Friday, January 6, 2012

What Causes Insulin Resistance? Part I

Insulin is an ancient hormone that influences many processes in the body.  Its main role is to manage circulating concentrations of nutrients (principally glucose and fatty acids, the body's two main fuels), keeping them within a fairly narrow range*.  It does this by encouraging the transport of nutrients into cells from the circulation, and discouraging the export of nutrients out of storage sites, in response to an increase in circulating nutrients (glucose or fatty acids). It therefore operates a negative feedback loop that constrains circulating nutrient concentrations.  It also has many other functions that are tissue-specific.

Insulin resistance is a state in which cells lose sensitivity to the effects of insulin, eventually leading to a diminished ability to control circulating nutrients (glucose and fatty acids).  It is a major contributor to diabetes risk, and probably a contributor to the risk of cardiovascular disease, certain cancers and a number of other disorders. 

Why is it important to manage the concentration of circulating nutrients to keep them within a narrow range?  The answer to that question is the crux of this post. 


Cellular Energy Excess

There has been a tremendous amount of research into the molecular mechanisms of insulin resistance in the last few decades, and certain things have become clear about it.  The first is that it appears to be a 'deliberate' process-- cells activate specific signaling pathways that down-regulate insulin responsiveness.  The rationale for this becomes clear when one considers what insulin does: it drives energy into cells.  Insulin resistance is how the cell says "stop sending me more energy-- I have too much already!"  It is a deliberate response to mitigate the negative effects of cellular energy excess.


Why would a cell want to prevent energy excess?  Because, just as chronic energy excess is toxic to a whole person, it is toxic to the cell.  I read an interesting paper in 2009 titled "Insulin Resistance is an Antioxidant Defense Mechanism"  (1).  The authors presented compelling evidence that exposure to excess nutrients causes cells to produce excess reactive oxygen species, which in turn shuts down insulin signaling.  This was presumably due to the fact that the mitochondria, the cells' tiny furnaces, were overloaded with energy.  Adding powerful antioxidants to the cells prevented insulin resistance because it blocked this signal.  They also showed, using genetic models, that this process was operative in whole mice, and similar findings have been reported by Dr. Peter Rabinovitch's group here at UW (2).  Insulin resistance protects the mitochondria, and hence the cell, from damage due to energy excess.

This is consistent with countless other studies showing that exposing cells to excess nutrients, particularly free fatty acids, causes insulin resistance.  These findings have been extended many times to living, breathing humans as well.  Increasing circulating free fatty acids in humans rapidly induces insulin resistance (3, 4, 5, 6, 7).  Suppressing free fatty acid levels restores insulin sensitivity in obese people with insulin resistance, including type 2 diabetics (8).

For a somewhat technical discussion of the role of mitochondrial dysfunction in insulin resistance and obesity, see below**.

If a cell takes up more energy than it burns (which it will do if it is chronically exposed to excess), energy accumulates, typically in the form of fatty acid metabolites (acyl-CoAs, ceramides, diacylglycerols) in the cytoplasm.  These play a major role in insulin resistance (9, 10), and may represent a second mechanism by which this response is activated in response to cellular energy excess.

So if cellular energy excess causes insulin resistance, what causes cellular energy excess?  Consuming energy (food) in excess of what the body can constructively use-- sort of.  The answer to this is not totally straightforward, because we have a special organ, fat tissue, dedicated to mopping up circulating energy excess to keep it from damaging other tissues.  However, when energy intake chronically exceeds the amount of energy that is being consumed, and fat tissue accumulates, it begins to do its job less effectively, allowing the exposure of other tissues to excess nutrients (11, 12). 

Energy balance (energy in vs. out) has a powerful effect on insulin sensitivity.  Experimental overfeeding studies in humans have shown that increasing 'energy in' causes insulin resistance in parallel with fat gain (13, 14, 15).  Reducing calorie intake and losing body fat via virtually any diet imaginable, including simple calorie restriction, low-fat diets, and low-carbohydrate diets, causes an apparent increase in insulin sensitivity (16, 17, 18), and so does exercise, which increases the 'out' side of the equation (19).  People who practice long-term calorie restriction for life extension have very low fasting insulin and glucose, suggesting high insulin sensitivity (20).

This week, I came across a very interesting study from the Women's Health Initiative here in Seattle (Fred Hutchinson Cancer Research Center).  It investigated the relationship between energy intake and diabetes risk (21).  Other studies have shown little evidence for a relationship, which is puzzling given the fact that overfeeding and resulting fat gain causes insulin resistance in animals and humans, and insulin resistance is a major diabetes risk factor.  However, observational studies are known for the fact that participants misreport energy intake, and that the degree of misreporting varies.  For example, in this study of postmenopausal women, they reported eating 1,416 kcal/day. 

To correct for potential under-reporting, the investigators brought in a technique called doubly labeled water calorimetry, which permits the accurate and unbiased determination of calorie intake***.  They used it to derive an equation by which they were able to mathematically correct for under-reporting.  After correction, the average calorie intake was 2,073 kcal/day.  Also after correction, it was reported that a 20% higher energy intake (corresponding closely to the increase that has occurred in the US in the last 40 years) was associated with a 2.4-fold higher risk of developing diabetes.  This effect appeared to be due primarily to the fact that higher energy intake was associated tightly with higher body fatness. This reinforces the robust link between excess energy intake, insulin resistance, and the development of diabetes.

Conclusion

In summary, a variety of lines of evidence suggest that insulin resistance, in large part, is a cellular defense mechanism against energy excess.  Cellular energy excess is caused primarily by the chronic consumption of energy in excess of what is expended.  Fat tissue can mop up the excess energy for a while, but if the excess is chronic and fat tissue enlarges (particularly abdominal fat), other tissues will be exposed to progressively more energy (fatty acids and glucose), and cells will act to protect themselves by reducing insulin sensitivity.

