a few days in a windowless room, in randomized order.

During one stay in the room, the investigators re-created the normal day/night rhythm outside that the participant’s internal clocks were used to. When the sun shone outside, they lit the room brightly, and the participants were active and ate their meals. When it was night outside, they switched off the lights, and the participants slept, in line with their internal clock.

During the second stay, the investigators, over time, shifted the normal day/night rhythm by 12 hours, such that after a few days, the room was dark when it was daylight outside, and the participants slept. And when it was night outside, they lit the room brightly, and the participants were awake, active, and ate their meals. Food intake and hours of sleep were matched between these conditions, but at the end of the lab-simulated night shift condition, the participants were a lot more insulin-resistant, without a difference between the conditions in body weight.

Insulin resistance can result from working (and being exposed to light and eating) at night, such as in night shift workers. This effect can be triggered within a few days during which an artificial night shift is created in a windowless room in research participants.
Insulin resistance can result from working (and being exposed to light and eating) at night, such as in night shift workers. This effect can be triggered within a few days during which an artificial night shift is created in a windowless room in research participants.

10. Puberty

There are two physiological states in which the body normally becomes insulin resistant, and puberty is one of these. The effect is fairly sizeable, with around a 20-40% or so reduction in insulin sensitivity in both boys and girls who are going through puberty. This effect is reversible, so by the end of puberty, they return to their pre-puberty insulin sensitivity.

11. Pregnancy

This is the second physiological state during which insulin resistance develops.

As a normal pregnancy progresses, the mother becomes more and more insulin resistant, usually becoming 40-60% less insulin sensitive by the third trimester when compared to before or after the pregnancy. If the woman is able to compensate for this massive insulin resistance by producing more insulin, she will remain glucose tolerant, but quite frequently, pregnant women are not able to fully compensate, in which case they become glucose intolerant and potentially develop gestational diabetes. Because the insulin resistance is transient, the gestational diabetes may go into remission again once the baby is born.

12. Certain Medications

It is well known that several classes of medications cause insulin resistance. These include particularly anti-retroviral drugs, which are drugs to treat HIV infection, 2nd generation antipsychotics, and corticosteroids. This is not an exhaustive list, and the main point I’d like to make here is that if you take any medications for an extended period of time, I think you want to have a conversation with your doctor about whether the medication can lead to things like weight gain, insulin resistance, or other side effects. Obviously, do not stop taking your medication just because you are worried about insulin resistance, and instead, always make sure to discuss your concern with your physician.

13. Certain Medical Conditions

There are quite a number of medical conditions that induce insulin resistance.

From what we already discussed, it shouldn’t be a surprise that this includes all acute infections and all chronic inflammatory conditions, including autoimmune diseases. As a rule of thumb, the more severe the inflammation and the higher the portion of your body that is affected by the inflammation, the more likely it will be that systemic insulin sensitivity is impaired. So if you had a little infection on your big toe, that big toe will be insulin-resistant, but the rest of your body will not be affected much. However, if you have a major autoimmune disease that affects a large portion of your body, or several tissues, such as Lupus, you may well become very insulin resistant.

Next on the list are conditions that affect hormone levels in your body. Thyroid disease is a common one, as both hyper- and hypothyroid conditions have been linked to insulin resistance. Cushing’s Disease is another example. In Cushing’s Disease, the body makes too much cortisol chronically, and just like chronic stress-induced increases in cortisol levels cause insulin resistance, so does Cushing’s Disease.

Another common medical condition worth mentioning here is sleep apnea. Sleep apnea is associated with insulin resistance, but the observational data cannot tell us with a high degree of confidence whether sleep apnea triggers insulin resistance, or whether insulin resistance is present in sleep apnea sufferers only or mostly because these patients also tend to be overweight or obese. It is, therefore, noteworthy that treatment of sleep apnea with CPAP, that is, continuous positive airway pressure, improves insulin sensitivity, suggesting that a cause-and-effect relationship is underlying the observed associations between sleep apnea and insulin resistance.

And then I’d like to mention a condition that is associated with insulin resistance, but with a somewhat complex cause-effect relationship: polycystic ovary syndrome, or PCOS. It is complex because insulin resistance could well be a cause or consequence of PCOS. Many of you have requested a separate blog post about PCOS, and I may tackle this in much more detail soon. 

