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How Inflammation Makes You Fat and Diabetic (And Vice Versa)


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In the previous article in this series, I argued that diabesity is an autoimmune, inflammatory disorder. In this article, we’re going to review the evidence linking inflammation to obesity and type 2 diabetes (T2DM) and learn why inflammation may be the single-most important mechanism driving the diabesity epidemic.

The inflammation-diabesity connection is a hot topic in the scientific literature. A Pubmed search for “inflammation diabetes obesity” turns up more than 1,800 articles. The association between these conditions has been known for decades. In fact, more than 100 years ago high doses of salycilates – a class of anti-inflammatory compounds which includes aspirin – were used to treat T2DM. In 1876, a physician named Ebstein found that sodium salycilate could make the symptoms of diabetes completely disappear. (In case you’re wondering why doctors don’t use this therapy today, it fell out of favor due to the serious side effects caused by high doses of salicylates.)

Though the association between inflammation and diabesity is well-known, questions remain. Does diabesity cause inflammation, or does inflammation cause diabesity? How and why does the body initiate an inflammatory response to diabesity? Does obesity itself cause inflammation, or is inflammation caused by something secondary to obesity (like high blood sugar or triglycerides)?

I’m going to try to answer those questions in this article. Let’s dive in.

How Inflammation Causes Diabesity

There are several lines of evidence that inflammation directly causes obesity and diabetes.

First, inflammation has been shown to precede the development of diabesity. Elevated levels of inflammatory cytokines predict future weight gain, and infusion of inflammatory cytokines into healthy, normal weight mice causes insulin resistance.

The idea that inflammation precedes diabesity is supported by the observation that humans with other chronic inflammatory conditions are at higher risk of developing T2DM.

For example, about one-third of chronic Hepatitis C patients develop T2DM, and those with rheumatoid arthritis are also at higher risk.

Second, inflammation begins in the fat cells themselves. Fat cells are the first to be affected by the development of obesity. As fat mass expands, inflammation increases. One mechanism for this may be dysfunction of the mitochondria (the “power plant” of our cells) caused by the additional stress obesity places on cellular function. Another mechanism may be oxidative stress. As more glucose is delivered to the fat cells, they produce an excess of reactive oxygen species (ROS) which in turn starts an inflammatory cascade within the cell.

Third, inflammation of the fat tissue causes insulin resistance, which is the primary feature of T2DM. TNF-α, a cytokine (small protein) released during the inflammatory response, has been repeatedly shown to cause insulin resistance. Several other proteins involved with inflammation, such as MCP-1 and C-Reactive protein, have also been shown to cause insulin resistance.

Fourth, inflammation of the brain (specifically the hypothalamus) causes leptin resistance, which often precedes and accompanies insulin resistance and T2DM. Leptin is a hormone that regulates appetite and metabolism. It does this through its effect on the hypothalamus. When the hypothalamus becomes resistant to leptin, glucose and fat metabolism are impaired and weight gain and insulin resistance result.

Finally, inflammation of the gut causes leptin and insulin resistance. This may occur via an increase in lipopolysaccharide (LPS), an endotoxin produced by Gram-negative bacteria in the gut. LPS has been shown to cause inflammation, insulin resistance in the liver and weight gain.

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How Diabesity Causes Inflammation

Up until relatively recently, fat was considered an inert tissue with no biological activity. The idea was that it was just, well, there. It didn’t do much other than store excess energy.

We now know, however, that fat tissue is a metabolically active endocrine organ that secretes hormones and inflammatory cytokines such as IL-6 and TNF-α. The metabolic activity of fat is the key to understanding its role in diabesity.

Why would obesity cause inflammation? There are two basic theories. The first is that obesity-induced inflammation is actually a protective mechanism that prevents the body from losing mobility or fitness. Fat storage is an anabolic process, which means it builds up the organs and tissues. Inflammation, on the other hand, is a catabolic process. Catabolism breaks down organs and tissues. It’s possible that the activation of catabolism via inflammation is the body’s attempt to keep weight within acceptable bounds. Evidence that experimentally induced local inflammation in fat tissue improves insulin resistance and causes weight loss supports this theory.