In the next few posts, I'll discuss other causes of insulin resistance, and eventually, how it can be addressed.


* And particularly, keeping total circulating energy (glucose plus free fatty acids) relatively constant.  Therefore, when a mixed meal is eaten, as circulating glucose increases, insulin orchestrates a corresponding decrease in circulating free fatty acids.  As glucose declines back to baseline, fatty acids rise to baseline in parallel.  If fatty acids do not decline appropriately as glucose enters the bloodstream, as occurs in obesity due to fat tissue insulin resistance, cells are exposed to energy excess, which results in insulin resistance and sometimes cell damage/death in other tissues (e.g., lipotoxic and glucotoxic beta cell death).

** One of the ideas that has appeared in the blogosphere lately is that dysfunction of mitochondria, defined as a lowered capacity to oxidize fuel (particularly fat), causes insulin resistance. On its face, the idea is logical, and it has been the subject of a fair amount of research.  Reducing the mitochondria's ability to burn fuel should make it more easy to overload, and make it more likely to initiate the protective response of insulin resistance.  Diabetics have fewer mitochondria, and insulin resistant people have less mitochondrial oxidative phosphorylation in muscle tissue (22).  I would like to believe that mitochondrial dysfunction is a factor, but the evidence does not consistently support it (23).  One of the reasons is that deliberately reducing mitochondrial fuel oxidation in mice does not impair insulin sensitivity, to the contrary, it improves it (24, 25, 26).  The evidence connecting mitochondrial deficiency and insulin resistance/diabetes in humans and animals has not been very consistent.  There are two sides to this debate, each with valid points, and I don't think it has been resolved definitively yet.  I'm currently skeptical but open to new information. 

Then there is the idea that mitochondrial dysfunction causes obesity.  Now, we have entered into the realm of pure speculation.  This idea doesn't make sense to me on several levels, and my suspicions are reinforced by the fact that mice with reduced mitochondrial activity do not gain fat, and are in some cases leaner than normal (27, 28, 29).  As far as I know, obesity is not a general characteristic of humans with mutations in mitochondrial genes that cause dysfunction, although I'm not sure it has been studied systematically (30).  This idea is on very thin ice!

*** Actually, it measures energy expenditure, which can be used to calculate energy intake if body composition remains stable (or changes in ways that are measured).

85 comments:

Todd Hargrove said...

Thanks for another great post.

Is it possible that one can suffer the negative effects of chronic energy excess even while being weight stable?

Imagine a yo yo dieter who gains twenty pounds one year, loses it the next and then repeats this process for ten years. Over a ten year stretch they are weight stable, but I assume they have suffered some damage from the prolonged stress of chronic energy excess.

If so, the question becomes, how long do these intervals of energy excess need to be to cause damage?

Is it possible that a lean and weight stable person experiences daily intervals of energy excess (that is eventually offset to a well functioning desire to move), but that is temporarily stressful enough to cause some damage?

Part of the reason I ask is that I am a lean weight stable guy who has always eaten a ton. Since incorporating some of your ideas about food reward, I am pretty sure I have been eating a lot less. And feeling better. Even though I haven't lost any real weight. Interesting.

Scott W said...

Oh boy...a discussion of insulin and glucose. Let's see how long it takes the first low-carb dogma to show up in comments.

Thank you for another thoughtful and analytical post.

Scott W

Christopher said...

Exercise does more to increase insulin sensitivity than simply increasing the out side of the energy balance.

Jim said...

This sets the stage very clearly. I look forward to seeing what you build on top of this.

vladex said...

It's really wrong how in these insulin/diabetic posts it is never reported the true cause of diabetes and insulin resistance.Corticosteroids (Cortisol) release all the nutrients a body has (fatty acids,amino acids,glucose)into bloodstream in an alarming situation and they must be spent or they will cause insulin resistance. Now in modern, civil and urbanized society people are taught to never respond aggressively and this causes them still to release cortisol with all of its energy reserves but they are never spent. This is a much more clear case of insulin resistance. Just google "glucocorticoids cause whole body insulin resistance"

FrankG said...

So what causes a body to stay in a state of chronic excess energy intake, and how does the body respond in respect to insulin secretion, in a state of Insulin Resistance?

When you say that one of insulin's roles is "...discouraging the export of nutrients out of storage sites" does this include inhibiting the release of fatty acids from fat tissue?

FrankG said...

These postmenopausal women who can't be trusted to accurately report their diet -- why bother asking them at all, why not just use the doubly labeled water calorimetry and take them out of the loop completely? Maybe House is right... "everybody lies".

Should we care about the composition of their calorie intake, as assumed from their calorie expenditure? Do we care what kind of diet provided that energy or is a calorie just a calorie just a calorie? When the researchers corrected for their under-reporting, did they make any assumptions about where the extra that they were eating came from?

FredT said...

under-reporting

Yes well, remember that food labels are allowed a error of +- 20%, and they typically are -40 to + 0, so it is not all the subjects.

Try computing using an scales and Atwater factors then compare those results to a meter, and see what you get.


I don't know, we just did testing.

Alvaro said...

Completely useful..good source, thanks anyway!

Yves said...

Interesting, but the suggestion to just eat less seems silly for a lot of people.

How do you explain skinny diabetics if they are in calorie balance? I have been insulin resistant at sub 10% body fat for years (not diabetic), exercise and don't usually eat much.

I think the key has more to do with the ROS, or something like that. If we acknowledge that there is variance in insulin sensitivity when controlling for weight, lean mass, exercise, calorie intake, etc. then it seems like that should be the focus.

One example is reducing iron to improve insulin sensitivity. So far I think I have had success with my own n=1 but the jury is still out. This study shows an improvement in insulin sensitivity without a change in diet or body weight, exercise, etc. But by reducing iron levels:

http://www.ncbi.nlm.nih.gov/pubmed/11591239

Colpo has written about this in more detail

FrankG said...

