(Article referenced below was brought to may attention by Cristian Stremiz - thanks)
Insulin resistance blocks insulin-based transport of glucose into cells that are already overloaded with nutrients. The spilling-over of excess high energy electrons in the mitrochondrial electron transport chain onto oxygen produces superoxide. Superoxide is the trigger to block the import of still more glucose. Thus, insulin resistance is a cellular defense against sudden death by superoxide and other reactive oxygen species (ROS).
High Energy Electrons of Glucose Are Used to Make ATP
Cells are biochemical machines that turn on genes to produce enzymes to convert the high energy electrons on the carbon and hydrogen atoms of glucose into ATP energy and molecular components of the cell. The high energy electrons are systematically depleted of energy, protons are pumped to produce a proton gradient across the inner mitochondrial membrane, ATP is made using the proton gradient and the low energy electron are passed off to oxygen molecules to make water. That is a quick summary of cytoplasmic glycolysis, the tricarboxylic acid cycle (mitochondrial matrix) and the mitochondrial electron transport chain. The final step of transferring the depleted electrons to oxygen to make water is how oxygen is consumed in respiration. Note that if everything works well, the high energy electrons of glucose, which could suddenly release all of their energy directly interacting with oxygen and start a fire, just produce water. Another bad alternative would be for the high energy electrons to bind to molecular oxygen making superoxide.
Cells Adjust their Glucose Individually to Match ATP Use
If the supply of ATP from the mitochondrial electron transport chain of a cell gets low, this triggers the migration of vesicles with glucose transport proteins to the cytoplasmic membrane. Since the number of transport proteins determines the rate of import of glucose, then more transporters means an increase in glucose and more ATP. Type 2 diabetes and insulin resistance represents the others extreme, i.e. what happens when cells get too much glucose, max out their capacity to make ATP and high energy electrons build up in the electron transport chain.
High Blood Sugar Triggers Insulin Production to Import the Glucose into Cells
Superoxide Is a Reactive Oxygen Species (ROS)
Oxidation stress is the reason that plant antioxidants, vitamin C and N-acetyl-cysteine are recommended to avoid inflammation. One of the major sources of oxidation stress is the production of superoxide. Cells produce an enzymes, superoxide dismutase, to convert superoxide into hydrogen peroxide, and catalase to convert hydrogen peroxide into oxygen and water. Superoxide can also interact with nitric oxide to produce the nitric oxide radical. Unfortunately, superoxide can also produce hydroxyl radicals that can react with unsaturated lipids to produce lipid peroxides. Thus, superoxides can contribute to the production of many ROS, cause oxidation damage and trigger inflammation.
Many Different Processes that Produce Insulin Resistance all Produce Superoxide
The trigger for insulin resistance appears to be mitochondrial superoxide accumulation. A recent article used numerous mouse models of insulin resistance that mimic the typical human risk factors for insulin resistance and type 2 diabetes, e.g. excess nutrition, physical inactivity, pregnancy, polycystic ovarian syndrome, metabolic syndrome, inflammation, oxidative stress, anti-inflammatory corticosteroids, etc. and demonstrated that in each case mitochondrial superoxide accumulated. Moreover, mutant mice with lowered superoxide dismutase were more susceptible to insulin resistance and mutants producing an overabundance of superoxide dismutase were resistant to insulin resistance.
Insulin Resistance Is a Natural Defense Against Energy Excess
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.
reference
Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, Richardson AR, James DE.Insulin resistance is a cellular antioxidant defense mechanism.Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17787-92. Epub 2009 Sep 30.
39 comments:
fascinating stuff. If there were no insulin resistance (as response to excess energy input), would the immediate consquences be worse than the long term effects of hyperglycemia?
Caphuff,
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.
Does this knowledge imply anything that can be done to increase insulin sensitivity if you are insulin resistant?
Donn,
Please forgive my single-mindedness. When I start to write these articles, I have the logic all arrayed in my mind. Unfortunately I tend to forget that not everyone is in my head and so I leave out the things that I use all of the time.
The consequence of an inflammatory diet tends to be superoxide production via one or another form of inflammation. Thus, the Anti-Inflammatory Diet and Lifestyle that I have outlined, systematically addresses most of the inputs that will lead to superoxide accumulation and insulin resistance. This also explains why fasting is anti-inflammatory.
Thanks for your question.
doc, thanks for the response. Of course (d'oh!) you spelled it out pretty clearly in the first paragraph of your post: "insulin resistance is a cellular defense against sudden death by superoxide and other reactive oxygen species."