The second theory is that obesity-induced inflammation is simply a malfunction that was never selected against in human evolution. Obesity and its related disorders have been extremely rare throughout human history, and have only become common in the past 40 years. The surplus of modern, processed foods that accompanies diabesity is also a relatively new phenomenon. It’s possible that the stresses of obesity are similar enough to the stresses of an infection that the body reacts to obesity in the same way it would to an infection: via inflammation. Supporting this theory is evidence that the same intracellular, inflammatory stress pathways are activated in both obesity and infection.

Whichever theory is correct (and they probably both are, to some extent), it’s clear that diabesity causes inflammation. Insulin and leptin resistance impair glucose metabolism. When fat cells become insensitive to insulin, they can’t store any more glucose and hyperglycemia results. Excess sugar in the blood causes glycation, a process where a sugar molecule binds to a protein or a fat, and leads to the formation of advanced glycation endproducts (AGEs). AGEs are inflammatory and are associated with T2DM.

Obesity also contributes to inflammation by up-regulating certain genes involved with the inflammatory response. These genes control the expression of white blood cells called macrophages that play a key role in inflammation. As the concentration of macrophages in the fat tissue increases, the release of inflammatory byproducts such as TNF-α, IL-6 and MCP-1 also increases. This means that the more fat tissue you have, the more inflammation it will produce.

Putting It All Together

Collectively, these findings are consistent with the theory I presented in the last article that obesity is an autoimmune, inflammatory disorder.

As we’ve seen, inflammation is both the cause and the result of diabesity. Once obesity and/or insulin resistance have been established, each can further stimulate the production of inflammatory cytokines, forming a vicious cycle of inflammation and diabesity.

It follows, then, that the key to preventing and treating diabesity is reducing inflammation. Unfortunately, few clinicians treating diabesity today understand this. Focusing exclusively on regulating blood sugar and fat hormones without addressing other potential causes of inflammation is bound to produce inferior results.

What are these “other causes” of inflammation? In a phrase: the modern lifestyle. Specifically, dietary triggers (fructose, wheat and industrial seed oils), stress, poor sleep, gut dysbiosis and environmental toxins all cause inflammation on their own. When combined together, they are an explosive mix.

We’ll talk about each of those factors in future articles. For now, the takeaway is that inflammation is probably the single most important mechanism driving the diabesity epidemic. Keep this in mind as we discuss the lifestyle factors that contribute to diabesity, because almost all of them relate back to inflammation in some way.

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Join the conversation

  1. @ Marianne

    My c-reactive protein came down from 35 (yes, 35!) to 2.5 recently just by starting on Metformin. Has your doc checked your fasting insulin levels? High levels insulin is inflammatory. It could also explain why your weight loss is so difficult. Turmeric and Krill oil and aspirin are anti-imflammatory. Hope this helps!

  2. Marianne: it really depends on what the source of the inflammation is. That’s the missing piece of information here. It’s possible there is some immune dysregulation or chronic infection causing that inflammation that hasn’t been identified yet.

  3. I have found your article very interesting as I have been obese for 20 years, no amount of dieting or exercise has helped me loose weight. For the last 2 years the glands on my neck have been swollen. I have been treated for chronic fatigue by my naturopath. I had high metal readings of mercury and copper which she has treated with certain supplements, I now do not have chronic fatigue in fact I have boundless energy. I eat no breads, cereals, sugar, starchy foods, have been doing this for one and half years with no weight loss. I eat a diet high in vegetables, with some meat, mostly organic chicken and eggs with some red meat occasionally.

    I started taking Olive leaf extract 6 months ago I lost 10 kg on this, then I did Dr Simeons HCG diet and I lost a further 11 kgs but now my weight is static. Still have at least 30 kg to loose.

    After reading your article I have bought fish oil and will see if this brings down my inflammation, because the glands on my neck are still very swollen and at times painful.

    I have been tested for diabetes but my sugar levels are good, as is my cholesterol, in fact all the blood tests ran by my doctor were good, except that it showed that I had high inflammation in my body.

    Do you have any other suggestions of how I can reduce inflammation?