Are you suggesting that Insulin secretion is increased "in response to an increase in circulating nutrients (glucose or fatty acids)." ..?

As a diabetic myself I was not aware that dietary fat drives up the need for insulin? Are you sure about this?

I'd also caution you to use an unbiased scientific method to take another look at some of your assumed cause and effect. You draw conclusions that are closer to being simply subjective opinions.

Evelyn aka CarbSane said...

@Frank: I believe Stephan is referring to the well-documented effect on basal insulin secretion by free fatty acids (not dietary fat).
I blogged on this here if your interested.

Evelyn aka CarbSane said...

@Yves: There are genetic, and apparently forms that develop in utero/early infancy of IR. I think what Stephan is describing is how someone becomes IR through lifestyle.

FrankG said...

@Evelyn

If the raised insulin level is telling the body to hang on to its stores of fat -- or as Stephan phrased it "...discouraging the export of nutrients out of storage sites" how do we get an increase in circulating free fatty acids other than from dietary fat..?

But dietary fat does not increase insulin levels so how does this feed into Stephan's reasoning that: Insulin Resistance (IR) is a down-regulating mechanism resulting from too much insulin trying to force too much "energy" into the cells.

If insulin is not raised by dietary fat then what is raising the insulin and ultimately leading to the IR?

FrankG said...

Not forgetting of course, that IR causes the body to secrete ever higher levels of insulin in an effort to overcome the IR, which adds to the above scenario -- including "...discouraging the export of nutrients out of storage sites" -- and if unchecked, feeds back into itself in a downward spiral.

gunther gatherer said...

Hi Stephan, you said:

"Therefore, when a mixed meal is eaten, as circulating glucose increases, insulin orchestrates a corresponding decrease in circulating free fatty acids."

Here we have the main explanation for why low-fat, high carb diets work against insulin resistance and fat loss, why Asians and Kitavans are lean, who killed JFK, etc.

But it makes it sound like stuffing yourself on sugar is the best thing you can do for insulin resistance. Is this the case? It's not hurting the Asians any,though I don't know their overall statistics for diabetes or IR.

And by the way, do you still feel dietary fat to be innocuous then? Even if it doesn't cause CVD directly, it could eventually do so simply by making you diabetic first.

Arnu619san said...

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http://www.sapientarticles.com
God bless you

Evelyn aka CarbSane said...

@Frank: Nobody disputes that one of the major roles of insulin is to (a) stimulate fatty acid uptake and (b) suppress fatty acid release in adipocytes. The question is, does this regulation for the purpose of fat mass regulation? No. It would appear not. It's purpose is to regulate circulating substrates. In the LIRKO's it appears the fat tissue remains insulin sensitive and the low circulating FA's would be consistent with insulin doing it's job. Indeed I think the FA's are lower than normal, which would be consistent with hyperinsulinemia w/o enlarged fat cell mass. And yet they don't get fat because insulin doesn't give a damn about your fat cell mass. I blogged on this in What does insulin regulate anyway? The muscle IR is probably because with persistent hyperglycemia, one of the major routes of glucose disposal -- non-oxidative route, e.g. glycogen synthesis -- is swamped.

The mice don't overeat despite the balance of the trig/FA cycle tilted in favor of storage in the adipocytes and they don't get fat. Damn that CICO.

Ned Kock said...

Nice post Stephan. One interesting thing that I have noticed from some studies is that removal of fat cells (surgically) and unnatural/forced fat uptake by peripheral tissues (growth hormone therapy) tend to significantly decrease insulin sensitivity in the short term. One example is discussed here:

http://bit.ly/u9tRtr

This is consistent with fat cells, and their functions, being protective against insulin resistance – but up to a point. Clearly there is a threshold above which adipocytes start rejecting fat, and lipotoxicity ensues; this threshold varies from individual to individual, and probably also based on diet and other factors. There is a connection with ceramide; I still think TNF is a major factor:

http://bit.ly/ctXS9a

Peggy Holloway said...

I believe there is a strong genetic component, having seen nearly everyone in my family show signs of insulin resistance and experience health issues that are resolved by eliminating carbohydrates from our diets. Some of us have had problems with obesity and weight management, but many have not. Very thin family members have still experience the symptoms of insulin resistance, such as mood disorders in response to carbohydrate consumption. That fact makes me highly skeptical that it is being fat that "causes" insulin resistance. I rather believe that in some, being insulin resistant by nature/genetics causes obesity.

Peggy Holloway said...

My sister and I followed low-calorie, low-fat diets for years (boring - salads and tuna) and couldn't control our weight and progression to Type II Diabetes. We did not "lie" about what we ate. My sister spent 3 months on the 25-point Weight Watchers diet (around 1200 calories a day) and walked four to five miles a day. In 3 months, she gained 10 pounds and got her diagnosis of "diabetes." I do not believe that obese people eat too much and give themselves diabetes or that they lie about what they eat. Please live one day in my body before you try to tell me that it is not carbohydrates and the high insulin levels induced by their consumption that cause weight gain and high blood sugar. Fortunately I figured that out for myself 12 years ago, cut sugar, starch, and flour and now eat many more calories a day in the form of fatty meat, cheese, and eggs and have not had any trouble maintaining a normal weight, blood sugar, HDL, triglycerides, along with more energy than I know what to do with, cycling 1000s of miles a year on 20 grams/carbs a day.

JBG said...

"The authors presented compelling evidence that exposure to excess nutrients causes cells to produce excess reactive oxygen species, which in turn shuts down insulin signaling. This was presumably due to the fact that the mitochondria, the cells' tiny furnaces, were overloaded with energy. Adding powerful antioxidants to the cells prevented insulin resistance because it blocked this signal."

Is this saying that antioxidants, by blocking the signal that induces IR, are helpful? Or that they are harmful?

JBG said...

"However, when energy intake chronically exceeds the amount of energy that is being consumed, and fat tissue accumulates..."

