Saturday, January 7, 2012

What Causes Insulin Resistance? Part II

In the last post, I described how cellular energy excess causes insulin resistance, and how this is triggered by whole-body energy imbalance.  In this post, I'll describe another major cause of insulin resistance: inflammation. 


In 1876, a German physician named W Ebstein reported that high doses of sodium salicylate could totally eliminate the signs and symptoms of diabetes in certain patients (Berliner Klinische Wochenschrift. 13:337. 1876). Following up on this work in 1901, the British physician RT Williamson reported that treating diabetic patients with sodium salicylate caused a striking decrease in the amount of glucose contained in the patients' urine, also indicating an apparent improvement in diabetes (2).  This effect was essentially forgotten until 1957, when it was rediscovered.

What is sodium salicylate?  It is an anti-inflammatory drug very similar to aspirin*. It is important to note that high-dose aspirin is not a good long-term treatment for diabetes due to its side effects.

Modern research has confirmed that high doses of aspirin or related compounds have a striking effect on diabetics, not only lowering blood glucose but also increasing insulin sensitivity (3).  In 2001, a landmark paper in the journal Science confirmed that aspirin has this effect due to its inhibition of a specific inflammatory signaling pathway** (4). Since then, it has been shown that blocking inflammation in various other ways prevents the development of insulin resistance (5, 6, 7). 

Inflammation and energy excess are tightly interlinked.  Flipping the calendar back to 1993, Dr. Gokhan Hotamisligil and colleagues showed in another landmark paper that blocking an inflammatory signal prevents the insulin resistance caused by obesity (8), and similar findings have been reported many times since then (5, 6, 7).  This suggests that energy excess causes insulin resistance in part by engaging inflammatory pathways in the body.  The concept has received additional support from studies showing that salicylate can block the insulin resistance caused by acute energy excess due to infusing fatty acids into the circulation (9).  Since insulin resistance is a protective mechanism against cellular energy excess, suppressing it with anti-inflammatory drugs may not be the greatest idea.

Energy excess causes inflammation, and inflammation causes insulin resistance.  However, inflammation can be caused by other factors, and this can also contribute to insulin resistance.  For example, inflammatory substances that mimic infection can cause insulin resistance (10).  The digestive tract is full of these substances, and normally the gut barrier does a good job of keeping them out of circulation.  However, under certain conditions these can enter the circulation in larger amounts, and this is thought to contribute to insulin resistance (11).  It's worth emphasizing that the type of inflammation linked with insulin resistance is not the same powerful, acute inflammation that you might get at the site of a physical injury.  It is a low-grade, chronic type of inflammation.

The immune system is extremely complex, and "inflammation" is a catch-all term for a number of different related processes in the body.  Specific types of inflammatory signaling play an important role in insulin resistance.  Others do not, for example, the transient inflammation that follows strenuous exercise.  The inflammatory pathways activated by energy excess and poor digestive health seem to contribute to insulin resistance.

* Acts by inhibiting cyclooxygenase-2 and NF-kB. 

** NF-kB pathway.


Jesús Bernal said...

What causes inflammation? Vegetable oils, gluten, high-fructose corn syrup?

New York said...

This is interesting, but difficult to parse when you are used to thinking (per Mr G. T.) that insulin resistance leads to energy excess rather than the other way around

Chris Tunstall said...


This looks like being a fascinating series of articles.

I wanted to ask you a question about one of the things you say, just to make sure I haven't missed anything. You say:

"Dr. Gokhan Hotamisligil and colleagues showed in another landmark paper that blocking an inflammatory signal prevents the insulin resistance caused by obesity (8)."

It's the "caused by" where I am stuck. I don't have access to the reference, but I have read a later paper by the same main author:

Here, it is said that "Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. ... However, the mechanisms linking obesity to insulin resistance and diabetes in humans remain largely unknown."

The authors seems to be at pains to say that obesity and IR are associated, but to go no farther.

So, my question is, are we able to say that obesity causes insulin resistance? Or is this still controversial, as I had thought?

Thanks for any reply.

allison said...