14. Menopause

When women go through menopause, their insulin sensitivity tends to decline, for a number of potential reasons. For one, hormonal changes often lead to weight gain, and depending on their personal fat threshold, this by itself could lead to an increase in visceral and ectopic fat mass. On top of any weight gain, women also experience a shift in their body fat distribution, with an increase in their visceral fat mass even independent of any weight gain. As one would predict, such an increase in visceral fat mass is associated with an increase in insulin resistance. And lastly, the hormonal changes occurring during menopause may also contribute to insulin resistance independent of their effect on body fat mass and distribution.

15. Old Age

A higher age is strongly associated with greater insulin resistance. This reduction in insulin sensitivity with older age is thought to be related to a number of changes in body composition that occur with age. For one, aging is associated with a reduction in muscle mass, and low muscle mass, as we discussed earlier, is associated with insulin resistance. This age-related loss of muscle mass is called sarcopenia. There also seem to be functional and molecular changes in aging muscle that contribute to muscle insulin resistance. Aging also is associated with a shift in the body fat distribution, with a reduction in subcutaneous fat mass and an increase in visceral fat mass. So, in other words, the personal fat threshold seems to decline with aging, and we may gain visceral fat even if we don’t gain fat mass overall.

Aside from these changes in body composition, also consider that sleep deprivation, certain medical conditions, and medication intake increase with age, and may contribute as well to lower insulin sensitivity in older individuals. In women, as we just discussed, one such condition is menopause, which seems to accelerate the increase in visceral fat mass and insulin resistance that occurs normally with aging.

The data that I have seen suggests that we should be able to maintain reasonably normal insulin sensitivity as we age if we avoid the loss of muscle mass, the gain of fat mass, and the co-morbidities that often come with age. That is, obviously, easier said than done, but what I am arguing is that maybe aging itself is not necessarily per se all that negative, but that it’s the weight gain and sedentary lifestyle that usually comes with it.

16. A Poor Diet

Now, this is a nutrition website, and I would do you a disservice if I rushed through all of the dietary factors that are linked to insulin resistance. I will, therefore, just tease here that over the next 20 or so blog posts, we will discuss a large variety of dietary factors, including calorie intake, alcohol, a variety of vitamins, minerals, and trace elements, advanced glycation end products, the role carbohydrates, fat, protein, and certainly also the effects of specific carbs or fats such as fructose, long-chain saturated fatty acids, medium- and short-chain fatty acids; probiotics and prebiotics, different spices, and supplements, and not just discuss how these are linked to insulin resistance, but also go into detail about how we can utilize each of these factors to improve our insulin sensitivity. 

Summary and Conclusions

What I am hoping you can now appreciate is that there is no single cause of insulin resistance. It is therefore important to be clear about which of these factors we personally are exposed to, because to normalize insulin sensitivity, we need to address the specific cause or causes.

The top 16 causes of insulin resistance
The top 16 causes of insulin resistance

This is something that, in my opinion, is done too little in modern clinical medicine. Insulin resistance doesn’t per se have any symptoms, and is usually ignored in primary care. And only once we develop high blood sugar levels or diabetes, if we develop these, do we start to intervene, but only by treating the high blood sugar, not always by trying to address the insulin resistance or its root causes.

When you consider the different causal factors that can trigger insulin resistance, please be clear that for each, there is often a dose-response relationship such that, say, a little bit of visceral fat and ectopic fat causes mild insulin resistance while a very large amount of visceral fat combined with severe fatty liver disease leads to massive insulin resistance. Same if you are taking a corticosteroid medication: taking a low dose for a few days will have very different effects than taking a high dose over a longer period of time.

Also, consider that the effects of these different triggers may be cumulative. For example, if a lean and highly active girl enters puberty, her insulin sensitivity will worsen, but from very good to good. However, if a girl with abdominal obesity enters puberty, the insulin sensitivity may worsen from poor to very poor, and that girl may then be at risk of developing type 2 diabetes. 

Lastly, let me be clear that some of the potential causes of insulin resistance mentioned in this blog post pose a bit of a chicken-and-egg problem. For example, low muscle mass does cause insulin resistance, but insulin resistance also makes it harder to gain muscle mass. Similarly, insulin resistance is thought to play a role in the development of PCOS, but PCOS is also thought to lower insulin sensitivity. This is actually something that is typical for this literature: because insulin plays such an important role in many biological processes in our body, insulin resistance and the hyperinsulinemia that results from it also have many downstream effects, and it’s therefore not always easy or even possible to clearly say what causes what in the first place.