    • Marianne, serrapeptase which Enerex brought to North America over 30 years ago is a very powerful natural anti-inflammatory with the added benefit of digesting any non living tissue. We only distribute it to health care professionals but you can find it online by looking for Enerex serrapeptase. In addition Vanderbilt University has completed studies showing the power of curcumin on inflammation. Isohumulones which are a molecule of hops and perluxan which is also from hops are great at inflammation and blood sugar help. Isohumulones are in a product called Diabetes Defense made by pharma Defense and perluxan can be found in a product called IsoRelief made by SMS medical (I think)

  4. I mentioned this researsch because this kind of research is growing atleast in Europe. We have to know how to deal with it. For example this type single high fat meal worsens the symptoms of asthma. I think these results fit to the picture but I think we have to be more clever than those low fat high fibre proponents. We do have advantage because we know that for example dairy fat is very good in healing or atleast relieving inflammatory diseases like asthma.
    I think this all is understandable if we truly understand how innate immunity works and how its responce can be modified towards more tolerant phenotype. If you have no idea what I mean I think there could be much more interesting reading. Problem is that I don’t think that answer can be found in any written book so far. It hasn’t been done yet.

    • westie,

      I understand. Thanks for the interesting dialogue. As you probably gather from the blog, I have a lot of respect for scientific research. But it’s important to remember that science isn’t limited to RCTs. Anthropological study, evolutionary biology, observation and plain old common sense are also important. When there’s a conflict in the data, I think it’s wise to look back on the hundreds of thousands of years of human history and see what our healthy ancestors (who were free of modern, chronic disease) ate. Modern research can give us some answers, but there’s too much we still don’t understand. That’s especially true when it comes to the immune system, which is so vastly complex we’re only beginning to have the faintest idea of how it works.

    • I’ll comment more on this later, when I have a chance to read more carefully, but I’m wary of drawing any conclusions from studying the effects of foods on individual markers that we don’t fully understand. This comment in the text raises a huge red flag:

      In this context, it is important to state that our recent data demonstrate that the consumption of orange juice with an HFHC meal prevents not only oxidative stress and inflammation but also the increase in LPS concentrations and the increase in the expression of TLR-4 and SOCS3 observed after ingestion of the HFHC meal alone (20).

      And again in the conclusion:

      In contrast, orange juice intake does not induce oxidative stress, inflammation, SOCS3, TLR-4, or an increase in plasma LPS concentrations.

      So, to prevent diabetes we should be eating a low-saturated fat diet and drinking plenty of orange juice. Wait a second, I think that’s already been tried – and it failed miserably. We know that excess fructose intake is one of the primary contributing factors to an increase in obesity, T2DM, metabolic syndrome and NAFLD. We also know that traditional peoples who eat high amounts of saturated fat (without dietary toxins like wheat, liquid fructose and omega-6 PUFA) don’t develop T2DM or CVD. The Inuit got up to 80% of calories from fat – a lot of it saturated – and were free from chronic diseases like T2DM & CVD.

      Also, studies have shown that SAFA does not decrease insulin sensitivity.

      When all of this is taken together, I am very skeptical of interpreting the data from this study as evidence that SAFA contributes to or worsens T2DM (in the absence of high carbohydrate intake and/or insulin resistance).

    • westie,

      I read through the study and I’m still not impressed – largely for the reasons I mentioned above. It highlights the problem with drawing conclusions from single-meal studies, which are useful in identifying avenues for exploration but don’t tell us anything about the long-term effects of that particular macro/micronutrient composition.

      See this article on Hyperlipid for more on why this type of thinking isn’t sound.

  5. I have to ask because I don’t understand what you just wrote. If serum FFA (which are mainly SAFA) increase the macrophage related inflammation through TLR-4 why it is opposite with dietary SAFA? Saturated FFA directly bond and activate TLRs and/or they increase the responce of macrophages to acivation made by LPS.
    In either way SAFA seems to increase inflammation.

    • Lipotoxicity is the result of metabolic derangements caused by high-carb diets and food toxicities from grains, vegetable oils, and fructose. In a healthy person, SAFA are readily burned in the mitochondria for calories with no toxic byproducts. Also, SAFA can be elongated and desaturated in the liver to transform 16-carbon SaFAs created from carbs into SaFA or MUFA that are relatively deficient. So lipotoxicity isn’t evidence for the dietary toxicity of SAFA, and high SAFA diets – by removing toxins – are essential to healing the metabolism and eliminating lipotoxicity.