Speaking of the relationship between our modern, industrial McDiet and degenerative disease, I saw this monstrosity and wondered why I spent $100 on a pastured, organic turkey for Thanksgiving when I could eat a McPiglet instead.

I've always marveled at the fact that Costco has so many "handicapped" parking stalls. Basically, they want to make it easier for all of the obese and diabetic customers to roll those flatbed carts out to their cars and load them up.

Geoff said...


It seems very likely to me that overeating causes insulin resistance, but it's a pretty big leap from that to say that overeating causes inflammation. Isn't it possible, or maybe even likely, that the thing that is causing the overeating is also the thing that is causing the inflammation? In other words, if you overeat foods that are non-toxic; i.e. meats, starches, fruits, vegetables; inflammation would not occur, though insulin resistance still may in the short term.

This alternative explanation would play right into my armchair theory that there are certain foods that are inherently toxic, particularly wheat and vegetable oils, and that these also happen to be hyper-rewarding (which may be the cause of them being toxic, or may just be the reason that such toxic foods have become so ubiquitous while others have not). Interested in your thoughts.

JBG said...

"...inflammatory substances that mimic infection can cause insulin resistance (10). The digestive tract is full of these substances..."

Could you give a few examples?

Stephan Guyenet said...

Hi Jesus,

Poor digestive health and improper nutrition, which probably has many contributing factors. I'll get to some of them in a later post.

Hi New York,

Yes, there is a lot of research that is difficult to understand from that perspective.

Hi Strontium,

Many people including myself say that obesity causes insulin resistance, but that's shorthand for a process that is more complex. In a sense, obesity is actually protective against insulin resistance, because it represents the fat tissue sequestering energy that would otherwise create a situation of energy excess on other cells in the body. However, the protection runs out when the fat cells fill up and become insulin resistant.

Also, once fat cells/tissue expand too much, fat cells begin to die and the tissue becomes heavily infiltrated with immune cells and inflamed.

So fat accumulation is a protective mechanism against energy excess (in other tissues) that progressively becomes less effective as fat cells fill up. So what causes insulin resistance is the failure of fatty acid trapping and increased inflammation that occurs when fat cells fill up. Shorthand, obesity causes insulin resistance.

What Hotamisligil was referring to in the quote you pasted is that the exact mechanism by which this occurs (e.g. which inflammatory factors are most important) is not clear.

Hi Geoff,

Overeating consistently will lead to inflammation due to energy excess, however that doesn't mean that the foods themselves aren't causing inflammation by other mechanisms as well.


As far as I'm aware, the main players that have been identified are bacterial lipopolysaccharide, lipoproteins and flagellin. These bind to dedicated extracellular receptors called toll-like receptors (TLRs).

Geoff said...


"Overeating consistently will lead to inflammation due to energy excess"

I'm still somewhat skeptical of this claim. Have there been studies done without the use of franken-oils, wheat and HFCS? If so, I would be really interested to learn more. If not, then I would expect that on an clean diet, the body would burn off or store all extra energy in an appropriate way that does not trigger an inflammation response.

Then there's the question of whether or not it is even possible to overeat on high quality, healthy food sources. If fatmass is regulated in the brain, it would seem that this would not be possible or at least very difficult for most people.

John said...


Stephan wrote something relevant to your question a while back, about the Massas.

Zorica Vuletic said...

" So what causes insulin resistance is the failure of fatty acid trapping and increased inflammation that occurs when fat cells fill up. Shorthand, obesity causes insulin resistance."

But what is causing the fat cells to fill up? Not obesity. In order to reach obesity you need to have an excess of insulin, which then leads to obesity and inflammation which then leads to failure of fat cells to fail to trap fatty acid then to insulin resistence.

This is if you're only looking at the role of insulin. I am not talking about other metobolic factors here. Insulin is one of the easiest and biggest issues to address though.

I just feel it is a bit naive to say 'obesity causes insulin resistence'.

Morris said...

Excellent article and great series. You say “This is consistent with countless other studies showing that exposing cells to excess nutrients, particularly free fatty acids, causes insulin resistance”. Do you mean by “particularly FFA’s” that this is due to the 2.5 ratio of FFA: glucose caloric value ie once in excess the higher caloric value produces additional damage more quickly? Or is there an implication that FFA’s are inherently more damaging?

