Monday, January 9, 2012

What Causes Insulin Resistance? Part IV

So far, we've explored three interlinked causes of insulin resistance: cellular energy excess, inflammation, and insulin resistance in the brain.  In this post, I'll explore the effects on micronutrient status on insulin sensitivity.

Micronutrient Status

There is a large body of literature on the effects of nutrient intake/status on insulin action, and it's not my field, so I don't intend this to be a comprehensive post.  My intention is simply to demonstrate that it's important, and highlight a few major factors I'm aware of.

Magnesium status is a determinant of insulin sensitivity.  Although the evidence is not totally consistent, several studies have shown that improving magnesium status can reduce insulin resistance in diabetics and non-diabetics (1, 2, 3).  This may be partially related to the fact that diabetes depletes magnesium stores.  A four week low-magnesium diet reduced insulin sensitivity by 25 percent in healthy volunteers (4), although I would like to see this replicated using a more rigorous study design.

Iron may be another important factor.  Although intuitively most people have a "more is better" approach to micronutrients, the evidence suggests that for many nutrients, the healthiest intake is a happy medium-- not too low and not too high.  This seems to be true for iron.  A useful measure of body iron stores is the blood concentration of ferritin, an iron storage protein.  In general, the higher a person's ferritin level, the lower his or her insulin sensitivity (5, 6).  This association is confounded by the fact that ferritin increases in response to inflammation, so it needs to be viewed with caution.  However, studies have shown that reducing iron stores can increase insulin sensitivity in people with high ferritin (7, 8).  This is typically done by repeated phlebotomy, or blood drawing. 

One study showed that people who donate blood have a higher insulin sensitivity than people who don't (9), although it's difficult to be certain that this difference was not due to other factors.  Personally, I give blood about once a year, because I want to help people in need of a transfusion, but also because it may have some side benefits to my health (as long as I don't dip too low-- low iron is a problem too).  I recently received my "one gallon" pin, indicating that I've given blood eight times in the Seattle area since 2002.

It's best to get your ferritin checked before using phlebotomy to reduce iron stores.  There's no use in reducing ferritin if it's already low.  It's possible that our bodies are adapted to a constant loss of iron through intestinal parasites, injury and menstruation, and our body's evolved tendency to hoard iron doesn't serve us well in an environment where iron-rich foods are plentiful, we have few intestinal parasites, we don't often lose blood due to injuries, we have access to contraceptives that stop menstruation, and most women live well into their post-menopausal years*.

In recent decades, nutrition science has begun to explore the fascinating world of non-essential nutrients.  As it turns out, these can have a powerful impact on health, including insulin sensitivity.  Polyphenols are one class of non-essential nutrients that appears to be important.  Numerous studies have shown that polyphenols and polyphenol-rich foods can increase insulin sensitivity, or attenuate the development of insulin resistance, in animals and humans (10, 11, 12, 13, 14).  Some of the foods that have been commonly studied in this regard are chocolate, green and black tea, coffee, berries, citrus fruits, red wine and a variety of spices.  These may act by increasing the defenses of cells against oxidants and inflammation by a process called hormesis (15, 16, 17).

There are certainly other dietary factors involved, some of which are unknown to science, and some of which are simply unknown to me.  The broader point is that eating a diet composed of natural, minimally refined foods will offer an appropriate range of nutrients for most people.