It took me a minute to figure out that, contrary to a use earlier in the paragraph, when you say "consumed" here you must be meaning "used up" rather than "taken in".

psychic24 said...

I guess i'm a bit confused. If insulin resistance is a mechanism by which the body attempts to refuse excess nutrients from entering cells (as well as keeping things from leaving), why would the body increase insulin output? To counteract its own protective mechanism seems idiotic….not to mention pointless?

Aravind said...

Nice post. Looking forward to the next part in the series Stephan.

BTW - down another couple more pounds with the High Carb Low Reward diet. Some people are convinced that I am going to get diabetes from all these carbs. I will blame you when that happens.

Thomas said...

Gaining 10 lbs in 3 months on 1200 Kcal/day while walking 4-5 miles per day. Really? The only way this could happen is if 1)there's a severe hypothyroid condition (in which you wouldn't be walking 5 miles a day), 2)the person weighs only 5 lbs, 3)the person is really an alien with a never before seen, other world metabolism, or.... 4)intake is being under reported. I'll take number 4.

allison said...

I believe it was Rogge's recent paper on mitochondrial dysfunction that cited studies showing that obese individuals suffered from damaged and missing mitochondria. This was said to account for the diminished capacity for exercise in obese subjects.

If IR is caused by a excess free radicals and a build-up of fatty acids in the cytoplasm, wouldn't the mitochondria play a central role? The unpaired electrons originate inside the mitochondria, don't they? If free radical leakage is killing off or damaging the mitochondria, wouldn't that further diminish the cell's ability to utilize fatty acids for energy? The mityochondria become damaged or die, diminishing the ability to utilize fatty acids, which then become backed up and wind up in places they don't belong.

I'm just spitballing here, but it seems like this is all related, or at least occurring in parallel.

Sue said...

Psychic 24:
"I guess i'm a bit confused. If insulin resistance is a mechanism by which the body attempts to refuse excess nutrients from entering cells (as well as keeping things from leaving), why would the body increase insulin output? To counteract its own protective mechanism seems idiotic….not to mention pointless?"
In the case of glucose it likes to maintain about 5g in the blood so it wants to remove any excess.

Peggy Holloway:
"Very thin family members have still experience the symptoms of insulin resistance, such as mood disorders in response to carbohydrate consumption."
I don't think a symptom of insulin resistance is mood disorders?

psychic24 said...

I understand it likes to maintain a certain amount of glucose in the blood, otherwise we have glucotoxicity, that's exactly my point though…. Why reduce insulin sensitivity if you're only going to pump out more insulin to counteract the effect….

Richard said...

The proposal made by Stephan is fine, and I do not think it is being properly understood by some of the more combative comments. Stephan notes that ANY reduced calorie diet will get weight down and therefore get insulin back under control.

But insulin is not the only issue in the world.

There are good reasons to avoid (any? or excess?) wheat consumption, and good reasons to avoid excess PUFA, and to eat more saturated fat as opposed to PUFA and "excess" carbs.

Similarly, a weight reduction diet that works is preferable to one that does not work, so maybe we need to focus on what works, both short and long term. In the short term almost any calorie reduction diet works, and the problem is maintenance. Long term carb reduction works. I do not think anyone is recommending carb elimination other than for emergency or intervention weight loss.

We also have to factor in the other health issues here, including the proper level of system inflammation, avoidance of "foods" with negative impacts, etc.

This discussion reminds me of the discussion of whether cholesterol is a cause or a result of the underlying heart and artery health problems. Do people die from high cholesterol? Most likely they do not. The idea here is that insulin excess and then failure of the insulin producing cells (Diabetes?) is one result, not a cause, of a human dietary problem (although Diabetes causes its own "set" of problems), and the problem that results in Diabetes is long term excess caloric consumption.

So yes, the answer is "eat less" and similarly "eat fewer calories." And then the follow on issue is how to do that. Stephan seems to recommend simple food. Low carb is pretty simple.

berto said...

Psychic 24,

Don't assume the body is being governed by thinking agents. This actually makes perfect sense when you think of it in terms of a common negative feedback loop - your housing thermostat.

It (your hypothalamus) has no idea that the window is broken and letting cold air in - it's just keeps sending the signal to crank out the heat.

Individual cells defending themselves from exposure is a distinct issue from hyperinsulinemia, mechanically speaking.

Many systems come together to make the organism work - and they don't "know" what's going on with each other.

-Al

Peggy Holloway said...

My sister's story is anecdotal, I understand, but it supports the insulin theory of fattening. Gary Taubes writes about just such individuals who eat very little, are active, and still gain weight because of the effect of insulin when individuals who are insulin-resistant consume a carbohydrate-based diet. That is exactly what happened to my sister, and to me to a lesser extent. I learned as a teenager when I went on my first diet, weighing and measuring every bite, counting every calorie, figuring out how much I had to exercise to meet the magic formula of a 3500 calorie deficit that would result in a pound loss, that "calories in, calories out" doesn't work. Substituting fat for carbohydrates means that my body is receiving a form of fuel it can use, ketones, rather than glucose, which my insulin-resistant cells cannot utilize, so the calories will be stored as fat.
As for the mood disorders, my brother, when he was an organic vegan, thought he had chronic fatigue syndrome. When my daughter was last a vegetarian, she experienced insomnia, depression, and bulemia. My son had severe ADHD as a teenager. I have alternating waves of anxiety and brain fog when I eat carbs. We all have seen vast improvement in these conditions on VLC diets. I am absolutely convinced that ADHD, depression, eating disorders, and chronic fatigue are all related to insulin resistance.

majkinetor said...

Fat induces physiological insulin resistance and there is nothing wrong with that. I don't see how it relates to excess-nutrients-are-poison conclusion.

For all we know, it could be programmed response to starvation with which FFA are used as main fuel and insulin resistance must occur to spare glucose to the brain and other tissues that depend on fermentation.