From a free article “The Costs of Breathing” by Nick Lane in Science, Oct 14/’11, p184: “Senescent cells survive by glycolysis, often with high mitochondrial ROS leak, which gives rise to oxidative stress. This drives epigenetic changes and the expression of proinflammatory factors (3) associated with chronic inflammatory conditions such as diabetes, and cancer” . The article is about evolutionary selection for ROS leakage rates in mitochondria. The quote implies that damaged cells limp along increased glucose metabolism. This view if I interpret correctly is not just blogosphere musing. My personal experience (ya I know) does not contradict this kind of process.

Geoff said...


But do we know that the Massas show signs of inflammation when they overeat? Do we have CRP measurements on them, for example? It seems completely plausible to me that they are fat and insulin resistant, but their biomarkers for health and disease are still generally within what we would consider to be healthy ranges. Even more plausible given that when they stop actively forcefeeding themselves, their fatmass normalizes very quickly.

John said...


Since "their fatmass normalizes very quickly," I would guess no to "do we know that the Massas show signs of inflammation when they overeat?" But that's just a hunch.

Yves said...

Stephen, I look forward with great interest to your next post touching on the role of digestive health!

The literature seems to suggest that high fat diets contribute to impaired intestinal ability and an increase in endotoxin exposure in rats/mice. Do you think this is applies to humans as well? The findings seem paradoxical; don't bacteria metabolize primary carbohydrates? This would put diets like GAPS flat on their face!

Anonymous said...

"Many people including myself say that obesity causes insulin resistance, but that's shorthand for a process that is more complex."

I have a friend who is very thin, but is also insulin resistant. What explains his insulin resistance? Clearly his fat tissues are not taking up the energy he is consuming. In some people do muscle tissue and fat tissue lose insulin sensitivity at the same time?

FredT said...

So now have insulin resistance causes obesity, insulin resistance is caused by overeating. Then once we become insulin resistance, aka overfed, we have a physical desire to maintain that overfed state as long as food is pleasureful and available. OK. More ELMM advise comming?

CarbSane said...

@marchwinds: You've actually hit on it with "Clearly his fat tissues are not taking up the energy he is consuming." ... thus, as in the obese person who has topped off their fat storage capacity, excess delivery of fatty acids to the other cells occurs.

Francis St-Pierre said...

Food for thought. Some research on fasting has uncovered potential benefits of this practice.

It would seem to me that the inflammation you're referring to might be caused by constant eating, i.e. grazing throughout the day. This grazing in turn might be associated with excess caloric intake.

In other words, someone could be eating massive amounts of calories in one sitting, and this could potentially cause less inflammation that someone eating fewer calories, but over throughout the day.

Any thoughts?

Anonymous said...

The link to the aforementioned study on inverse association between hsCrp and vitamin K2 intake:

Anonymous said...


Consistent with your post a recent study found that hsCrp is inversely related to intake of vitamin K2 directly related to diabetes risk. The hazard ratio was 0.75 for the highest versus lowest quartile. It was hypothesized that the increased diabetes risk was due to increased inflammation associated with vitamin K2 deficiency.

Almost all vitamin K2 in the western diet comes from animal fats, about half of it from aged cheese. Consumption of animal fat has decreased by 40% in the last 50 years in large part due to government recommendations. The reduction in animal fat consumption has greatly increased deficiency of vitamin K2 which greatly increases risk of diabetes.

The link to the study is on preceding post.

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ProfessorEd said...

The popular literature suggest insulin resistance leads to beta cell exhaustion in which eventually the beta cells can no longer produce more insulin, and then to diabetes?
What is the evidence for this?
Assuming it is so, the policy implication would be to try to hold down the total insulin production in order to make them last longer. Just as if you want your car to still be running after 10 years you would minimize the mills driven, it would seem that trying to limit the load on the beta cells would be good. If this is right, this would seem to be a strong argument for eating more fats and less carbohydrates, as well as for eating lower glycemic index foods in general.
Yet most discussions of diet seem to focus on merely wish diets reduce or increase insulin resistance, rather than on postponing the transition from only insulin resistance to diabetes.
Am I missing something?

