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.
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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Tags: diabetes, fat, inflammation, obesity, type 2
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.
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.
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.
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.
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>.
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.
@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?
@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!
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.
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.
I ment something like this:
A high fat meal (even dairy fat) can increase inflammation like high BS. Also SOCS-3 is increased and that is related to leptin resistance:
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.
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?
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!
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