That's what I get for skimming and then blurting out a question that has already been answered.
It is striking though that insulin resistance in the context you describe serves a beneficial purpose. Hyperglycemia is a pretty good deal as compared to instant organ failure!
Interesting, as I have managed to come up with the exact opposite conclusion in my own personal research. That is, calorie restriction, carbohydrate restriction, and a low metabolism (low body temperature) intensify insulin resistance long-term while the opposite yields lessened insulin resistance (which represents the negative feedback loops that cause one to return to a weight set point over time - i.e. - overfeeding leads to increased metabolism and decreased hunger, calorie restriction yields lowered metabolism and incresaed hunger).
Art, I would have to second Matt's comment. I have seen many studies that show excess antioxidant supplementation hurts the metabolism. I grant you that superoxide radicals could be dangerous enough that we have to deal with them no matter what the metabolic cost.
I do have this study though that seems to suggest the opposite:
Reduction in Mn-superoxide dismutase (SOD2) corrects insulin resistance due to high fat feeding in oxidative tissues of mice
Mary Elizabeth Conniff1, Freyja D James1, Ting-Ting Huang2 and David H Wasserman1
1 Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
2 Neurology and Neurological Sciences, Stanford University, Palo Alto, CA
ABSTRACT
SOD2 is a mitochondrial antioxidant enzyme responsible for converting superoxide radical to H2O2. Certain levels of H2O2 are essential while excessive levels are harmful to normal metabolic function. We hypothesized that reducing the formation of H2O2 by decreasing SOD2 expression by 50% would improve metabolic function. SOD2+/–mice and wild type (WT) littermates (n=14/13) were chow or high fat fed (HF) for 3 months. Catheters were placed in the jugular vein and carotid artery. 5 days later a hyperinsulinemic glucose clamp was performed. 2-deoxyglucose was given for analysis of tissue glucose uptake. Body weight, 5 h fasted blood glucose or insulin levels were not different between SOD2+/– and WT on either diet. Glucose infusion rate (mg/kg/min) to maintain euglycemia was similar in SOD2+/– and WT on chow (49±4 vs 49±6) and HF (32±3 vs 35±4). The rates of glucose uptake (Rg; µmol/100gtissue/min) in vastus lateralis muscle were not different between SOD2+/–and WT on either diet. Heart Rg was significantly higher in SOD2+/–compared to WT (174±9 vs 130±13) but there was no difference in diaphragm Rg (46±19 vs 46±8) on chow. WT mice on HF had impaired insulin stimulated glucose uptake in heart (71±9) and diaphragm (22 ± 3). Heart Rg (167±26) and diaphragm Rg (157±12) were not impaired by HF in SOD2+/–. A 50% reduction in SOD2 activity corrects the HF induced insulin resistance that occurs in highly oxidative tissues, such as diaphragm and heart. Supported by DK 54902 and DK 59
Hi Art,
I thought you might enjoy this article on the relationship between n-3 consumption and superoxide:
http://www.circ.ahajournals.org/cgi/content/full/91/4/1123
Stephan,
That article is certainly entertaining. Who would guess that fish oil would be a good treatment for inflammatory cardiovascular problems? Maybe an anti-inflammatory diet could avoid the whole issue.
Thanks.
Aaron,
We seem to be comparing lots of different organs under different conditions.
The meeting abstract that you provided seems to conflict with a recent article from the senior author of the same group. They showed that decreasing hydrogen peroxide by using a transgenic mouse with extra mitochondrial catalase, reduced insulin resistance. This would be the same thing as reducing superoxide build up by removing the product of superoxide dismutase. The abstract you cited has not been published, nor was it referenced in the more recent paper from the same lab.
The article that I referenced showed that less superoxide dismutase increased insulin resistance on a normal diet and increased superoxide dismutase provided resistance to insulin resistance on a high fat diet.
Anti-oxidant treatments to reverse insulin resistance would be difficult. The mitochondrial superoxide and hydrogen peroxide would simply deplete the cellular antioxidants even if the glutathione pool was expanded. The cellular ROS could always be produced at a higher level than the bodywide level of antioxidants. Most phytochemical used as antioxidants also have many more side effects.
The major controversy is over whether superoxide or H2O2 is the trigger for insulin resistance. There seems to be general agreement that excess mitochondrial superoxide is the initial source of the signal.
Thanks for the discussion.
Matt,
We seem to be comparing physiological explanations with molecular models. I also seem to have a different view of insulin resistance. Hunger is yet another mechanism.