When your body is 'hacked' so this response occurs without fasting, we can get all sorts of damage.

Txomin said...

Thank you for this very informative post.

The following sentence is particularly interesting: "This is consistent with countless other studies showing that exposing cells to excess nutrients, particularly free fatty acids, causes insulin resistance."

Particularly free fatty acids? Not glucose? I'll keep this in mind.

Regarding the comments about calorie reduction leading to weight gain, honestly, it does not compute. Please reduce your calorie intake to zero and, if you still gain weight, make yourself available to science so that we can once and for all eliminate world hunger. I wish this were funny.

Jenny said...

How do we account, then, for the several studies that find increased insulin resistance in the slim, young first degree relatives of people who have Type 2 diabetes?

The argument that being fat is creating their insulin resistance wouldn't hold for them. There are several studies of that ilk:

Insulin resistance in the first-degree relatives of persons with Type 2 Diabetes. Straczkowski M et al. Med Sci Monit. 2003 May;9(5):CR186-90.

Beta cell (dys)function in non-diabetic offspring of diabetic patients M. Stadler et al. Diabetologia Volume 52, Number 11 / November, 2009, pp 2435-2444. doi 10.1007/s00125-009-1520-7

Peggy Holloway said...

My family is a glaring example of the phenomenon you are referencing. My son is exceedingly sensitive to carbohydrate consumption and is skinny as rail. That's why I can't ignore the genetic component. My father and grandfather had "Type II Diabetes" (I put it in quotes because I have problems with acknowledging that there is such a thing, since everyone in my family has learned that our blood sugar can be normalized with proper diet and that high glucose is the result of eating carbohydrates in the presence of our genetic IR) and so did my son's paternal grandfather. I have never been obese, although I struggle to keep my weight normalized when I eat carbohydrates. I have nephews who are coaches and have always been very active and thin, but they are incredibly hyperactive and emotionally over the top (as kids we saw their behavior go out-of-control when they ate a lot of sugar and junk, which was most of the time). One of these ostensibly healthy young men just failed a medical exam to get a school bus driver's certification because of high blood pressure. Connection to IR? I think so.

rodeo said...

>>Jenny

That's because BMI is a crappy way of measuring body fat. Ned Kock has this post about BMI and being skinny fat:

http://healthcorrelator.blogspot.com/2011/08/men-who-are-skinny-fat-there-are-quite.html

That being said I do acknowledge that there is a connenction between genetics and type 2, but I don't think it's relevant if your body fat is low enough.

Judi O said...

I think the genetic component is strong. I have always worked hard at my health, eating a whole foods diet and avoiding things like fast food. I've also been very fit my during adult life - on top of my regular workouts I was a performer in a taiko ensemble for four years. I have never been overweight. At 5'6" I weigh what I have always weighed as an adult - between 130 and 135 1bs. Even so I discovered about 1 1/2 years ago that I am prediabetic. I maintain a 5.5 A1C by using my meter to figure out what I can tolerate carbwise. Strength training helps, too. I am not cured. Also kind of interesting - my bg runs about 15 to 20 ml higher from October through March with no change in diet or exercise.

psychic24 said...

@ Berto

"It (your hypothalamus) has no idea that the window is broken and letting cold air in - it's just keeps sending the signal to crank out the heat.

Individual cells defending themselves from exposure is a distinct issue from hyperinsulinemia, mechanically speaking.

Many systems come together to make the organism work - and they don't "know" what's going on with each other."



So your statement is saying that the brain is acting as a distinct entity from your fat tissue. I'm kind of getting the impression you're agreeing with Taubes' latest blog post. This "What causes INsulin resistance" post is kind of pointing to the "body rules" paradigm Taubes advocates, rather than the "brain rules" one that food reward is a proponent of...

Stephan Guyenet said...

Hi All,

A number of people have brought up the fact that some people are lean and insulin resistant. That is true. There are a number of possible reasons.

One reason is that body fat accumulation is very important, but it isn't really the cause of insulin resistance, it's just a major factor contributing to cellular energy excess. Body fat accumulation is actually protective against the severe insulin resistance that occurs if energy excess happens without body fat exapansion (lipodystrophy), but eventually if it accumulates too much it loses some of its effectiveness. If body fat is not as good at mopping up excess energy in some people (due to genetics, epigenetics, nutrition or whatever other factors), that will expose other tissues to excess energy even in the absence of obesity.

Also some people have a lean BMI but actually carry a fair amount of abdominal fat, which is the worst kind for at least two reasons. The other possibility is that the insulin resistance is not due to cellular energy excess, but to another factor. I'll be discussing these other factors in later posts.

A last factor is that some people have pancreatic damage that causes poor blood glucose tolerance in the absence of insulin resistance. This can be due to autoimmune disease for example.

Hi Todd,

I suspect it is possible, but I don't know for sure. Some people can "burn off" excess calories to a greater degree than others, but that doesn't mean it's healthy to force your body to deal with the excess.

Hi FrankG,

Yes, it does include inhibiting the release of fatty acids from fat cells, temporarily. However, this does not imply that it causes accumulation of fat inside fat cells over a 24 hour period. The rate-limiting step for fat balance is fat oxidation, not release from fat cells.

Insulin also suppresses fatty acid oxidation, temporarily, while increasing glucose oxidation. In this way, the body shifts substrate use based on diet composition to keep total kcal in/out balanced, with no net effect on body fat accumulation.

Regarding your question about dietary fat increasing insulin requirements, I was referring to circulating fatty acids rather than dietary fat. Generally, as long as energy balance is maintained, circulating fatty acids will remain stable and dietary fat should not increase them. There may be exceptions in the case of extreme carb restriction, but it is not generally true that dietary fat increases circulating free fatty acids.

Hi JBG,

My guess is harmful. ROS are natural signaling molecules, and although they're harmful in excess, blocking them completely is a very bad idea. I think that would be nearly impossible to do as a human taking typical dietary supplements though.