  6. Westie,

    I agree that the size of the adipocytes may be more significant than fat mass, but there’s plenty of evidence that expanding fat mass alone can cause lipotoxicity.  Plasma free fatty acid (FFA) levels are increased in obese patients.  FFAs activate macrophage-like cells via the LPS receptor Toll-like receptor (TLR)4.  Also, FFAs can undergo phosphorlyation to ceramide, which has been shown to promote inflammation and originate secondary metabolites with the same effect.

    Both adipocyte hypertrophy and hyperplasia activate inflammatory pathways and stimulate FFA release, which in turn stimulates macrophages through TLR4, which in turn causes increased expression of TNF-a, MCP-1 and other pro-inflammatory cytokines.

    I agree that n-6 PUFA is pro-inflammatory, whereas SAFA and MUFA are not.  I’ve argued this elsewhere on the blog at length.

  7. Thanks for informative post, Chris. You took quite a big bite with this one. I totally agree with importance of the inflammation in the diabesity. Couple of things I’d like to comment.
    You wrote that expanding of the fat cells leads to the inflammation of the adipose tissue. I have to disagree with that. It seems that the size of the fat cells is a driving force for adipose tissue inflammation not the fat mass. PPARg agonists are meds that are used against the malfunction of the fat storage seen in diabesity or metabolic syndrome.
    Another thing is that inflammation is something that is made by our own cells. It is highly dependent on the state of our immune cells. The responce to the inflammatory stimuli like LPS can differ markedly in different situations. High omega-6 for example blunts the immune responce and that leads to higher mortality for infections and cancer. Dietary saturated fatty acids have opposite effect on immune system.

  8. @Chris –  My omega-6 consumption is very low for past couple years, I eat grass-fed beef, take fermented cod liver oil, drink raw milk from pastured cows.  Only oils at home are olive & coconut. 

    I do have some tomato and potato, but I can eliminate them.  Also, legumes I eat rarely.  Wheat I do have small amounts of daily.  I’ll eliminate them, too.

    However I have a lot of weight to lose, but could that cause my C-reactive protein to be 20+ instead of 2?  Oh, also my fasting insulin is always high and insulin is inflammatory, yes?  Recently started on Metformin.  Thanks!

    • Laurel: may be worth a try to eliminate all grains, nightshades and legumes for a 3-4 week trial. I don’t think raw dairy is a problem for most people, but some do have issues with caesin so I’d eliminate that too. This isn’t forever – you’re just trying to figure out if there are any dietary triggers. If the inflammation improves, you’ll know something in your diet was contributing. Add one food back in at a time, every 3 days. Watch for symptoms.

      • Do you have experience with milk butyrophilin sensitivity?
        You mention some people have a problem with casein. I just found out that I’m fine with that but I react to milk butyrophilin (according to Cyrex lab test) so I have been told to avoid all dairy even ghee. It’s such a shame as I do eat fermented raw dairy and lots of ghee and butter as part of my healthy fat and probiotic intake.
        I’m hoping that after some gut healing I can reintroduce it in the future. It seems to be a rare sensitivity as I can’t find much information on it online.

  9. Laurel,

    The most important thing is to identify the cause of the inflammation.  Have you done that yet?  Have you removed wheat, fructose (except small amounts of fruit) and industrial seed oils?  Have you tried going without legumes, nightshades and other grains?  Have you balanced your omega-6:omega-3 ratio?

    In terms of supplements, I like Meriva-SP.  A detox program using an anti-inflammatory diet and nutritional products would also be helpful.

  10. @Taylor –  Your theory that IR is due to over consumption of calories doesn’t explain all of the skinny T2 diabetics out there.  Like one of my grandmothers.  She was always tiny and yet lost her eyesight and legs to a raging case of T2.

    Regarding inflammation – mine is sky high and I’m always looking for supplements to help bring it down.  I’m taking a baby aspirin every day along with krill oil and turmeric.  Anything else that would help?

  11. I don’t think excess SFA or MUFA can cause insulin resistance, except in the presence of excess glucose.  If one limits glucose calories to 400-600 per day, they can eat all the SFA and MUFA they want.  Insulin and leptin resistance is cause, on the other hand, by excessive intake of highly refined carbs and by excess PUFA intake (primarily n-6).  So I don’t agree that macronutrient composition doesn’t matter – it’s the crucial element.