* Interestingly, there is an iron storage disorder called hemochromatosis in which the body absorbs much more iron than is normal or desirable, leading to a variety of health complications.  A mutation responsible for hemochromatosis (HFE C282Y) originated ~2,500 years ago in Europe and has undergone positive selection, rapidly increasing in prevalence to ~9 percent of Caucasians (18, 19).  This suggests that this mutation, or something linked to it, may have conferred a strong survival advantage to our (my) ancestors a few thousand years ago.  Why might this be?  While people who are homozygous (carry two copies) for C282Y are at risk of serious medical complications, people who are heterozygous (carry one copy) for C282Y have a lower risk of iron deficiency (20).  This would not have been important in the context of a hunter-gatherer diet rich in available iron from animal foods (which may be why this mutation was not selected for in the pre-agricultural environment), but in the context of an agricultural diet focused around grains, an iron-hoarding phenotype would have been advantageous.  The prevalence of cribra orbitalia and porotic hyperostosis, both skeletal indicators of iron deficiency, increased greatly in early agriculturalists compared to hunter-gatherers, suggesting a high prevalence of iron deficiency (Paleopathology at the Origins of Agriculture, edited by Cohen and Armelagos).  This suggests a strong selective pressure to evolve strategies to improve iron status.  Our genome reacted, producing an effective, if crude, adaptation to a grain-heavy diet.  In our current iron-rich environment, this adaptation is a liability because it increases the risk of iron overload.  Carriers of the C282Y mutation are probably better off limiting red meat and liver, or at least monitoring ferritin status and giving blood appropriately. 


Jane said...

A low magnesium intake is also associated with fasting hyperinsulinemia:

...which could explain why so many people think insulin causes obesity. Obesity is associated with fasting hyperinsulinemia, and obese people have been found in several studies to have a low magnesium intake.

Gretchen said...

Stephan, Your blogposts would be more useful if you made your references more easily accessible by either listing at bottom of page or having the links open in a new window so one could continue to read while a reference is downloading.

It's frustrating to sit there while some link finally opens (often after DNS lookup errors) only to discover it's something one has already read.

Don! said...

Gretchen, what browser and version are you using? If your browser doesn't offer an "open in new tab" or "open in new window" option for any and all links, you may want to consider upgrading.

Re: iron - one also ought to keep in mind that inflammation from undiagnosed celiac can prevent absorption of iron, resulting in very low ferritin levels.

Jeff Consiglio said...

Glad to see you addressing the importance of proper micro-nutrient status in regards to maintaining normal insulin and glucose handling ability.

I would also add chromium (Glucose Tolerance Factor),vanadium and perhaps even B vitamins to that list. Heck even potassium plays a role.

I've long thought that the reason it "appears" that carbs are "pathogenic" to some folks has a lot more to due with poor micro-nutrient status, sleep deprivation, stress - and of course, as you alluded to in previous posts in this series over-nutrition of calories - than there being anything evil about carbs per-se.

Jeff Consiglio said...

Oh more final thought...I train a guy who is the medical director of the local blood bank, and he and I have discussed the topic of iron quite a bit. He says he sees LOTS of folks with high iron levels. Still within the "normal" range, but at the high end of normal, and likely not healthy.

Conversely, many if not most of the young females who donate blood are LOW in iron. So your advice to get iron/ferritin levels checked is spot-on.

I lean strongly toward the idea that excess heme-iron (Which seems to "bypass" the body's iron regulation system) is indeed a health menace within the context of our modern "parasite-free" society. I know Walter Willet of Harvard fame ascribes to this idea, to at least some degree.

And the better health of blood donors seems to lend support to that notion...but we must also consider that blood donors are screened, and unhealthy ones tend to be weeded out from being allowed to donate. So this is of course a potential confounding variable when looking at that data.

Anonymous said...

Great job with the selfless act of giving blood, Stephan. That is very humanitarian of you. You're a good dude. :)

I commend you.

As far as true morbid obesity, I honestly believe the Internet is too full of this insulin stuff and neglecting the MOST important things.

We need to be looking at genetics ( obesity is as genetic as height) , and delving into the complex neural circuitry which regulates our body weight in much mor detail.The insulin thing, for the most part, is not where it is at.

Gastric bypass actually appears to work by favorably affecting the hormones in our gut , and re wiring how it interacts with the neural circuitry. In other wordfs, it somehow interfers with our system in a somewhat beneficial way for weight. We could not get the same result simply from eating 1,000 calories a day. The actual trauma/re routing of digestive system the surgey interferes with things in some way and does something beneficial for weight loss.

It is far from perfect though. Almost all patients are STILL obese after gastric bypass. They bave BMI's of 30 to 32, on ONLY 1.000 calories a day or less.