Hi Aravind,

Glad to hear it! Yes, you can blame me when you get diabetes.

psychic24 said...

Also, in line with this lack of synchrony idea, i just read a personal account from Robb Wolf's site, http://robbwolf.com/2011/11/07/the-reverse-challenge-a-personal-experiment/

The person here describes stomach fullness but unsatisfied in his head/mind--which caused him to eat more. I'm very interested in this distinctness concept because I experience it quite frequently. My mind is always unsatisfied until i ingest massive caloric amounts of food, so that by the time my mind is at ease , all the nasty side effects of overeating begin and negate whatever positive effect "satiety" was supposed to elicit. Any idea as to what causes this lack of coordination and what can be done to fix it?

JBG said...

Hi Judi O

You say, "...my bg runs about 15 to 20 ml higher from October through March with no change in diet or exercise. "

Here's a shot in the dark -- How's your 25(OH)D during the winter months?

Anand Srivastava said...

Wouldn't this argue for the Low carb diets?
We know that dietary fats get transmitted via lymph nodes to the fat cells. And don't need insulin for storage. This will prevent any free fatty acids in the blood. And will not require the cells to be forced to get the extra energy.

We also know that excess of glucose is toxic so we get increased insulin which forces the pancreas to create more insulin which forces cells to store the glucose.

A high fat diet should cause a person to spontaneously eat less, because the insulin remains low so that the cells are not forced to get more energy, and consequently less food is needed.

This will not matter if a large part of the body is not insulin resistant, because the cells with excess energy will be more resistant and will take in less food, but the insulin sensitive cells will get the larger share of the energy.

So I would think it would make sense for the morbidly obese to eat a low carb diet, but the simply overweight people to eat a high carb diet. This is probably why most low carb dieters get stagnated once they get into normal over weight category.

I guess the guiding factor would be to avoid foods which cause uncontrolled eating.

Subcalva said...

Insulin resistance is how the cell says"stop sending me more nutrients-- I have too much already!" It is a deliberate response to mitigate the negative effects of cellular energy excess.

Stephan, isn’t the cell saying “stop sending me more energy-- I haven’t got enough nutrients!"

Judi O said...

Hi JBG,

Good thought about the D - I am fine there. I have been working with the theory that we have less light this time of year and using a light therapy box. It did slow the progression down for about 6 weeks, but didn't halt it completely. I'm now using a low dose of metformin which seems to be helping. This seems to be fairly common with a lot of diabetics. Horses go through this as well and they call it seasonal rise.

Asim said...

psychic24:

In response to your question:

"Why reduce insulin sensitivity if you're only going to pump out more insulin to counteract the effect….
"


Dr. AYers has some interesting insights here that may answer your question:

http://coolinginflammation.blogspot.com/2009/11/superoxide-causes-insulin-resistance.html

psychic24 said...

@asim

This is the conclusion dr. Ayers makes: "Superoxide sensing and insulin resistance protect cells against too much energy input and oxidative stress, but without the ability to reduce blood sugar, hyperglycemia leads to the suite of degenerative reactions that provide the symptoms of type 2 diabetes."

That doesn't answer my question whatsoever. It just asks it in a more detailed way...

I.e. Why are out cells expressing insulin resistance (less insulin receptors) if our body (pancreas) is just going to have to pump out more insulin to get rid of the sugar in our blood when the prior amount of insulin isn't achieving the desired effect (due to IR)...? It just seems like an idiotic mechanism, where the cells are acting based on a totally distinct set of parameters-- they're acting as individuals, not like constituents of a larger, integrated set of systems.

holly said...
This comment has been removed by the author.
holly said...

i'm 5'8 and 110 lbs (gluten free) with IR. try telling me to lose weight and exercise more, i dare you!

Sanjeev said...

psychic24 said ...

I.e. Why are out cells expressing insulin resistance (less insulin receptors) if our body (pancreas) is just going to have to pump out more insulin to get rid of the sugar in our blood when the prior amount of insulin isn't achieving the desired effect (due to IR)...?
______________

I don't know what you're asking here exactly - maybe

" why didn't evolution come up with a perfect feedback mechanism to deal with every possible situation, including all pathologies" ?

Sanjeev said...

still trying to understand the question, how about this rephrase:

" why are some people born with higher insulin resistance than others, when their pancreas will just have to pump out more insulin to account for it?

Why can't everyone just be born with perfect insulin sensitivity so the pancreas can always produce next to zero insulin?"

Sanjeev said...

"What causes INsulin resistance" post is kind of pointing to the "body rules" paradigm Taubes advocates, rather than the "brain rules" one that food reward is a proponent of...
______
or maybe someone's creating illogical false dichotomies, setting up a straw man that he can knock down later?

Sue said...

Interesting post about insulin resistance occuring in fat cells first:
http://adipo-insights.blogspot.com/2010/08/fat-fails-first.html

psychic24 said...

@ Sue

Muscle and adipose tissue are the only ones with glucose receptors that are insulin dependent (i.e. glut 4). So obviously they'd be the first to feel the effects?

@Sanjeev

If you're trying to be a pr*ck then you're doing a bang up job. Actually, seeing as how many parts of the body are rather well integrated (e.g. the leptin negative feedback loop,etc), this poorly constructed feedback between IR cells and the pancreas is definitely a legitimate question. By the way, Taubes' so called "illogical dichotomy" seems pretty solid; you take in incorrect food (i.e. insulin stimulating foods in his opinion) that causes a disruption of the hormonal milieu of the peripheral tissues, which ends up signaling the brain to stimulate appetite for more of these inappropriate foods. Meanwhile food reward bypasses the peripheral tissue (at least initially) and right away causes pathology of the brain. So please, before letting lose your astute critiques, grow an ounce of humility first.

Sue said...