That’s it for this blog post. I hope this was informative and can bring you on the path to preventing or reversing your insulin resistance. This was quite a lot, and I apologize that, by necessity, I had to cover all of these triggers of insulin resistance in a somewhat superficial fashion here. As we discuss different strategies for reversing insulin resistance in future blog posts, we will tackle each in more detail, including concrete changes we can make to our diet and lifestyle to – ideally – normalize our insulin sensitivity.

Take care!


  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report. June 29, 2022. Accessed on October 2, 2023.
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10 Responses

  1. Dear Mario (if I may say so),

    As always, we were impressed by the carefulness and the clarity of your argument.
    Please continue your mission.

  2. Very good content!!
    My questions
    At which fasting insulin value range (mircoU/ml) do we speak of normal values, at which range of increased (critical) values and at which range of pathological values?
    In what range of values is the switching limit (mircoU/ml) between storing fat and burning fat? Are there things that have an influence on this switching limit, and if so, which ones?

    1. Dear Franz,

      Thank you for your kind feedback.

      Answers to your questions are not very straightforward, largely because I think very differently about this topic. The way you phrased this suggests that the body is always burning only carbs or only fats. That is not usually the case. Unless someone is on an extreme diet (keto, for examples), the body burns a mix of carbs and fats throughout the day, and the degree to which fats are burned certainly decreases with increasing insulin (and glucose) levels in blood. I don’t think we could possibly define an absolute insulin concentration at which fat oxidation is completely stopped in all cases, simply because other factors and particularly the sensitivity of cells to insulin differ from person to person, and also change within a person over their lifetime.

      As to your first question about normal vs. elevated fasting insulin, I would suggest you also consider the fasting glucose concentration, and calculated the HOMA-IR index, as I outline in the video linked below. In that video, I also provide guidance on what I would consider normal vs. mildly vs. severely elevated.

      The reason it’s important to factor in fasting glucose is that fasting insulin could be very low and still highly abnormal if at the same time fasting glucose concentrations are elevated (as in someone with untreated type 1 diabetes, for example). Therefore, it’s best to evaluate insulin in relation to blood glucose.


      Hope this is helpful.

      1. Excellent point from Mario. Always evaluate a certain titer of blood glucose in relation with its serum insulin level (taken at the same time). A morning fasting glucose of 105 with serum morning insulin of 4 gives a normal HOMA-IR, whereas a morning fasting glucose of 90 with an insulin of 10 gives a HOMA-IR in the insulin resistance territory. If one is looking for “glucose control”, doing morning BMPs without doing a serum insulin at the same time is not good medicine practice. However, this is what is being taught by conventional medical curriculum. “Science is settled” LOL

      2. Dear Mario,
        Thanks for you answer!
        In order to clarify my questions in more detail and thus make it easier to answer, my questions relate specifically to people with type 2 diabetes and overweight (BMI approx. pre-obesity) and from when the body has access to fat stores (specifically fisceral + subcutaneous) during nighttime sleep or fasting times (IF 16: 8, OMD, 0 calorie fasting up to a maximum of 3 days). E.g. Dr. Lustig and also Dr. Fung (I’ve already seen several of their lectures) say very clearly in their lectures that when insulin levels are elevated, the body has no access to its aforementioned fat stores and therefore no fat burning takes place! My question is what does these insulin levels mean in numbers? Both also emphasize very clearly that the insulin level is the decisive factor. The HOMA-IR index is a reasonably useful measure of insulin resistance, but I am asking me whether the insulin value alone isn’t more meaningful here?

  3. Hi Mario, hier mal ein deutscher Kommentar 🙂 Was ist deine Meinung zu den Ernährungs-Docs? Ist ja doch häufig eine Überschneidung zu deinen Videos da, von dem her würde ich gerne deine Einschätzung wissen 🙂

    1. Hi Flo,
      Ich lebe zwar gerade vorrübergehend in Deutschland, habe die Ernährungsdocs aber noch nie angesehen. Kann also leider dazu keinen Kommentar abgeben.

  4. As a physician and research scientist, i applaud you for your rational and evidence based approach. You are addressing a critical public health issue that in one way or another , affects us all. I am a bit tired of all the enthusiastic low carb, vegan, paleo, high carb, etc, etc blogs and vlogs espousing nutritional approaches without much evidence. The earth is indeed round! Science does matter. Please keep up the good work. Your information is very informative and helpful. Thank you.

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