CarbSane said...

The LIRKO mouse is but one case that demonstrates that wearing out the pancreas does not appear to be an issue. The hyperinsulinemic tend to have higher beta cell mass although it may not be functioning properly in response to glucose.

Peggy Holloway said...

I keep replying here because my family is such strong evidence for insulin resistance being a natural genetic condition since we have not evolved to handle a carbohydrate-based diet.
In our family, the insulin-resistance can lead to weight issues, but many of us have never been overweight. The health problems we have when we eat carbs are clear evidence. We all have these problems - GI problems and mood/energy swings to name a few. We all have spectacular health and well-being when we restrict carbohydrates and eat high fat diets. So, the answer to the question "What causes insulin resistance?" remains simply and clearly: genetics/evolution

Gabriella Kadar said...

There seem to be 'inconsistencies' with the obesity/diabetes corollory. Examples of exceptions abound. For example: the skinny, hyper-emotional Italian dude who owns a scrap yard. He's physically very active and hardworking but he's type 2 diabetic. I think his emotional volatility concommitent with adrenaline release, dumping of glucose into the bloodstream from the liver stores and then whatever happens with pancreatic insulin release may be the means by which his insulin insensitivity has developed. He's been on a relatively low carb diet for a very long time. But it's not saving him from the diabetes. Possibly meditation and controlled breathing and controlled emotions would help more.

Nancy Kelly said...

Insulin helps the body use blood glucose for energy. Gud Info.


greg said...

very informative series of articles about insulin resistance. it helps me understand why it's happening.

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Dann white said...
This comment has been removed by the author.
Dann white said...

Very informative.
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Ian said...

In the study 'Metabolic endotoxemia initiates obesity and insulin resistance' do they say what type of fat is in the high-fat diet that increases the LPS-containing bacteria in the gut?

I thought saturated fats were generally accepted as 'anti-inflammatory'. Does that study suggest otherwise?

lisao said...

I don't think it can be said to cause it because not everyone that is obese, (whatever your definition of what that is, the flawed and ridiculously stringent bmi system or the older height and weight charts or something other arbitrary contrived system) has insulin resistance. And it can be corrected by diet nutritional and exercise changes with little or no weight loss. I would cite the health at every size author from UC Davis, can't remember her name.

Unknown said...

"Also, once fat cells/tissue expand too much, fat cells begin to die and the tissue becomes heavily infiltrated with immune cells and inflamed."

Hey Stephan, you mention that the fat cells will die, now are you implying that your now going to have less capacity to store? Yet we still see an imbalance between relative energy excess and energy expenditure, still favoring excess, besides the potentially beneficial aspect of fat cell death. What my desperate concerns to this are the following, which I hope you can clarify:
1. Do the fat cells get renewed again through cellular division, or are they permanently gone?
2. Can this be a reason why the disproportional fat accumulation in obese is so noticeable?
3. Do the existing fat cells just take the available energy excess that were within these cells before death, once these cells undergone death, the FFA eventually end up back into existing cells and start accumulating? Yet, if fat cells are at this moment insulin resistant, how will glyceroneogeonesis occur without carbohydrates to make glycerol, wouldn't they just accumulate in plasma.
4. Anything on pre dormant adipose tissue? prostoglandins+ angiotensin activating dormant fat cells to mature fat cells? Can this contribute to the overall potential of how much an obese individual can gain in weight?

Will be very curious on what you have to say!

Unknown said...

I'm sorry, but I don't buy the "insulin resistance is caused by overeating". I am 5 feet 4 inches and was 108 pounds until menopause. I always ate healthy my entire life and did not and still do not have a big appetite, so I do not eat much. I blew up at 47 years old and nothing works. I recently asked my doctor to order a c-reactive protein test to check for inflammation and it came back extremely high. Something obviously goes very wrong in your body that causes the insulin resistance as far as I'm concerned.

Robert Conroy L.M.T., C.M.T., M.T.I., C.E.P., C.N.C. said...

Spiking your insulin is what causes insulin resistance because your cells know too much insulin is toxic to the cells.