Most believe IR in fat cells last is what I am getting at:
http://adipo-insights.blogspot.com/2010/07/how-black-age-of-endocrinology-may-be.html

Matt said...

On the plus side, I can give up trying to lose weight.

I added the occasional sweet potato and carrots back into my diet and I gained 20 lbs in a month >_<

Caveat my squat and deadlift increased from 475 to 525 and 500 to 550 respectively. Of course my body fat scale claims I gained 5% body fat even on the "very athletic" setting.

Most of my body fat is abdominal. Oddly enough, the only thing that has caused me to lose weight a super low reward all meat & diet where I was drinking olive oil and heavy cream. My body fat set point in the prescence of any carbs over about 100g seems to be stuck @ 25%.

nano said...

Thanks for sharing the post. Insulin is necessary for the diabetic patient. More physical activities are good in the way of controlling the diabetics.

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preeti said...

Thanks for sharing the post. Insulin is necessary for the diabetic patient. More physical activities are good in the way of controlling the diabetics.

Regards: Treatment of osteoarthritis

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Evelyn aka CarbSane said...

@holly: Your IR is probably genetic/developmental in nature. It's not "caused" by your diet.

holly said...

both my parents eat crappy and are overweight but without blood sugar issues like mine. it is odd.

holly said...

i agree with whoever commented its related to cortisol dysfunction (in some cases)

Hans Keer said...

Hello Steven, As far as I understand the matter insulin also regulates the transport of amino acids into the cells. Do you agree? If yes, does IR also restrict the uptake of amino acids by cells? If yes, could this amino acid deficit cause cell dis-adjustment? VBR Hans Keer

Asim said...

psychic24:

If I understand your question correctly, the answer is actually in the comments, the second one to be exact when caphuff asked a similar question, of what would happen if there was no insulin resistance. Dr. Ayers responds:

"The immediate consequence would be cellular death via apoptosis. Sunburn is massive apoptosis of the skin in response to solar DNA damage -- large scale inflammation and peeling. Imagine if this happened to your organs -- multiple organ failure every time you overindulged. Type 2 diabetes and obesity is a better way to prepare for a winter of scarcity. A little starvation is the way to prepare for Spring."

Essentially, insulin resistance is being expressed blocks the glucose in the cell to protect against the immediate death of cells, because of the superoxide damage that necessarily results. It is essentially a trade-off.

Mzlittlekitten said...

here's a fact most people never come into account when comparing calories between LC and HC...normally if you roast or fry meat without adding oil to it some of the fat calories will naturally come out as grease reducing the overall calorie content leading the person eating it to overestimate their calories.Same also applies to meats such as chicken which have their weight bulked up with water.

Mzlittlekitten said...

here's a fact most people never come into account when comparing calories between LC and HC...normally if you roast or fry meat without adding oil to it some of the fat calories will naturally come out as grease reducing the overall calorie content leading the person eating it to overestimate their calories.Same also applies to meats such as chicken which have their weight bulked up with water.

Mzlittlekitten said...

here's a fact most people never *take into account

J. Stanton said...

I am surprised by the claim that the role of mitochondrial dysfunction in obesity and insulin resistance is "pure speculation" and "an idea that has appeared in the blogosphere lately".

This claim is materially false. "The blogosphere", of which this site is a member, did not originate this idea, and its involvement in obesity is not "pure speculation". The articles that mention it prominently cite the following, among many others:

Mary Madeline Rogge
The Role of Impaired Mitochondrial Lipid Oxidation in Obesity
Biol Res Nurs April 2009 vol. 10 no. 4 356-373

which contains sentences such as "Impaired mitochondrial function may account for the insulin resistance closely associated with increased intramyocellular lipid content in type 2
diabetes (Krssak et al., 1999; Pan et al., 1997)."

The fulltext is freely available online - and both my article and (highly recommended) Peter's excellent Metflex series on the subject provide additional citations and information.

I invite readers to determine for themselves whether the genetic knockout mice studies cited here apply to the mechanisms proposed by Rogge and others.

JS

psychic24 said...

@ Asim

Guess I'm really stupid because I still don't understand. You're saying cells are protecting themselves from IMMEDIATE death at the expense of causing vascular damage (among other things) via the hyperglycemia that results from the inability to clear glucose from the serum?

John said...

Dr. Guyenet,
Do you see obese/over weight/T2D patients in a clinical setting? If so, how many/day.
Thanks
Dr. John

Asim said...
This comment has been removed by the author.
Asim said...

psychic24,

Yeah... I don't see what is so strange about it... the body will send white cells to target an immediate threat of a pathogen which may end up damaging local tissue in the process. It's a similar analogy...

Immediate damage is prevented, while the effects of hyperglycemia would cause damage, over the long run. You've heard of chronic hyperglycemia, right?

Like I said, it's a trade-off when the body gets too much excess energy in it's cells.

psychic24 said...

This is what's hilarious: immediate death of fat/muscle cells (i.e. that's what's getting IR first) isn't so bad, the complications of hyperglycemia can vary from coma to heart disease to whatever else, and you're saying the body believes that to be preferential to apoptosis of a couple of worthless cells is logical?

dim sum massacre said...

Psychic24, as far as I understand it (maybe others with a better understanding of physiology can correct me if I’m wrong), insulin does the following:

1. Signals peripheral cells to increase their uptake of glucose from the blood stream.

2. Signals fat cells to decrease release of fat into the bloodstream.

3. Signals the liver to stop synthesizing glucose and releasing it into the bloodstream.

So, even if the muscle cells decide to ignore the signal from (1),insulin still has the effect of decreasing excess nutrients in the bloodstream via (2) and (3). Thus it’s not really the case that increased insulin is cancelling out the effects of the peripheral cells refusing to take in more energy. Instead, it actually serves to mitigate the amount of hyperglycemia/elevated FFA that results.