Also, medicines like Prozac, Paxil act on the SAME neiural circuitry that controls our weight . ( that is why Mike Tyson gained so much, plus his GENETICS- obesity runs in his family strongly)

It is is no surprise at all that those medicines cause massive weioght gain.

That tells us something about how hellishly complex true morbid obesity is. I think the insulin thing is barking up the wrong tree for the most part.

In both humans and animals body wiehgt is INVOLUNTARY controlled, except for us choosing to stay at the lower end of our set points - about 12 pounds or so.

Another thing the Internet gurus
( not you) get wrong is that mice ARE like us in MANY ways, especially weight regulation.

Mice are very valid in studying human weight regulation and Dr Friedman has confirmed it. I won;t name names, but I have seen the gurus from other nations spew misinformation about this.

Take care,


John said...


I mentioned this on Melissa M's blog, and I'll re-mention it here. I am a heterozygous carrier for haemochromatosis, yet I also have genotype for reduced carotene-to-retinol conversion. To me this seems somewhat contradictory, but I suppose it could suggest something about my ancestors and dairy.

I've seen that iron restriction increases arterial plaque stability and decreases lipofuscin accumulation.

kyle said...

tea and coffee both inhibit iron absorption.

another reason to avoid eating processed food; grains are "fortified" with iron.

Gretchen said...

Don, Thanks. I'm not very gifted at using computers and I was just left-clicking. Forgot there were other buttons on the mouse . . . I use Firefox, which I always confuse with Netflix. Well, they both end in x and have an f in the middle.

Thanks again.

Anonymous said...

I wanted to add to the iron thing, as far as coronary artery disease is concerned:

A clueless, nameless Internet guru spreads misinformation that pre menopausal women are protected.

They're NOT. Women ages 35- 44, pre menopausal, are NOT protected.

In fact, in this age group coronary artery disease is on the rise to a VERY WORRISOME degree.

Younger people in general ( 20's) are protected, but your GENDER has NOTHING to do with it.

*More WOMEN die of coronary heart disease than men,

* Coronary artery disease is the TOP cause death among all women over age 25. Most people do not know this !

I had to add this about iron. The misinformation on the Internet by these uneducated pompous gurus, and their equally uneducated followers, really, really, really annoys me.

Aravind said...

Hello Stephan,

Have you seen this Lustig video....not Sugar The Bitter Truth :-)

It's not that long and I would be curious on your take. He references the work of Michael Schwartz at U of Washington and the differences between chronic vs acute effects of insulin.

Your thoughts?


Aravind said...

Ok, and here's the link this time -

Stephan Guyenet said...

Hi Aravind,

I haven't seen that particular video, but I have spoken with and e-mailed with Dr. Lustig about this issue (his claim that insulin has different actions in the brain over short and long time periods). He sent me the references that he bases this idea on, and I looked at them, but in my opinion they do not support the hypothesis.

The strongest support comes from Dr. Lustig's own clinical trials with a drug called octreotide. This drug suppresses insulin secretion, among many other things, and does cause modest fat loss in obese people. But I haven't seen any evidence that the fat loss results from its effects on insulin rather than its numerous other physiological effects. Here's a list of its effects I lifted from Wikipedia:

"Since octreotide resembles somatostatin in physiological activities, it can:

inhibit secretion of many hormones, such as gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, TSH, and vasoactive intestinal peptide,
reduce secretion of fluids by the intestine and pancreas,
reduce gastrointestinal motility and inhibit contraction of the gallbladder,
inhibit the action of certain hormones from the anterior pituitary,
cause vasoconstriction in the blood vessels, and
reduce portal vessel pressures in bleeding varices.

It has also been shown to produce analgesic effects, most probably acting as a partial agonist at the mu opioid receptor."

The references I posted previously on rodent models with chronically elevated insulin but no fat gain seem inconsistent with Dr. Lustig's idea as well. I'm going to post more evidence soon along those lines. Not to target Dr. Lustig specifically, but simply because I find it interesting.

Aravind said...

Thanks for the prompt response!

garymar said...

"...Firefox, which I always confuse with Netflix."

Ha ha! And I can never keep Slovakia and Slovenia straight either.

Jane said...