The article that I cited merely explains why glucose transporters are not mobilized to the cell surface in response to insulin, when numerous conditions lead to mitochondrial superoxide accumulation. This paper seems consistent with the dietary and medical conditions that lead to insulin resistance. It seems that you disagree with the conditions that lead to insulin resistance, rather than the superoxide mechanism.
Art, this is another study that might fit in nicely with what Stephan had posted:
http://intl-hyper.ahajournals.org/cgi/content/full/37/2/529
Better Superoxide scavenging seems to leave NO (nitric oxide) to do more "important things". Seems like fish oil would spare NO too.
Another interesting corollary is looking at the naked mole rat:
http://biomed.gerontologyjournals.org/cgi/content/full/61/10/1009
<------ Which would lead to less superoxide and:
http://www.worldhealth.net/news/naked_mole-rat_unfazed_by_oxidative_stre/
The naked mole rat is able to maintain adequate NO production throughout its life.
However, I'm interested in the little tidbit where it says the naked mole rat had less reduced glutathione and much lower activity of the ubiquitous antioxidant enzyme, cellular glutathione peroxidase.
We know that a lower carb diet ups glutathione production -- Maybe we can spare our body of extra superoxide damage by partially relying on the oxidation of glucose for energy (anaerobic carb metabolism). Maybe that is the secret to the health of the Japanese.
Definitely makes me worry about excessive aerobic metabolism (ie, super low carb).
Art,
Very illuminating!!! Thank you for this post!! Unfortunately right before the best feasting of the year... where I shall be indulging and pushing my superoxides... *sigh* with pie and mashed spuds *YUMM*.
Aaron, Recall that NMR (naked mole rats) don't make insulin. At all. Peter described. Surprisingly, no insulin, no SOD or superoxides... Not surprisingly, exceptional longevity.
Stephan, I couldn't help noticing in Table 2 that the plasma fatty acid profile was 50% higher in 18:2 LA (n-6) in the non-fish oil group compared to high dose fish oil. Their consumption of dietary n-6 was the same (e.g. cr*pload of n-6 not unlike the S.A.D.).
I am always impressed what EPA and DHA can do! In an rat heart failure model, all doses of fish oil EPA+DHA 0.7, 2.3, or 7% of energy, the authors concluded, 'Dietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma ADIPONECTIN, suppressed inflammation, and PREVENTED CARDIAC REMODELLING and dysfunction under pressure overload conditions.'
Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction.
Duda MK, et al. Cardiovasc Res. 2009 Feb 1;81(2):319-27
(if I had CHF, I'd also be stuffing my face with substantial doses of CoQ10, Carnitine, vit C, NAC, etc -- ALL btw found in pastured hearts and organ meats; and other means to control insulin resistance)
-G
Hi G,
I noticed that too. I think the non-fish oil group actually ate less LA though, unless I'm remembering wrong.
Hey Stephan,
On Table 2, they had the dietary breakdown by % fatty acids. Honestly I don't know what the authors truly substituted, but they did have the foresight to 'match' the vit E content of both diets thus that would be less of a confounding factor. It appears to me that they substituted the oleic acid fraction with EPA DHA in the fish oil group. The n-6 is 15% vs. 12% which as you are aware may be a HUGE difference. Monkeys are interesting. I don't know if these are 'old world' vs. 'new world'. Are they strict herbivores (sounds like it)? Also the non-fish oil group are 'missing' 20% of the dietary fatty acids (when you add up... only ~80% total)? Are these from short- and med-chain fatty acids? I don't know what the authors did. All I know is that that the fish oil group rec'd 41% fat and 23% was pure EPA DHA for 12 months. WO-WOW. It's an !!amazing study you came across :) I wonder if they had done mental tests or water maze studies (like in rats) this fish oil group would've have superior neurobio outcomes as well?? So...Even herbivores might benefit from ultra high dose FISH OIL for cardioprotection given a high carb, pro-inflammatory diet? The LDL decreased and probably increased in size/buoyancy. The HDLs went down but that doesn't mean anything -- the buoyancy and HDL2b fraction increased since a corollary TG reduction occurred. Very COOL indeed. In the LAD, plaque regression occurred (albeit non-statistically significant, but I bet the coronary calcs reduced and I bet the echolucent parts reduced, the unstable parts of the plaque).
Dr BG, how can you conclude that low insulin is the sole determinant of the mole rats longevity? They live in a low oxygen environment -- they have highly saturated membranes, etc.