  12. Great post.  Has some ideas in common with some other blog posts I’ve come across recently on Carb-Sane Asylum and Adipo Insights and maybe a few others that have overturned my previous notions on insulin resistance.  The idea that was overturned is that obesity results from insulin resistance of muscle cells.  The idea was that muscle cells become insulin resistant which forces blood glucose to be taken up by fat cells and then converted to fat.  Now this blog post reinforces the new interpretation that it is only after the fat cells are overfilled and hence insulin-resistant (not accepting any more glucose) that blood sugar can no longer be adequately controlled and diabetes develops.  In other words the fat cells protect against diabetes up until they can’t accept enough glucose anymore.    What the heck is my point?
    Well considering all this, it seems to me that insulin resistance is in large part due to over-consumption of calories.  Even of fat calories.  Excess fat is taken up by fat cells which can fill them up and lead to the point where they won’t accept any more glucose.   So I really believe that overeating is one of the main contributors to insulin resistance and that is regardless of the macro-nutrient composition of the diet and regardless of the quality of the diet.   I’m just wondering what you think Chris.

  13. Yippee skippy!! Finally seems as if, after searching everywhere on the web, there might, just might be a ray of hope and answers to “questions no one wants to hear” — never mind find a  solution to — like: why do my joints hurt? why can’t I eat wheat without getting sick? why do I have little patches of eczema? whence the peripheral neuropathy? and are all these ailments related?” Most are greeted with the equaivalent of <SHRUG>.

    Thanks, Chris.

  14. We’ll be talking about how to prevent and, when possible, reverse insulin resistance at length in this series.  Stay tuned.

    As for exercise, we’ll also discuss that.  But the short answer is that high-intensity strength training is far more effective for improving insulin sensitivity than steady state cardio, because it more fully depletes glycogen stores in the liver and muscle.

    The other keys (which should reduce inflammation and pain) are removing dietary toxins (wheat, fructose & seed oils), fixing the gut (addressing chronic infections, intestinal permeability, and dysbiosis), managing stress and restoring proper adrenal function, balancing blood sugar and addressing essential fatty acid (EFA) imbalances.

    • Chris, I am not so sure. I am a F-65 and I love HIIT, my BG doesn’t. I am at the gym 2 hours a day and when I do HIIT my BG goes UP vs steady biking and resistance training my BG goes down. I am T2D and I had my BG at 90 after my w/o this week.

  15. Chris, I see now how my comment looks like I am asserting they work together as if you hadn’t already asserted it, and could even be construed as implying you are proposing inflammation as an alternative mechanism to insulin, which you are obviously not.  Sorry for the sloppiness.

  16. Chris,

    I definately think that there is something to the Inflamation and insulin resistance connection. But I wonder if there is even more.

    I would love to know how to reverse insulin resistence. I know what most recommendations are….exercise. But if exercise was the key to reversing it then why isn’t it the key to preventing it. What does one do when one reaches a pain threshold that prevents them from exercise? Particularly when it affects every major muscle group and every major joint.

  17. Forgive me.  I wasn’t sure if you had read the article, or were just asking a question about that particular mechanism.  In any event, this is a fascinating subject and could easily be the target of an entire series.  Maybe someday…

  18. Of course I read it.  I ought to have started my comment with more acknowledgement.  Your analysis and  insights, as I have come to expect from you, are careful, relevant, and reflect the most recent advances in our knowledge.  You did discuss insulin resistance as both a cause and effect of diabesity.  I was just mentioning another possible mechanism, that comes from the prolonged presence of insulin itself.  It may be a minor point.

  19. I believe the inflammation hypothesis is in some ways meant to supersede the insulin hypothesis, however, it’s quite possible that excess insulin is a significant contributor to inflammation, by both inhibiting prostaglandin production, and by activating delta 5 desaturase, which would increase the proportion of inflammation-causing prostaglandins — at least that’s how I understand it.

    • Amber: did you read the article? I discuss a few mechanisms by which insulin and leptin resistance contribute to inflammation. There are several I didn’t mention in the interest of keeping it from becoming a book. I think the upregulation of delta-5 desaturase is important, but probably not the primary one.