I am starting to doubt whether true nutritional iron deficiency actually exists outside the lab. We are told billions of people have it, but it seems to me more likely that the problem is an inability to utilise iron due to multiple micronutrient deficiencies, rather than a need for more iron.

'.. The prevalence of cribra orbitalia and porotic hyperostosis, both skeletal indicators of iron deficiency, increased greatly in early agriculturalists compared to hunter-gatherers, suggesting a high prevalence of iron deficiency..'

This 'iron deficiency' is being questioned. See 'The causes of porotic hyperostosis and cribra orbitalia: a reappraisal of the iron-deficiency-anaemia hypothesis'.

chief gabril said...

You eat your golden years the only channel to use dental floss applesauce. You can brush all day and still not reach the entire area of your teeth. Health is not the only danger.

Stair lift

Matthew D said...


Thank you for a wonderful post.

Might there be a book (of your doing) on the horizon that synthesizes the info on your blog?

Thanks again for pre-digesting all this good info for the layperson's brain :)

Swede said...


Is there a reason you only donate once per year? My local blood bank allows whole blood donations every 8 weeks, which works out to about 6 donations per year. I've reached three gallons over the past four years.

Bob Bejaan said...

So aside from possibly reduced insulin sensitivity, what are the problems of having too much iron? I eat beef 2 or 3 times a day, plenty of leafy greens, and often use cast iron pots and pans to cook with.

I have heard that semen contains lots of micronutrients and frequent sex/masturbation can deplete reserves of some nutrients. I wonder if semen contains much iron and if this could be a good way of getting rid of the excess (I refuse to give blood out of principle).

daveizmir said...

Dr Guyenet
This is on weight loss by food palatability as it may pertain to me. Four years ago I lost 40 pounds on a low-carb diet as a bachelor. My bach lives was typical, toss a full steak on the Foreman grill and eat it, the only greens were pre-prepared salads from the grocer. 1 ½ years ago I got married and quickly gained 15 stubborn pounds. My wife prepares pretty much the same low carb foods I was eating before, however they are marinated overnight, onions, ginger and a few vegetables added; typical Filipino fare sans the rice. There is more variation as chicken and pork are included and some stir fried type vegetables added no starches. I cannot say that my N=1 experience validates food reward theory, however, it makes me wonder why with around the same caloric intake in regards to fat and protein is consumed and carb intake may be marginally higher.
Just saying

Jane said...

'Excessive iron in specific tissue sites promotes infection and neoplasia. Moreover, elevated
iron is also a risk factor for cardiomyopathy, arthropathy, and an array of endocrine,
neurodegenerative and other chronic diseases. The metal, which cannot substantially be excreted, is hazardous in several ways. ..[it produces] hydroxyl radicals. The latter attack all classes of macromolecules. Hydroxyl radicals can depolymerize polysaccharides, inactivate enzymes, initiate lipid peroxidation and, not least, cause DNA strand breaks [1]. Furthermore, overabundant iron can serve as a readily available nutrient for invading neoplastic cells, as well as for bacterial, fungal and protozoan pathogens. Even microbial strains that are usually not dangerous can cause disease when present in iron-loaded tissues, fluids or cells
[2]. Vertebrate hosts maintain an iron-withholding defense system
[3] designed to prevent the accumulation of non-protein-bound (free) iron in sensitive sites and to sequester the metal in innocuous packages in ferritin. However, numerous behavioral factors and genetic modifiers can result in contravention of the iron-withholding defense system.'

- 'Iron loading in humans: a risk factor for enhanced morbidity and mortality', E D Weinberg 2007

Bob Bejaan said...

Thanks Jane. Guess I should cut back on the iron then.

Rich Wiltshire said...

Quercetin significantly increases my insulin sensitivity.

Kieran said...

Loving this series, thanks!

Wizard said...

"Gastric bypass actually appears to work by favorably affecting the hormones.... We could not get the same result simply from eating 1,000 calories a day."

Actually, a researcher in Newcastle, UK, has tested that by putting diabetic volunteers on 800 cal/day diets; within 2 months, their diabetes was completely reversed.