Asim said...
This comment has been removed by the author.
Asim said...

psychic24,

Strange, I thought we were speaking about cases of energy excess.. It's just fat/muscle cells that need glucose? Just because they get it first, doesn't mean other cells don't get it...

Further, your operating under the assumption that the complications of hyperglycemia would always be immediate and one would fall under a coma or heart disease right away... who eats until they fall into a coma and gets hearts disease immediately? the body has a whole set of protective mechanisms, including the release of homrones to suppress appetite..

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Stephan Guyenet said...

Hi J Stanton,

I've read the article you referenced. Keep in mind, just because an idea is published in the scientific literature doesn't mean it's not speculative. In this case, although well composed, the paper was a hypothesis review paper, presented no original data, and was published in an obscure journal (Biological Research for Nursing). It certainly falls into the category of speculative, and that is what I thought when I read it. In fact, I stand by my characterization of the mitochondrial dysfunction-obesity hypothesis as "pure speculation", since no experiment that has directly tested it has been able to produce obesity, in fact they seem to produce leanness as per the papers I cited.

Regarding the statement about these ideas being in the blogosphere lately, I didn't intend to imply that the ideas originated on blogs, only that they have been circulating on blogs lately.

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Edward Miller said...

Some of the questions abut insulin resistance to protect the cells at the expense of the body appear not to consider that some cells developing insulin resistance may protect themselves while diverting fuel to other organs. Imagine arm muscles are getting too much fuel and being damaged. They develop insulin resistance and are not damaged. The glucose they would have taken up is absorbed by other part of the body such as leg muscles. If the leg muscles are being used heavily, they will not be in energy excess and can take up the extra glucose.

If after some part of the body develop insulin resistance, the glucose from the blood is not being removed rapidly enough more insulin is released so bring the blood levels down. As long as there is not universal insulin resistance, this system seems efficient at directing nutrition to where it can be used, or where it does least damage. As different muscles change their need for fuel, this system seems to direct it to where it i best used, or does the least damage while being stored.

The problem would seem to be where all of the body develops insulin resistance and the pancreas keeps pumping up the levels of insulin to remove excess glucose from the blood. At least in the simplified versions, this eventually results in exhaustion of the beta cells and diabetes.

greg said...

great post.... following this blog about insulin resistance.

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Nyx said...

I am not sure if there is any value in becoming the 83rd comment, but I wanted to say that this post became of extra interest to me when I read the mitochondrial references. My son is currently being evaluated for suspected mitochondrial dysfunction/disease. He has already had one test that showed dramatically reduced activity by one of the enzymes (cytochrome c oxidase, aka complex IV), accompanied by increased numbers of mitochondria, possibly a compensatory mechanism. I still have a lot to learn about this stuff, but my understanding was that because of the nature of mito, it can lead to obesity. Just like some diabetics are super-skinny and others wind up obese, mito manifests in different ways. My kid is super-skinny, but I have worried that he could become obese later. Mito means a problem with energy and exercise intolerance, so I think this adds complexity to the analysis. I do know that they recommend focusing on the medium chain fats rather than the longer ones (pufas), because -- I think -- the longer ones cause a back-up in the respitory chain and can therefore lead to increased oxidative stress, I think? also in simple terms because you get more energy but yet use less in order to metabolism the medium chain fat. So, I don't know how that relates to insulin resistance exactly, but ... somehow it all sounds kind of related ....

Daniel Bassett said...

Hi Stephen

Please forgive me for my nutrional naievete but I was hoping you could clarify some questions I have on your article....and it was a very well written and easily understood article!!!

If 1) fatty acid accumulation in cells leads to insulin resistance, and 2) the more fat tissue we have the less effective it is, would it be fair to say that losing weight (and by this I mean fat from cells) would have a snowball effect, or a positive feedback loop, since you would be increasing your insulin sensitivity more and more which would then further enhance your weight loss? If this statement is true then why do you think this is not observed when people go on diets?

Or could it be that as you release fat from the cells during weight loss increases free fatty acid levels and thus also leads to insulin resistance. It really seems like a catch 22. YOu need to get the fat out of the cells but if you do the high amount of free fatty acids will increase your insulin resistance too!!! Do you think on a ketogenic low carb diet the amount of fat leaving the cell would be enough to make an impact on insulin resistance?

From reading your post it seems you are a proponent, at least in part, of the model that calories in = calories out matters. GAry Taubes seems to think this has no explanatory power and that it is largely hormones - unless I am mistaken. I wonder if 1) that overfeeding studies in humans that caused insulin resistance were due to an increase in carbs not calories, 2) reducing fat by any diet (low calorie/fat or low carb) results in increased insulin sensitivity but maybe all these diets reduce carbohydrates to some extent, and 3) people who are on CRON diets would also likely have very low carbohydrate intake. Could it be that the benefits we are seeing are simply due to a reduction in insulin due to lowered carbohydrate intake? I guess the thing I would need to do is to look at all these studies and try to consider whether carbohydrate was reduced in all of them.

Sorry for the long response but am hoping you can clarify some issues for my own sake. Again great post!!!!!

spenc193 said...

Something we have to remember also is the actual mechanism insulin uses to transport energy within the cell, and it is this factor that can explain IR and diabetes in low body fat individuals. Insulin requires translocation of the GLUT receptor from the inner membrane surface to the outside surface. This requires a proper composition of membrane fatty acids, particularly of the omega 3 and 6 types. They maintain membrane fluidity. But a severe imbalance of n-3 to n-6 can disrupt translocation of GLUT-4, and given the severe ratio of around 20:1 (n-6 to n-3) in the standard american diet, we are hampering this mechanism. We have to balance our PUFA intake while also keeping it within a certain range, because oxidative states in the body can cause PUFA to be a problem in general. I would think proper vitamin E intake, a ratio of 2:1 of n-6 to n-3, and perhaps n-acetyl cysteine and r-lipoic acid with meals (along with proper exercise) would end insulin resistance.