I feel that insulin is still poorly understood for its exact role in human longevity -- I know you have to privy to the fact that they are many compounds in the body that potentiate insulin-like effects in the body --Glucagon, cortisol, adrenalin, growth hormone,thyroid, and potassium all do this. Even if absolute insulin levels are low, all of these compounds can multiple insulins' effect on the body. Just as you can have high insulin -- and low insulin-like effects.
I know that aerobic metabolism throws out a lot of oxygen radicals-- if this theoretically leads to a decrease in available SOD in humans -- we may need to rethink ultra high fat diets. That is all I am saying.
Hey Aaron,
We can't... but we can only surmise given the weight of the evidence.
Have you read Cynthia Kenyon's worm research?
http://high-fat-nutrition.blogspot.com/search/label/Cynthia%20Kenyon%20link
Anyhow, being extremely vain (not unlike other female scientists *hee*) I've cut out carbs to stay lean and to prevent AGEs damages like skin wrinkles. But not on Thanksgiving...
-G
I am very interested in buying latest Dr Eades´ book you recommend here. I am so interested in his support of saturated fats. I have become probably disagreed with Dr Barry Sears about avoiding as much as possible all saturated fats.
Lol. Dr. B G, in Thanksgiving you can take a starch blocker supplement before meals if you take glycemic carbs. About it, there is in the market a new supplement compound that blocks dietary sucrose, called Phase 3.
@Adolpho: If you block absorption of a macronutrient, you tend to find that it makes a re-appearence at the end of your GI tract.
In the case of fat-blockers, you get diarrhoea & "soily oilies" and in the case of carb-blockers, you get diarrhoea & severe flatulence, just what you need when all of your nearest & dearest are with you!
Does superoxide dismustase (SOD) break down superoxide? I wonder if that means that SOD ingestion (via a product like glisodin), which increases cellular levels of SOD, would be bad for those who are insulin resistant? Interestingly, glisodin is also supposed to confer some UV protection.
Stephenb,
I don't think that eating superoxide dismutase or any other enzyme will have any effect on cellular enzyme levels. The eaten enzymes will always stay in the gut and have no impact on other areas. Enzymes don't move around in your body. In fact, since enzymes are large proteins, they don't even move around easily within cells and are usually made where they are used within cells. The mRNAs are moved from the nucleus to the place where the proteins will be made on ribosomes and used.
Note that gliadin is used as a carrier for the enzyme. Gliadin is the major trigger for celiac and most people are probably sensitive to it.
Thanks for the comments.
Cristian,
You advocate polytheism? The pantheon or another Mt. Rushmore, perhaps.
Peter interpreted a great paper. But the evidence just showed that the omega-3 fats increased the circulating endotoxins, it didn't actually show that the omega-3s + ethanol increased leaky gut. Another interpretation is that ethanol causes leaky gut and the bacteria (particulate endotoxin) migrate to the liver. In the liver ethanol increases inflammation with the bacteria and this inflammation produces lots of lipid peroxides enhanced by easily oxidized omega-3s. The combined liver damage causes a persistent lysis of bacteria in the liver and the rise in circulating endotoxin. There is a difference, since this scenerio would not suggest that omega-3s have a negative impact on gut permeability.
This does bring up the question of whether omega-3 supplements should be seen as a short term correction to offset another source of inflammation, or whether they are good bodywide all of the time. I am leaning toward the first and assuming that humans evolved with an adaptation for high oxygen consumption and limited glucose availability. Superoxide was not a problem unless it produced seasonal insulin resistance and prewinter fat deposition. Under these conditions, oxidation stress would be no big deal and vitC would be available when it was needed (in times of fruit excess.)
It would be interesting to look at the impact of vitD on endotoxin levels, since the antimicrobial peptides of innate immunity are under vitD receptor control.
Thanks for your comments and measured adulation.
What about using SOD delivered in a liposomal cream? Would that be an effective way to supplement with it? Or is there no effective way of increasing SOD levels via supplementation?
Switters,
I don't have much hope for supplementing SOD. I think that it makes more sense to avoid the ROS in the first place. It is to hard to get the SOD to the superoxide.
Thanks for your comments.
Please see the following papers for some explanations for the variable effect of Sod2 on mitochondrial H2O2 production:
http://dx.doi.org/10.1016/S0891-5849(02)00861-4
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443724/
http://dx.doi.org/10.1016/j.freeradbiomed.2007.02.015
These papers may help explain why Sod2+/- and overexpressor animals show such confounding results in various studies. The new paradigm seems to be that low [ROS]=physiological signaling vs high [ROS]=pathology. We've come a long ways from the days where the only good ROS is a dead ROS.
Brugg,
Thanks for the references. The experimental results seem far more complicated than the control mechanisms. As you indicate, it is probably a matter of starting with the wrong preconceptions.
I am always ready to read about insulin thanks a lot for this nice informative post about insulin. I like it so much.
Smith ALan
Hello Dude,
Many people with insulin resistance and high blood glucose have other conditions that increase the risk of developing type 2 diabetes and damage to the heart and blood vessels, also called cardiovascular disease. These conditions include having excess weight around the waist, high blood pressure, and abnormal levels of cholesterol and triglycerides in the blood. Thanks a lot......
Regulatory T Cells
Dr.Art Ayers,
I am writing in a desperate need of your opinion, as one of my firends just going to make a tough decision.And before she act as her doctos said I would really like to know yr opinion or if we are lucky enough, your advice.
her state:
- inzulin resistency (affirmed yesterday by directed blood sugar testing process)
- polycystic ovarian syndrome (affirmed by Ultra Sound )
plus she is not having period at all
she is saying: her testosteron level is high, feminine hormon levels low.
Am sorry, I am not a specialist at all, and not native english.
Her doctors says nothing abut diet only focusing on medics:
plan:
-Rigesosft medicine for her period problem
-Diané medicine on her 4th day of Period , take it for 2 months
-Only after these, they wanna take care of inzulin resistency, by taking Metformin
Not a word about her diet at all.
I am writing in a hope you have any idea or advise, or any wise comment of yours, so seh could understand her situation better and the possible ways out.
Am already made her aware of your great blog, and major concerns, as well the anti-flamatory diet.
Please ket me know anything, shall she do the process advised by her docs, and/or any wise steps she shall take.
Thank you in advance,
and bless ya for the great job or yours.
Adam
Adam,
I think that PCOS is an inflammatory disease primarily caused by diet. Changes in diet and patience should be all that is necessary to regain health.
The anti-inflammatory diet that I recommend at the top of my blog should provide all of the answers and since gut flora are transmitted among people, all of your friend's contacts should also switch to the diet.
Main Points:
1. Most people showing extreme symptoms of chronic inflammation, such as your friend, also have low serum vitamin D. Get it tested, supplement with high doses of vitamin D3, and retest.
2. Your friend is probably obese from eating a high carbohydrate/low saturated fat diet. She should be eating a high fat/no carb diet.
3. Your friend is also eating too much vegetable oil (omega-6) and not enough fish oil (omega-3). Eliminate processed foods and vegetable oils. Eat only butter, coconut oil or olive oil. Supplement with fish oil.
4. Eat fish, meat, eggs, dairy as your primary source of calories. Avoid carbohydrates.
5. Grains could be a major contributor to inflammation, so eliminate them. If you have to have a small amount of carbohydrates, eat a little rice or potato. (No sugar, bread, pasta -- check everything to make sure that it doesn't contain high fructose corn syrup)
6. Plenty of low starch vegetables. Your friend also has a messed up gut flora, so fresh, uncooked local vegetables are the major source for her to eat the needed bacteria.
This is all that is needed to reduce weight, correct vitamin D levels, shift to a high fat/low carbohydrate diet and eliminate dietary inflammation. This should start to improve her hormone balance quickly, especially if she starts to lose weight. The saturated fats are very important.
You can also look up my articles on using the Drs Eades Cure Diet to help in the shift to the high fat diet.
Appretiate your very quick and detailed answer. I am on my way to tell all of it to her.
I am sure patience is needed, am having arthritis in both my knees, and soften up cartilage. Am following anti-flamatory diet, so let the time work the other half :D
Thanks again,
We are following yr articles. (ohh recently found yr other older blog, started on water, found it really great! )
Hello,
This is a very good site to know about Insulin resistance being as much as six times as sensitive to the hormone as those identified as most resistant. The content of your site is very informative. Thanks...
Dr. ayers what happens when we go high carb (sourdough wheat) high fat(lots of butter)?
It’s really a great and helpful piece of data. I’m glad which you shared this helpful info with us. Please maintain us up to go out with like this. Thanks for sharing.
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That is why a proper treatment is always must for Type 2 Diabetes.We should try to have some changes in our life style to prevent diabetes.
I love the way you write and share your niche! Very interesting and different! Keep it coming! Raul
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